THE BODY FLUID (BF)PROPERTIES EXPLANATION

OVERVIEW- Definition: Body water n its dissolved substances. 60% of body weight is due to body fluid. In 70 kg man, 42 kg is due to BF.- Calculation: Total BF = Plasma Volume x 100 > Plasma Volume = 3500 mL. 100 – haematocrit > Haematocrit = e % of blood cells volume.

COMPARTMENTS

Intracellular Fluid (ICF)- Fluid inside e cells. 40% of body weight (25 L).- Is measured using D2O, 3H20, n aminopyrine.- Calculation: V= BF – ECF.

Extracellular Fluid (ECF)- Fluid outside e cells. 20% of body weight (15 L).- Is measured using insulin, mannitol, n sucrose (difficult to measure because e limits of thin space are ill-defined).- 2 divisions:a) Inside vascular system (25% of ECF n 3 L).- 2 types:1) Plasma – measured using Evans Blue which bound to plasma proteins. 2) Blood cells measured by using tagged blood cells.b) Outside vascular system (75% of ECF n 12 L).- Known as interstitial fluid. Found in synovial joints, bathing cells, as well as ant. n post. sites of cells.

COMPOSITIONS1) Mainly water (excellent solvent).- carries nutrients n waste products into n out of body cells.- participate in chemical digestion.- acts as lubricant such as mucus in respiratory tract.

2) Electrolytes (ions) n non-electrolytes (urea, glucose, etc).- control osmosis of water b/w compartments.- maintain acid-base balance.- cellular excitality.

FACTORS DETERMINE

AMOUNT OF BF

1) Weight of e body (2/3 is due to BF). 3) Sex – for male n female of e same body weight, male has

2) Age - Infant: 75% is BF. greater fluid volume than female (amount of water in - Adult: 60% is BF adipose tissue is low compared to muscle).

PRESSURE PROPERTIES

1) Hydrostatic pressure – pressure exerted by water (blood pressure) <outward force>.2) Oncotic pressure or colloid osmotic pressure – pressure exerted by plasma protein n colloids

<inward force>.3) Osmotic pressure – pressure necessary to prevent solvent migration to e concentrated region

<inward force>.4) Osmoles – concentration of osmotically active particles.5) Osmolarity – no. of osmoles per liter of solvent.6) Osmolality – no. of osmoles per kg of solvent.

pH OF BF- Definition: Negative logarithm of proton (H+) <logarithm to e base of 10 of e reciprocal H+ concentration>.- pH of pure water at 25oC, in which H+ n OH- present in equal no. is 7.- For each pH unit less than 7, e H+ concentration is increased 10 folds, n for each pH unit above 7, it is decreased 10 folds.

BUFFER SYSTEM- A buffer is a substance that has e ability to bind or release H+ in solution, thus keeping e pH of e solution relatively constant despite e addition of considerable quantity of acid n base.- Buffer system of BF: carbonic acid, H2CO3 n plasma protein.

CHEMICAL CONSTITUENTS N ELECTROLYTE DISTRIBUTION

- Electrolytes distribution in ECF n ICF is maintained by:a) Selectively permeable membrane (fully, semi, n impermeable).b) Sodium-potassium pump – maintains sodium n potassium ions concentration in ECF n ICF.- Factors affecting e passage of molecules across e membrane:a) Molecular size (inversely proportionate). b) Solubility in lipids.

TONICITY

- Distribution of water inside n outside of cells is dependent on osmotic pressure. Normally, osmolarity inside n outside e cells is equal: 290 – 300 mosm/L (ECF: 80% due to sodium n chloride ions, n ICF: > 50% due to potassium ions).- Tonicity: term to describe e osmolarity of a solution relative to plasma.a) Isotonitic: solution that has e same osmolarity with plasma. c) Hypotonic: solution with lesser osmolarity than plasma.b) Hypertonic: solution with greater osmolarity than plasma.

APLLIED PHYSIOLOGY

OEDEMA- Definition: E abnormal collection of fluid in e interstitial spaces. 3 main causes:a) Increased capillary hydrostatic pressure – due to obstruction of blood in venous system. Eg: failure of Rt. ventricle.b) A decreased in e plasma colloid osmotic pressure. Eg: excessive loss of albumin in e urine (kidney disease).c) Obstruction of lymph vessels – accumulation of albumin in interstitial space. As a result: significant rise in colloid osmotic pressure of e interstitial fluid n eventually becomes oedema.

Filtration Absorption

Capillary: 25 mm Hg

Venule: 10 mm Hg

Arteriole: 32 mm Hg

Interstitial Fluid

TISSUE FLUID EXCHANGE1) Hydrostatic pressure is higher in capillaries than in tissue

space n tends to drive fluid out of capillaries by filtration (outward).

2) Colloid pressure is higher in blood plasma than in interstitial fluid because plasma proteins are retained inside it. This tends to draw water out of capillaries by

osmosis (inward).3) Colloid pressure is uniform through out capillary length

while hydrostatic pressure falls from arteriolar to venular end.

4) Thus, at arteriolar end, water is mainly filtrated, while at venular end, water is reabsorbed back. This is important

to maintain blood volume.5) In lungs, capillary hydrostatic pressure is lesser than

colloid osmotic pressure, therefore there is no filtration to keep e alveoli wet.

6) In kidneys, hydrostatic pressure is higher than colloid

GENESIS OF RESTING MEMBRANE POTENTIALPROPERTIE

SEXPLANATION

OVERVIEW - Definition: e constant membrane potential present in non-excitable n excitable tissue when they are at rest.- Normal values: -70 mV (nerve) n -90 mV (cardiac muscle).

CONTROLLED FACTORS

- Factors controlling resting membrane potential:a) Unequal distribution of ions or non-electrolytes (proteins). - Main ions in ECF: sodium, chloride, n carbonate ions. - Main ions in ICF: potassium n phosphate ions. - Main electrolytes in ICF: proteins. - Net positive charge outside n net negative charge inside.b) Selective permeability of plasma membrane to ions n non-electrolytes. - Potassium ion permeability is 100x greater than that to sodium ions. - Not permeable to protein, organic phosphate, n organic ions (> negative charge inside).c) Sodium-potassium ions pump.- 3 sodium ions out of cells for every 2 potassium ions pumped in leading to net loss of +ve charge inside e cell.

- Magnitude of resting membrane potential is determined by:a) Mainly distribution of sodium, potassium, n chloride ions n proteins.b) Permeability of membrane to sodium n potassium ions, organic phosphate.c) E activity of sodium-potassium ions pump.

NERVE N MUSCLE FIBERS

-Nerve cells n muscle fibers are different because:a) Easily excitable (able to produce action potential when stimulated).b) Can generate n transmit electrical impulse following stimulation.

- When a nerve being stimulated, e following r generated:a) Action potential (propagated potential).b) Non-propagated local potential.

- Stimulus: Any condition in e environment capable of altering RMP.

PROPAGATED ACTION

POTENTIAL

Characteristics:1) Treshold stimuli can only generate action potential.2) Obey all or none law (superthreshold stimuli → amplitude of action potential remains e same).3) Has refractory period (period of time during which e neuron cannot generate another action

potential). 2 types:a) Absolute refractory period: period of time during which a second action potential cannot be

initiated even with a very strong stimulus (responds to e time during which Na+ gates r not in their resting conformation).

b) Relative refractory period: period of time during which a second action potential can be initiated but only by a stronger than normal stimulus (superthreshold stimulus: respond to e time during which K+ gates r not yet closed).

FUNCTIONS 1) Transmission of nerve impulse along nerve fibers. 3) Contraction of muscle.2) Release of chemical transmitters in synapses. 4) Activation or inhibition of

glandular secretion.IMPULSE

PROPAGATION

1) Saltatory Conduction - In myelinated fibers n 100x faster.

2) Continuous Conduction- In non-myelinated fibers n slower.

LOCAL NON-PROPAGATED POTENTIAL

Characteristics:1) Does not obey all or none law. 3) Can summate (add up) to reach threshold.2) Cannot transmit impulse. 4) Has no refractory period.

ACTION POTENTIAL

MICROCIRCULATION

1 32 4

+ 40

+ 20

0

- 20

- 40

- 60- 70- 80

A

1 2

Memb. Potential (

mv )

A = DepolarizationB = repolarization1 = Absolute refractory period2 = Relative refractory periodB

Threshold stimulus

The permeability of the membrane to Na+ ( i.e Na+

conductance increased as a result of opening of voltage gated Na+ channel )

SYNAPSE AND SYNAPTIC TRANSMISSIONPORTIONS EXPLANATIONOVERVIEW - Definition: The junctional region where one nerve ends and the other begins. A nerve impulse

is conducted from one neuron to another across a synapse. - A synaptic junction between neurons has 3 parts :. Synaptic end bulb: contains synaptic vesicles, neurotransmitter (produced here) n mitochondria. . Synaptic cleft: prevents action potential from electrically passing b/w neurons n too wide for a direct spread of current from one cell to another.. Postsynaptic membrane: contains receptors of neurotransmitter.- Neurons which is located before a synapse is called ' Presynaptic neuron ' and after a synapse is ' Postsynaptic neuron '.

FUNCTIONS . Relay nerve impulses. . Sometimes amplifies the incoming nerve impulse.. Disperses the impulses in all directions. . Sometimes decreases the number of transmitted impulses.. Selects which ones are to be allowed to pass and which ones are to be blocked.

PROPERTIES . One way transmission: Impulses never pass backwards from e ganglion cell to e terminal knob.. Synaptic delay: Terminal knobs fire considerably before e ganglion cells fire. Synaptic time or synaptic delay depends on e no. of terminal knobs n e type of ganglion cells. It varies b/w 0.5 to 1.0 ms.. Summation: 2 types: (a) Spatial summation: 2/> terminal knobs fire simultaneously at different points on e surf. of e cells towards 1 postsynaptic membrane. (b) Temporal summation: One terminal knob fires repetitively towards a single postsynaptic membrane which increases e total density of negative charge outside e membrane. . Distribution action: A nerve impulse reaching from 1 neuron may be distributed to many other neurons which communicate through e common synapse.(a) Divergence: 1 single incoming axon may stimulate 2 2nd order neurons, each of which in turn stimulates 2/> neurons.(b) Convergence: A no. of different nerve fibers can converge on a single ganglion cells. Ant. from cell is e final common pathway of a no. of impulses coming from above towards different neurons.. Facilitation: e passage of 1 impulse facilitates e passage of subsequent impulses. This explains e phenomena of memory when facilitation allows subsequent impulses to pass through e same pathway > easily than e 1st.. Commutator action: Synapses can alter e path of an impulse by offering different degree of resistance.. Oscillatory circuit: An input impulse passes through a series of neurons to e output neuron n from at least 1 of e neurons a branching fiber passes back to e beginning neuron of e circuit. E neurons will continue firing for prolonged intervals of time due to after discharge.. Parallel circuit: E input neuron stimulates 1 after another of a series of neurons n each one of these neurons in turn gives rise to a single fiber that passes directly to e single output neuron.. Seat of fatigue: Probably synapse is e physiological seat of fatigue in e nervous system.

Na+ influx into the cell (depolarization) (opening of voltage gated Na+ channel is short-lived and soon closed. Therefore Na+ conductance decreased).At the same time, the permeability of the membrane to K+ increases as a result of opening of voltage

gated K+ channels. It leads to K+ efflux (repolarization). (The opening of K+ channel is

slower and more prolonged then the opening of Na+

channels.)Na+- K+ pump restores the concentration

IONIC BASIC OF LOCAL

RESPONSE (Non-propagated local potential)

When a neuron is stimulated with subthreshold stimulus, the permeability of the membrane to Na+ increased at the point of stimulation and

there is influx of Na+ into the cell (depolarization) leading to decreased RMP

(more positive, less negative).

In a resting neuron, the

membrane is more permeable to K+ than Na+

SYNAPTIC JUNCTION

1) Chemical Synapses. - In this type of synaptic junction, stimulation of a postsynaptic neuron is caused by a chemical (neurotransmitter transmitter released by the presynaptic neuron.- Chemical synapses are divided into two types :(a) Excitatory synapse:- Neurotransmitters depolarize the postsynaptic membrane ® resting membrane potential ¯ (less negative) ® excitatory postsynaptic potential (EPSP).(b) Inhibitory synapse:- Neurotransmitter hyperpolarize the postsynaptic membrane ® resting membrane potential ( more negative ) ® inhibitory postsynaptic potential (IPSP). 2. Electrical Synapses. - In this type of synaptic junction, ionic current spread directly from one cell to another through tubular structure called connexons (gap junction).

FATE OF NEURO-

TRANSMITTER

- Chemical neurotransmitter in nervous system: Acetylcholine (Ach), Catecholamines (adrenaline, noradrenaline), Dopamine, Substance P, GABA (Gamma-amino butyric acid), Glycine.- Fate of Acetylcholine: Enzyme Acetylcholine Esterase splits Ach into Acetate (diffuse into ECF) n Choline (actively transported back to axon teminal).

NEUROMUSCULAR JUNCTIONPORTIONS EXPLANATIONOVERVIEW - It is e junctional region between e axon of motor nerve and muscle fibre.

- As e axon of motor nerve supplying a skeletal muscle fiber approaches its termination, it losses its myelin sheath. E axon of motor nerve divided into a number of terminal and bulbs which fit into depression in e motor end plate: e thickened portion of e muscle membrane.- E space between the nerve ending and motor end plate: e cleft (s comparable to the synaptic cleft). E whole structure is known as neuromuscular or myoneural junction. - Each muscle fiber has only one neuromuscular junction-unifocal (98 percent). However, few muscle fibers (eg: extra occular muscle) have more than one neuromuscular junctions (2 percent).

STRUCTURES a) Nerve terminal: synaptic end-bulb which contains vesicle filled with Ach.

b) Synaptic cleft: space filled with extracellular fluid (ECF).

c) Muscle fiber membrane: corresponds to postsynaptip membrane (motor end plate).

ACETYLCHOLINE SYNTHESIS

Acetyl CoA + Choline Acetylcholine Choline + Acetate

DISTURBANCE PATHOPHYSIOLOGYDECREASED

ACH RELEASED1) ↓ Ca2+ ionic concentration in ECF.2) ↑ Mg2+ ionic concentration in ECF.

PREVENT BINDING OF

ACH

1) Curare:- Compete with Ach for e receptor protein (bind reversibly).- Results in muscle relaxation.- Used widely as muscle relaxant drug during general anesthesia

2) Alpha-Burgarotoxin:- Chemical extracted from snake venom.- Binds irreversibly to Ach receptor.- Victims become totally paralyzed.

PREVENT ACH HYDROLYSIS

1) Anticholine esterase drugs.- eg: neostigmine- Reversibly combines with choline esterase.- Allow Ach to accumulate in e cleft: giving a more favourable opportunity to act on e receptors.- Used in myasthenia gravis.

2) Organophosphate compounds.-Irreversibly combine with anticholine esterase.- Results in long term increase in neuro-muscular transmission (prolonged exaggerated stimulation of post-synaptic

3) Nerve gas poison.- Diisopropyl flurophosphate.- Abdominal cramps, respiratory distress, n convulation.

4) Myasthenia Gravis.- An autoimmune disorder.- Antibodies destroy Ach receptor.- Failure of NM transmission at NM junction.-Tiredness + progressive paralysis of muscle.

5) Lambert-Eaton Syndrome.- Muscle weakness is caused by antibodies against 1 of e Ca channels in e nerve ending at NM junc.- This decreases e normal Ca influx that causes

Acetylcholine EsteraseCholine Acetyltransferase

SEQUENCE OF EVENTS OCCUR AT EXCITATORY SYNAPSE

(1) When a nerve impulse reaches axon terminal of a presynaptic neurons, the membrane of the axon

terminal is depolarized by action potential.(2) Depolarization of the axon terminal causes voltage

gated calcium channels to open.(3) Permeability of axon terminal to calcium increased.

(4) Calcium ions diffuse in axon terminal from ECF.(5) The increase in calcium ions in synaptic end bulb

causes some synaptic vesicles to diffuse with the membrane.

(6) Release neurotransmitter into synaptic cleft by exocytosis.

(7) Acetylcholines diffuse across synaptic cleft and binds to the receptors on postsynaptic membrane.

(8) Neurotransmitter-receptor complex opens specific ion channels.

SEQUENCE OF EVENTS AT INHIBITORY

SYNAPSE(1) Inhibitory

neurotransmitter is synthesized in axon terminal

of presynaptic neuron and stored in vesicle.

(2) Gamma-amino byteric acid (GABA) is released.

(3) Bind the receptor protein on postsynaptic neuron.(4) Opening of chloride

channels.(5) Permeability of

postsynaptic membrane to chloride increased.

(6) Hyperpolarization (more

Myelin sheath

Axon

Terminal end bulb

Mitochondria

Vesicle ( Ach. )

Cleft

Motor end plate

Muscle fibre

Neuromuscular

Junction

membrane).- Used as insecticides like malathion.

acetylcholine release.

1) Quantal Release of Transmission: At rest, small quanta (packets) of Ach are released randomly.Vesicles fuse to e nerve cell membrane spontaneously n at random → Area of fusion breaks down releasing Ach by exocytosis → At motor end plate, Ach binds to its receptor → Permeability of motor end plate towards Na+ increases → Depolarization of motor end plate → Miniature end plate potential (MEPP) <Amount of Ach released varies directly with calcium concentration and inversely with magnesium concentration>.

2) When Presynaptic Neuron is being stimulated.

A nerve impulse reaches e ending, results in depolarization of axon terminal → Voltage gated Ca2+ channels open → Permeability of membrane towards Ca2+ increases → Ca2+ trigger e fusion of vesicles to nerve cell membranes <amount of Ach released is proportional to Ca2+ influx → Ach released into synaptic cleft → At motor end plate, Ach binds to its receptor → Chemically gated Na+ channels open → Na+ influx → Depolarization of motor end plate → End plate potential (EPP), if EPP exceed firing level → Action Potential

3) Muscle ContractionEnd plate potential is propagated across surface membrane n down T-tubule of muscle cell → Action potential triggers Ca2+ release from sacroplasmic reticulum → Ca2+ released from lateral sacs bind to

CARDIAC OUTPUT (CO)PORTIONS EXPLANATION

OVERVIEW- Definition: Amount of blood ejected from Lt. or Rt. ventricles into e aorta or pulmonary trunk per minute respectively (i.e. amount of blood ejected by each ventricle, not e total amount pumped by both ventricles).- Means that volume of blood flowing through pulmonary circulation is equivalent to e blood flowing through e systemic one.

EQUATION- Cardiac Output, CO = Stroke Volume, SV x Heart Rate, HR- At rest, SV = 70 mL, HR= 75 beats/min, so, CO = 70 x 75 = 5.25 L/min.- During exercise, CO can be increased 4-5 folds.- Cardiac reserve = (Maximum volume of blood e heart is capable to pump) – (CO at rest).

REG

ULA

TIO

N

STROKE VOLUMEEND DIASTOLIC VOLUME

- Frank-Starling Law of e heart: Energy of contraction is proportional to e initial length of e cardiac muscle fibers.- E resting length of cardiac muscle < optimal length. - Thus, in initial cardiac muscle length (stretch), ↑ e contractile tension of e heart following systole.- Cardiac muscle length increases with increasing EDV.- EDV ↑→ cardiac muscle length ↑ → Vigor (strength of cardiac muscle↑→ expulsion of greater blood volume into aorta ↑ → stroke volume↑→ cardiac output↑.

- Factors affecting EDV:a) Venous return (VR): ↑ VR, ↑ EDV.

- Sympathetic stimulation produces venous vasoconstriction →↑ venous pressure →↓ venous filling capacity → ↑ VR.- Skeletal muscle pump: ↑ Muscular activities → ↓ venous filling capacity → ↑ venous pressure → ↑ VR.- Respiratory pump: Pressure different (Lower pressure in chest wall, but higher in abdomen n limbs) → squeezes blood from lower to chest veins → ↑ VR.- During ventricular contraction, atrial cavities ↑ → ↓ atrial pressure → ↑ vein to atria pressure ratio → ↑ VR-↑ total circulating blood volume → ↑ VR.

b) Atrial contraction:- E greater e atrial contraction, e greater will be e ventricular filling, e greater VR (but not that 70% of ventricular occurs passively before atrial contraction).

c) Distensibility of ventricles:- Pericardial temponade, myocardial infarction, n myocardial infiltrative disease all decrease ventricular distensibility, n reduce VR.

d) Duration of diastole:- E longer e duration of diastole, e longer e blood filling into ventricles, e higher VR.

HEART CONTRACTION OR MYOCARDIAL ACTIVITYRelated to e extrinsic control by factors which are originating outside e heart, mainly e action of cardiac

sympathetic nerve n hormonal action.

SYMPATHETIC STIMULATION PARASYMPATHETIC STIMULATIONSympathetic stimulation.

↓Release of ephinephrine, norephinephrine, n dopamine.

↓Increased Ca2+ influx into cytoplasm from sarcoplasmic

reticulum n ECF.↓

Cardiac muscles generate > contraction force through greater cross-bridge cycling.

↓> rapid n > forceful contraction of ventricles.

↓Increased stroke volume (Inotropic Effect).

↓Increased cardiac output.

Parasympathetic stimulation.↓

Release of acetylcholine.↓

Decreased Ca2+ influx into cytoplasm.↓

Reduced myocardial (atrial muscle) contraction.

↓Reduced stroke volume.

↓Reduced cardiac output.

HEART RATE- Primarily determined by rate of spontaneous depolarization of SA node.- Determinants:a) ANS that innervate SA node. c) Plasma electrolytes.b) Hormone thyroxine. d) Body temperature.

1) Sympathetic Effect.- Sympathetic stimulation → release of ephinephrine → increased Ca2+ influx into cytoplasm → increased rate of spontaneous depolarization → shorthened e time required for SA node to reach threshold → SA node fires more frequently → increase heart rate (Chromotropic Effect).

2) Parasympathetic Effect.- Parasympathetic stimulation → release of acetylcholine → increased membrane’s permeability towards K+ → > K+ ions efflux → decreased rate of spontaneous depolarization → prolonged e time required for SA node to reach threshold → SA node fires less frequently → decreased heart rate.

AB

NO

RM

ALIT

IES

1) Hypertension. - A condition due to e chronic elevated atrial blood pressure.- Heart need to generate more pressure in order to eject a normal cardiac output.- Heart may be able to compensate for a sustained increase in afterload by enlarging (hyperthrophy). 2) Heart failure.- Refers to e inability of e cardiac output to keep pace with body’s demand for supplies n removal of wastes. - Either 1 or both ventricles may progressively weaken n fail.- When a failing ventricle is unable to pump blood out, e veins behind it will be congested with blood.- 2 most common reasons of heart failure:a) Damage to e heart muscle as a result of a heart attack or impaired circulation to e cardiac muscle.b) Prolonged pumping against a chronically increased afterload or sustained elevation in blood pressure.

CARDIAC CONDUCTING SYSTEMPORTIONS EXPLANATION

OVERVIEW - Composed of modified cardiac muscle that is striated but has indistinct boundaries n fewer organelles n myofibrils.- It generates n distributes e electrical impulses that stimulate cardiac muscle fibers to contract.

COMPONENTS

Sinoatrial Node (SA Node). Located at e junction of e sup. vena cava n e Rt. atrium. Characteristics: Able to spontaneously n rhythmically generate action potential Explanation: Cell membrane of sinus fibers r periodically very permeable to Na+ ions even in 1

resting state. Thus, Na+ entry causes depolarization n action potential. This leakiness to Na+ ions does not cause e sinus nodal fibers to remain depolarized all e time because of e 2 events occur during e course of action potential, which r:

(a) Inactivation of Ca2+ - Na+ channels after opening (b) Opening of K+ channel.

Self-excitation, recovery from action potential, drift of e resting potential to firing level (this process continues indefinitely throughout a person’s life).

SA node’s action potential per minute = 70 – 80. >> Prepotential/pacemaker potential r normally prominent only in SA n AV nodes. Atrial n

ventricular muscle fibers do not have prepotential, they discharge spontaneously only when injured or abnormal>>

Internodal Tracts. 3 bundles of atrial fibers which conduct impulses from SA node to AV node:

1) E ant. internodal tract of Bachman.2) E middle internodal tract of Wenkebach.

3) E post. internodal tract of Thorel.Atroventricular Node (AV Node).

Located in e Rt. post. portion of e interatrial septum near e mouth of e coronary sinus. E fibers of e internodal tracts converge n interdigitate with e fibers in e AV node. AV node slows down e speed of electrical transmission. This delay permits enough time for e

contracting atria to empty their contents into e ventricle before ventricular contraction is initiated. AV node has a one-way conduction from atrium to ventricle. AV node’s action potential per minute = 40 – 60. Causes of slow conduction through AV node:

1) Size of AV node muscle tissues r smaller than atrial muscle fibres.2) Fewer gap junctions in AV node muscle results in greater resistance to conduction.3) Resting membrane potential > negative than atrial muscle tissues.

AV Bundle / Bundle of His. Means a bundle of fibers from AV node running towards e interventricular septum. Gives off 2 branches at e top of e interventricular septum: Lt. bundle branch which divides into ant. n post. fascicles/branches, n continues along inner side of

e Lt. ventricle n gives rise to smaller Purkinje Fibers. A Rt. bundle branch which is e continuation of e bundle, continue along e inner side of e Rt.

ventricle, n gives rise to smaller Purkinje Fibers.Purkinje System.

E terminal ramifications of e conducting system which spreads to all parts of e ventricular myocardium.

ABNORMALITIES

Abnormal heart rhythm (arrhythmias).- May be caused by:

1) SA node irregularities.2) AV node irregularities.3) By disturbance of conduction system.

Heart block.An interruption in conduction, i.e. some or all of e impulses fail to reach ventricles.

- 2 types:1) Incomplete heart block: Atria beat normally but conduction through AV node is slowed.2) Complete heart block: Conduction from AV node is severely hampers atria beat normally, but

ventricles beat independently at 20 – 40/min.Ectopic foci.

In conduction defect, a site other than SA node may become excitable n initiate beat on its own but e normal beat.

ELECTRICAL PATHWAY OF THE HEART.

Action potential originates in SA node n 1st spreads through out both atria, from cell to cell via gap junction.Interatrial pathway: extends from SA node within Rt. atrium to Lt. atrium (A wave of excitation spreads across e gap

junctions throughout e Lt. atrium at e same time similar spread is being accomplished through out Rt. atrium.Internodal pathway: extends from SA none to AV node. This pathway directs e spread of action potential originating at SA

node to e AV node to ensure sequential contraction of e ventricles following atrial contraction.↓

A slow transmission of action potential from atria to ventricles through AV node. This delayed time (0.1 sec) enables atria to become completely depolarized n to contract, emptying their contents into e ventricles, before ventricular depolarization n

contraction occur.↓

Depolarization of ventricular muscle starts at e septum of Lt. ventricle n then spreads to Rt. across e midportion of e septum.↓

Spread down e septum to e apex of e heart via Rt. n Lt. bundle branches.↓

Impulses enter Purkinje fibers n spread to entire endocardial surface of ventricular muscles.↓

Spreads to epicardial surface of ventricle n e last parts to be polarized are posterobasal part of Lt. ventricle n Pulmonary

SYSTEMIC ATRIAL BLOOD PRESSUREPORTIONS EXPLANATION

OVERVIEW - Pressure: e force per unit area.- Blood pressure (BP): e force exerted by e contained blood on a unit area of blood vessel wall, n e force is imported by e contraction of e heart (expressed in terms of displacement in mm Hg).- Systolic blood pressure (SBP): e peak pressure in e atrial system during systole.- Diastolic blood pressure (DBP): e minimum pressure in e atrial system during diastole.- Pulse pressure, PP = Systolic BP, SBP – Diastolic BP, DBP.- Mean atrial BP = e average pressure through out e cardiac cycle (it is slightly less than e value halfway b/w SBP n DBP because systolic is shorter than diastolic).Mean Pressure = DBP + 1/3(Pulse Pressure) = DBP + 1/3(SBP – DBP)

NORMAL VALUE

- For resting young adult in e sitting n lying position, Branchial Atrial Blood Pressure:SBP = 90 – 130 mm HgDBP = 60 – 90 mm Hg

Pulse Pressure = 30 – 50 mm g

MEASUREMENT 1) Direct Measurement.- Cannula is inserted into an artery n connected to a mercury manometer or recording device.2) Indirect Measurement or Clinically measured BP.- E lateral or side-pressure exerted on e vessel wall by contained blood.

DETERMINANTS

- E amount of blood entering e arterial system which is determined by cardiac output.- E amount of blood leaving arterial system through e arterioles which is determined by e resistance offered by e arterioles of various vascular beds – total peripheral resistance.- Thus, Blood Pressure = Cardiac Output, CO x Total Peripheral Resistance, TPR.

PHYSIOLOGICAL VARIATIONS

1) Age: SBP n DBP gradually rise with age. 4) Physical Exertion: Particularly isometric exercise rose BP.2) Circadian Rhythm: SBP of 5-10 mm Hg rise in afternoon. 5) Eating (after meal): SBP rise due to increase in CO. 3) Emotional Excitement: Transient rise. 6) Gravity.

REGULATIONS Reasons of regulation:1) It must be high enough to ensure sufficient driving pressure in order for e brain n other tissues

to receive adequate flow, no matter what local adjustments are made in e resistance of e arterioles supplying them.

2) E pressure must not be so high that it creates extra work for e heart n increases e risk of vascular damage n possible rupture of small blood vessels.

SHORT TERM - Within seconds.- Adjustment is accomplished by alterations in cardiac output n total peripheral resistance, mediated by means of ANS influences on e heart, veins, n arterioles.1) Neural: E cardiovascular Reflex.

Baroreceptor Reflex. Includes a receptor, an afferent pathway, an integrating centre, an efferent pathway, n effector

organs. Low pressure baroreceptors: atrial baroreceptor (volireceptor) n in pulmonary circulation. High pressure baroreceptor: systemic arterial baroreceptor (carotid sinus baroreceptor n aortic

arch baroreceptor) n Lt. ventricular baroreceptor). E integrating centre: e cardiovascular control centre located in e medulla within e brain stem. When BP rises: High pressure baroreceptors increase e rate of firing in their respective afferent

neurons, n as a result, cardiovascular control centre increases parasympathetic activity n decreases sympathetic activity.

When BP falls: Low pressure barorecetors increase e rate of firing in their respective afferent neurons, n as a result, cardiovascular centre increases sympathetic activity n decreases parasympathetic activity.

Chemoreceptor Feedback Control. Receptors located in e carotid n aortic arteries. Sensitive to low oxygen or high acid level in blood. Act by reflexly increasing BP by sending excitatory impulses to cardiovascular centre. Eg: Hypoxic, hypercepnie, acidosis resultant from stagnation due to hypotension stimulates e

receptors. Central Nervous System to Ischcaemic response.

Compensating rise in e BP as a result of intense vasoconstriction. May be high enough to cause reflex bradycardia.

2) Hormonal Reflex. Noradrenaline: Adrenaline system – increases BP. Renin-angiotensin: Aldosterone system – increases BP. Antidiuretic hormones: Vasopressin system – increases BP.

LONG TERM - Minutes to days.- Control involves adjusting total blood volume by restoring normal salt n water balance through mechanisms that regulate urine output n thirst. - Mediated by renal body fluid pressure control system.

OTHERS - Lt. atrial volume receptors n hypothalamic osmoreceptors: important in water-salt n balance n affect BP by controlling plasma v.- Cardiovascular responses associated with certain behaviors n emotions n r mediated through e cerebral cortex-hypothalamic pathway. Responses include e widespread changes in cardiovascular activity accompanying fight-to-flight response n etc n slightly increase BP. - Hypothalamic control over cutaneous arterioles: results in cutaneous vasoconstriction which help

maintain adequate TPR, n increases BP.

HEART SOUNDPORTION

SEXPLANATION

OVERVIEW

- Normal heart produces 2 heart sounds which can be heard with a stethoscope during cardiac cycle.- E sounds are caused by vibrations set up within e walls of e ventricles n major arteries during valves closure, not by valves snapping shut.- Opening of valves does not produce any sound.- Normal sound: “lub-dup-lub-dup-lub-dup”.

1ST HEART SOUND

- Low –pitched, soft, n relatively long.- Often said to sound like “LUB”.- Associated with e closure of AV valves (tricuspid n mitral valves).- Signals e onset of ventricular systole.- Duration ~ 0.15 sec n frequency ~ 25 – 45 Hz.- Softer when heart rate is low because e ventricles are well filled with blood n e leaflets of e AV valves float together before systole.

2ND HEART SOUND

- High-pitched, shorter n sharper.- Often said to sound like “DUB”.- Associated with e closure of semilunar valves (pulmonary n aortic valves).- Signals e onset of ventricular diastole.- Duration ~ 0.12 sec n frequency ~ 50 Hz.- May become split during inspiration (physiological splitting) which due to e delay in closure of pulmonary valve.- Mechanism: Inspiration Intrathoracic pressure becomes > negative → ↑ venous return → ↑ stroke volume → ↑ muscular contraction of e heart → ↑ ejection time (prolonged) → pulmonary valve closes later than usual.

3RD HEART SOUND

- Soft n low-pitched.- Heard about 1/3 of e way through diastole in many young normal adult.- It coincides with e period of rapid ventricular filling n is probably due to vibration set up by e inrush of blood.- Duration ~ 0.1 sec.

4TH HEART SOUND

- Can sometimes be heard immediately before e 1st sound when atrial pressure is high or e ventricle is stiff in conditions such as ventricular hyperthrophy.- Due to ventricular filling n rarely heard in normal adult.

MURMUR - Refers to abnormal heart sound.- 2 types:

1) Pathologic: involving heart diseases.2) Non-pathologic: called functional murmur - > common in young people.

- Caused by turbulent blood flow which creates vibrations in e surrounding structures.- 2 types:

1) Systolic murmur: A murmur occurring b/w 1st n 2nd heart sounds (lub-murmur-dup).2) Diastolic murmur: A murmur occurring b/w 2nd n 1st heart sounds (lub-dup-murmur).

- 2 characteristics:1) Stenotic: Whistling murmur.2) Insufficient: Swishy murmur.

- 2 common causes:1) Stenotic valve: A stiff, narrowed valve that does not open completely. Blood must be forced through e

constricted opening at tremendous velocity, resulting in turbulence that produces an abnormal whistling sound.

2) Insufficient (leaky) valve: Valves which cannot close completely, usually because e valve edges are scarred n do not fit together propelly. Turbulence is produced when blood flows backward through e insufficient valve n collides with e blood moving in e opposite direction, creating a swishing or gurgling murmur.

THRILLS - Vibration which can be felt by e hand.

BRUITS - Heard over higher vascular region.

[Allah's Mercy over His Wrath]

When Allah decreed the Creation He pledged Himself by writing in His book which is laid down with Him:

"My mercy prevails over my wrath."

It was related by Muslim (also by al-Bukhari, an-Nasa'i and Ibn Majah).

[Actions for the sake of Allah only]

Allah Almighty had said:I am so self-sufficient that I am in no need of having an associate. Thus he who does an action for

someone else's sake as well as Mine will have that action renounced by Me to him whom he associated with Me.

It was related by Muslim (also by Ibn Majah).

CARDIAC CYCLEPORTIONS EXPLANATIONOVERVIEW - Defined as e sequence of events associated with 1 heart beat.

- Consists of a systole n diastole of both atria n ventricles,- Systole: Contraction phase (Occurs as a result of e spread of excitation across e heart).- Diastole: Relaxation phase (Follows e subsequent repolarization of e cardiac musculature).

PROPERTIES OF CARDIAC

CYCLE

1) Stroke Volume: E amount of blood pumped out / ejected by each ventricle with each contraction at rest.

Normal value: 70 – 90 mL.2) End-systolic Volume: E amount of blood remaining in e ventricle at e end of ventricular systole

when ejection is complete. Normal volume: 50 mL.3) End-diastolic volume: E volume of blood in e ventricle at e end of diastole. Normal value: 120 -1 30 mL.4) Ejection fraction = Stroke Volume - Normal value: 60% (valuable index of cardiac

function). End-diastolic volume

- Although Rt. n Lt. sides of heart have different atrial n ventricular pressure, they contract n relax at e same time n eject an equal volume of blood simultaneously.- During cardiac cycle, although events of e 2 sides of e heart are similar, they are somewhat asynchronous.- E processes:Rt. atrial systole proceeds Lt. atrial systole (SA node located on Rt. atrium). Lt. ventricle systole proceeds Rt. ventricle systole (Depolarization starts on Lt. ventricle septum).Rt. ventricle ejection before Lt. ventricle ejection (Resistance is low n pressure of pulmonary artery > aortic pressure).

VARIATION IN E LENGTH OF SYSTOLE N DIASTOLE

PORTIONS HEART RATE (75 beats/min) HEART RATE (200 beats/min)Duration of cardiac cycle 0.80 0.30

Duration of systole 0.27 0.16Duration of diastole 0.53 0.14

PHYSIOLOGICAL N CLINICAL IMPLICATIONS

NORMAL RANGE- Normal cardiac cycle: 0.8 sec. – 1 heart beat = 60 sec = 0.8 sec. - Normal heart beat: 75 beat/min. 75 beats

DURATION OF SYSTOLE N DIASTOLE- Duration of systole is much more fixed than diastole.- When heart rate increased, diastolic period is shorthened.- During diastole: a) Heart muscles rest. b) Ventricular filling occurs. c) Coronary blood flows to subendocardial portion of ventricles occurs.- Heart rate → ↓ period of diastole → physiological needs of heart cannot be done adequately → heart failure (prolonged).- Eg: a) Tachycardia >> High heart rate: > 100 beats/min. b) Bradycardia >> Low heart rate: < 60 beats/min.

1) LATE DIASTOLE(ATRIAL FILLING → VENTRICLE FILLING).

Both atria n ventricles r relaxed.As a consequence, pressure of both ventricles is lower than that of aorta n pulmonary artery

so that aortic n pulmonary valves r closed.Pressure in e atria is lower than that in e great

veins, so that blood flow into e atria n ventricles on each side (which r in continuity

as e atrioventricular valves r open).E rate of filling declines as e ventricle become distended (70% of blood flows passively from

atria to ventricle).

2) ATRIAL SYSTOLE

When SA node fires, atrial contraction occurs emptying 30% of remaining blood from atria to

ventricles.Volume of blood in ventricles at e end of

ventricles at e end of diastole is 120 – 130 mL (End-Diastole Volume).

3) VENTRICLE SYSTOLE

Following atrial excitation, e impulse passes through e AV node n specialized conduction system to excite e ventricle, n results in ventricles contraction.

Abrupt rise in ventricular pressure which causes AV valve to close (1st heart sound).Once e ventricular pressure exceeds aortic n pulmonary pressure, aortic n pulmonary

valves open.Blood is forced from Lt. ventricle to aorta n Rt. ventricle to pulmonary arteries (Ventricular

ejection).When ventricular pressure becomes lesser than aortic pressure, semilunar valves close (2nd heart sound) n ventricular filling occur again. (Dicrotic notch: Disturbance or notch

produced on e aortic curve pressure during e closure of aortic valve).

ELECTROCARDIOGRAM (ECG)PORTIONS EXPLANATION

OVERVIEW - Fluctuations in potential that represent e algebraic sum of e action potentials of myocardial fibers can be recorded extracellularly.- This is because, e body fluids are good conductors (e body is a volume conductor).- ECG: E record of these potential fluctuations during cardiac cycle.

MEASUREMENT - Can be recorded by using an active or exploring electrode connected to an indifferent electrode at zero potential (unipolar recording) or by using 2 active electrodes (bipolar recording).- In a volume conductor, e sum of potentials at e points of an equilateral triangle with a current source in e centre is zero all e time.- A triangle with e heart at e centre (Einthoven’s triangle) can be approximated by placing electrodes on both arms n e Lt. leg called standard limb leads. If connected to a common terminal, an indifferent electrode that stays near zero potential is obtained.- Depolarization (positive) moves towards an active electrode n repolarization (negative) moves in opposite direction.

LEADS a) Bipolar leads: these record e potential difference b/w 2 active electrodes.Standard Limb Leads:

Leads Positive Electrodes Negative Electrodes ResultsI Lt. Arm (LA) Rt. Arm (RA) LA - RAII Lt. Foot (LF) Rt. Arm (RA) LF - RAIII Lt. Foot (LF) Lt. Arm (LA) LF - LA

b) Unipolar leads: these have an active (exploring) electrode placed or a chosen site linked with an indifferent elsctrode. 1 being zero, e potential difference b/w e 2 represents e actual local potential. They r called “V” leads because they record values approaching meaningful voltages. Can also be placed at e tips of catheters n inserted into e esophagus or heart. 1) Unipolar Limb Leads.

aVR, aVL, as well as aVF for Rt. arm, Lt. arm, n Lt. foot respectively. (a = augmented, when e amplitude of deflection increased (These r recording b/w one limb n another 2).

2) Unipolar Chest Leads (Precordial Leads).V1 4th ICS, Rt. sternal border.V2 4th ICS, Lt. sternal border.

V3 Equidistance b/w V2 n V4.V4 5th ICS, midclavicular line.V5 5th ICS, ant. axillary line.V6 5th ICS, midaxillary line.

SEGMENTS a) P Wave. Represents atrial depolarization. Begins as e impulse spread from SA node across e atria. E activity of SA node itself cannot be

detected in ECG. Duration: 0.1 sec – indicates e time taken for e impulse to spread through atrial muscle. E magnitude of P wave is some guide to e function of atria. Because e impulse spread from Rt. to Lt. n downward, e P wave is: Upright in leads I, II, aVF. Inverted in leads aVR, III, aVL, n V1.

b) PR Interval. Measured from onset of P wave to e beginning of QRS complex. It measures e AV conduction time which includes atrial depolarization, AV nodal delay, n

conduction down e bundle of His to e ventricular myocardium. Duration: 0.12 to 0.20 sec (normal adult with normal heart).

c) QRS Complex. Represents ventricular depolarization. Q wave is a downward deflection preceeding an R wave which is an upward deflection of QRS. S wave is a downward deflection following an R wave. In e routine 12 leads ECG, e manifestation of atrial repolarization is submerged in QRS complex. Duration: 0.10 sec (upper limit for normal person).

d) ST Segment n T Wave. Represents ventricular repolarization. ST segment is e part b/w e end of QRS complex n e beginning of T wave. T wave is normally in e same direction as e largest part of QRS complex since repolarization takes

place in e reverse direction from depolarization. Derivation from normal r commonly associated with myocardial ischaemic. E hall mark of myocardial ischaemial infarction is ST segement elevation in leads overlying e area

of infarction, n ST segment depression in leads on e opposite side of e heart. At a later stage, ST segment elevation less pronounced as T wave inversion developed.

USES Detection of heart rate (both atrial n ventricular). Rhythm (regular or irregular) for diagnosis of arrhytmias. Conduction of cardiac impulse (delayed or block at e side of defect). Change in myocardial perfusion (ischaemic), structure (infarction n hyperthrophy), n function

(ventricular fibrillation or cardiac arrest). Change in plasma electrolytes (potassium n calcium), eg: when blood potassium decreases, T

wave decreases also. To detect heart block, atrial extrosystoli, atrial tachycardiac, atrial flutation, atrial fibrillation, n

APEX LEAD

S

myocardial infarct.

THE KIDNEYPORTIONS EXPLANATIONOVERVIEW - Bilateral paired organ, located retroperitoneally in abdominal cavity on both sides of vertebral column b/w T12

- L3 (Lt.) n L1 – L3 (RT).- Structural n functional units: NEPHRON which present up to one million units in each normal human kidney.

DIVISIONS a) Cortex: Outer portion. Place where Bowman’s capsule (BC), Proximal Convulated Tubule (PCT), a part of descending Loop of

Henle (LOH), n Distal Convulated Tubule (DCT) are located.b) Medulla:

Inner portion. Place where a part of descending Loop of Henle (LOH), a part of ascending Loop of Henle (LOH), n Collecting Duct (CT) lie.

FUNCTIONAL

ANATOMY OF

NEPHRON

a) Renal Corpuscles. Made up of BC, glomerular capillaries, afferent (AA) n efferent arterioles (EA) which lie mainly in cortex. BC: formed by invagination of capillaries into dilated blind end of PCT. Consists of 2 layers of simple

squamous epithelium. Visceral layer covers glomerulus n parietal layer forms e wall of corpuscle. Glomerulus: tuft of capillaries (6-7 loops) within BC. Afferent arterioles break into glomerulus n join again

to form efferent arterioles. Average capillary area is o.4 mm2 n total in human is 0.8 m2.b) Tubular System.

Made up of neck, PCT, LOH, DCT, n CT. Cells: flat (thin limbs of LOH), squamous to columnar. Brush border: > marked in PCT. Principle cells: in CT n response to ADH.

c) Juxtaglomerular Apparatus. Secretes substances involved in e control of kidney functions.

PARAMETERS CORTICAL JUXTAMEDULLARY

. Ouantity ( % of nephron )

. Calibre of arteriole

. Efferent arteriolesbecome

. Loop of Henle

85%

Afferent > efferent

Peritubular plexus

Short

15%

Afferent = Efferent

Vasa recta (straight arteries )

Long

FUNCTIONS a) HOMEOSTASIS1. Maintain e constant blood volume by eliminating excess water through urine.2. Regulates e normal pH of e blood.

Acidaemia: kidneys eliminate beta-hydroxybutric acid n acetoacetic acid with e urine n maintains normal pH.

Synthesize ammonia to neutralize acids in acidaemia to form neutral salt to maintain blood pH.

3. Regulates e osmotic relation b/w e blood n e tissues. Prevent e filtration of plasma proteins which maintain e normal osmotic pressure of

blood.4. Regulates e optimum concentration of different constituents of e blood.

Some are fully reabsorbed n some are eliminated if not required by body.b) EXCRETION

5. Eliminates waste products. Products which are normally formed in protein catabolism such as urea.

6. Eliminates e toxic products. Products are formed or introduced in e body in metabolic processes.

7. Excretes water through urination.c) SYNTHESIS

8. Manufactures new substances. Eg: ammonia n hippuric acid – substance formed from e conjugation of benzoic acid n

glycine.9. Secretes hormones – renin.

Under pathological conditions, kidneys secretes renin which causes vasoconstriction of blood vessels to maintain normal BP.

RENAL CLEARANC

E

- Definition: E volume of plasma that completely cleared of a substance per unit time.- C = uv mL/min. C = clearance, u = amount of substance in urine, v = urine flow/min., p = plasma concentration p of that substance.- Substances used: Inulin, creatinine, n radioactive iothalamate.- Characteristics of those substances: a) not produced by body, b) found in e root of certain plants, c) administered intravenously.- Normal values: 0 – 630 mL/min.- Other substances:

Reabsorbed substance: Totally reabsorbed substances have urinary concentration zero n clearance will be zero also.

Neither reabsorbed nor secreted substance: E amount will not be altered n equal to e amount excreted in e urine, n GFR will be equal to its clearance. Eg: inulin n creatinine.

Secreted substance: Have clearance greater than renal clearance (Substances which are almost 100% secreted have clearance equal to e renal plasma flow).

- Uses of clearance: To measure GFR n RPF. To study e renal handling of substances.

RENAL PROCESSE

S

Glomerular filtration. Tubular reabsorption. Tubular secretion.

GLOMERULAR FILTRATION RATE (GFR)PORTIONS EXPLANATION

OVERVIEW -Definition: Volume of ultrafiltrate filtrated by e glomerular membrane in a unit time.- Normal value: 125 mL/min n 180 L/day.

FILTRATION BARRIERS

- Consists of: a) Wall of e glomerular capillaries.

Consists of single layer of flattened endothelial cells which is perforated with fenestrae or large pores.

This make it 100x > permeable to water n solutes than other capillaries.b) An acellular gelatinous layer known as basement membrane.

Composed of collagen n glycoprotein. Collagen provides structural strength n glycoproteins discourage e filtration of proteins by being

strongly negatively charged which will repel e proteins which are also negatively charged. c) E inner layer of BC.

Consists of podocytes which encircle e glomerular tuft. Each podocyte bears many elongated foot processes that interdigitate with foot processes of

adjacent podocytes. Filtration slits (narrow slits b/w adjacent foot processes) provide a pathway through which fluid

exiting e capillaries can enter lumen of BC. - The glomerular membrane thus allows the following to pass through with ease :-a) Substance of molecular diameter less than 55,000 and less.b) Substance with molecular diameter 4 nm and less.c) Cations.

MEASUREMENT OF GFR

- Can be estimated by: a) excretion of a substance n b) plasma level of that substance.- Substance used must: a) finely filtered through glomerulus, b) neither secreted nor reabsorbed by tubular parts such as inulin.- Equation: GFR = KF (PGC – PT) – (GC - T), Where, KF = e glomerular ultrafiltration coefficient = permeability x effective filtration surface area. PGC = mean hydrostatic pressure in glomerular capillaries (GC), PT = mean hydrostatic pressure in e tubule, GC = e oncotic pressure of plasma in e glomerullar capillaries, T = e oncotic pressure of e filtrate in e tubule (negligible).

CONTROLLING FACTORS

OF GFR

a) Size of e capillary bed. E greater e effective filtration surface, e greater e volume filtered. GFR is reduced in old age, after nephrectomy, n in renal diseases due to loss of functioning

nephrons. There must be at least 75% destruction of nephrons before any significance reduction in GFR as

e remaining functional nephrons will undergo compensatory hypertrophy.b) Permeability.

GC is 50x > permeable than capillaries supplying skeletal muscles. In nephritis, e negative charges are thought to dissipated n proteins will be filtered out –

proteinuria or albuminuria.c) Forced involved in GF.

Generally: hydrostatic pressure difference favors filtration whilst oncotic pressure difference opposes it.

Pressure forcing fluid out (outward pressure): GC hydrostatic pressure (approximately 45 mm Hg).

Opposing pressure (inward pressure): Oncotic pressure of plasma proteins in GC (approximately 20 mmHg) n hydrostatic pressure in BC (approximately 10 mm Hg).

At afferent end, a mean net force of approximately 15 mm Hg forces water n solutes out. As blood passes from AA to EA, it is filtered out n proteins remains in the capillaries. As a result OP increases as blood approaches efferent end such that at certain point, known as filtration pressure equals zero. Here, no filtration takes place.

- Normally, about 20% of e plasma that enters glomerulus is filtered at e net filtration of 10 mm Hg -

“UNIQUE” GFR

- Glomerular filtration can be compared to tissues fluid formation except that: Glomerular pressure is higher than other capillary beds (> < 45 mm Hg). Glomerular capillaries permeability is higher.

Mean oncotic pressure is higher.

REGULATIONS 1) Determinants of GFR.a) Changes in renal blood flow.

↓ renal blood flow, ↑ filtration fraction.b) Changes in glomerular capillary hydrostatic pressure.

↑ PGC → ↑ GFR. ↓ PGC → ↓ GFR.

c) Arterial Blood Pressure. ↑ BP, ↑ PGC up to 80 – 90 mm Hg. If BP > 90 mm Hg, PGC remains constant with

increasing BP due to changes in renal vascular resistance. When BP < 50 mm Hg, GFR = 0 mL/min.

c) Changes in hydrostatic pressure in BC. Urethral obstruction. (↑ PT, ↓ GFR) Edema of kidney inside tight renal capsule. (↑

PT, ↓ GFR) d) Changes in concentration of plasma proteins.

Dehydration. (↑ GC, ↓ GFR) Hypoproteinaemia. (↓GC, ↑ GFR)

e) Changes in AA resistance. Constriction: ↑ resistance, ↓ PGC → ↓ GFR. Dilatation: ↓ resistance, ↑ PGC → ↑ GFR.

f) Changes in EA resistance. Mild to moderate constriction: ↑ PGC → ↑ GFR. Severe constriction: GC >> PGC = ↓ GFR. Dilatation: ↓ PGC → ↓ GFR.

g) Changes in glomerular ultrafiltration coefficient, KF.

Surface area of filtration: inner surface of glomerular capillaries that come into contact with blood.

Each tuft of glomerular capillaries is held together by mesangial cells.

Mesangial cells function as phagocytes n contain contractile elements.

Mesangial cells contract: ↓ surface area for filtration → ↓ KF → ↓ GFR

(when net filtration pressure remains unchanged).

Podocytes contract → no of slits open ↓ → ↓ permeability → ↓ KF → ↓ GFR.

2) Autoregulation. Spontaneous n inadvertent changes in

GFR are largely prevented by local intrinsic regulatory mechanism initiated by e kidney themselves.

Kidney is able (within limit) to maintain a constant blood flow into glomerular capillaries, constant glomerular capillary blood pressure, n a stable GFR.

a) Myogenic Mechanism. A common property of smooth muscle:

Arteriolar vascular smooth muscle contracts inherently in response to e stretch accompanying increased pressure within e vessels.

BP ↑: AA automatically constricts on its own when it is stretched → limit blood flow to glomerulus to normal despite elevation of BP → ↓ GFR.

BP ↓: AA relaxes inherently (unstretched) → blood flow to glomerulus to normal despite reduced BP → ↑ GFR.

b) Tubuloglomerular Feedback Mechanism.

Involves juxtaglomerular apparatus: specialized combination of tubular n vascular cells.

Here, smooth muscle cells are specialized to form granular cells (contains numerous secretory granules).

Here, tubular cells are specialized to form macula densa (MD) cells (detect changes in e rate at which fluid is flowing pass them through e tubule).

BP ↑ → ↑ GFR → MD trigger e release of locally acting vasoactive chemicals from juxtaglomerular apparatus adjacent AA constricts → ↓ glomerular blood flow → ↓ GFR → normal.

↓ BP → ↓ GFR → MD alter e rate of e release of locally relevant vasoactive chemicals from juxtaglomerular apparatus adjacent AA dilates → ↓ glomerular blood flow → ↑ GFR → normal.

3) Extrinsic Sympathetic Control.a) Sympathetic stimulation.

Mediated by sympathetic nervous system input to e AA is aimed at e regulation of BP. Only strong activation of sympathetic system has pronounced effect, such as in severe allergy

activation, brain ischemia, n severe haemorrhage. BP↓ → detected by arterial carotid sinus n aortic arch baroreceptor → initiates neural reflexes →

vasoconstriction → ↑ cardiac output n ↑ total peripheral resistance → ↑ blood pressure. BP↓ → detected by arterial carotid sinus n aortic arch baroreceptor → initiates neural reflexes →

vasoconstriction → ↓ GFR → ↓ urine output → ↑ BP. ↑ BP → sympathetic activity↓ → vasodilation of AA → ↑ GFR → ↑ urine →normal BP.

b) Hormonal n autocoids action. Norephinephrine (NE) n ephinephrine (E) constrict both AA n EA causing reduction of RBF n GFR.

However, constriction of EA only in severe condition. Endothelin: peptide released from damaged vascular endothelium. An autocoid n strong

vasoconstrictor of AA. Angiotensin II: a powerful renal vasoconstrictor n an autocoid n hormone. Constricts EA n results

in ↑ PGC → ↑ GFR. Endothelium derived nitric oxide: an autocoid which decreases renal vascular resistance n

results in ↑ GFR. Vasodilators: prostaglandins (PGE n PGI 2). N bradykinins.

RENAL BLOOD FLOW

(RBF)

- Blood flow: 1.2 L/min – 22% of cardiac output.- Functions:

Determines GFR. Modify e rate of solute n water reabsorption by kidney tubule. For urine concentration.

- Filtration fraction = 0.2 = GFR/Renal Plasma Flow.- Renal blood flow is estimated by using paraaminohippuric n PAH clearance.- Renal blood flow = Renal artery pressure – Renal vein pressure. Total renal vascular disease.

SURFACTANT

OVERVIEW Surface tension lowering agent

lining inside the alveoli Lipid + protein in nature

(dipalmitoyl phosphatidylcholine)

Secreted by type II cells (granular pneumocytes)

Completely formed after 28th week of gestation

Synthesis is increased by thyroid hormone and its maturation accelerated by glucocorticoids

Removed by alveolar macrophages

FUNCTIONS1) It prevents collapse

of the lungs during expiration by keeping the

alveoli distended.> If e surface tension is not

kept low when e alveoli become smaller during

expiration, they collapse according to Law of LaPlace’s.

> Law of LaPlace’s, P=2 T/rP = distending pressure

T = surface tensionr = radius of the alveolus2) It reduces the effort

of breathing thereby reducing the pressure required to inflate the lungs (Important in new-borns).

> After birth, e newborn makes several strong

inspiratory movements n e lung expands (1st breath).

Surfactants keep them from collapsing against.

3) It prevents pulmonary oedema (transudation of fluid from capillaries into alveoli).

> Forces favoring transudation exceed e

oncotic pressure will favor pulmonary edema. But

surfactant lowers e surface tension force to nearly zero,

thereby preventing pulmonary edema.

CLINICAL IMPORTANT Hyaline membrane disease: In

premature babies, their surfactant system is not well developed yet. However, e lungs’ surface tension is high n there will be many areas which e alveoli are collapsed.

Patchy atelectasis: associated with surfactant deficiency in patients who have undergone heart surgery which a pump oxygenator was used n pulmonary circulation is interrupted.

Abnormalities from deficiency in surfactant:1)Occlusion of a main bronchus2)Occlusion of 1 pulmonary

artery3)Long term inhalation of 100%

02

Surfactant deficiency occurs in cigarette smoker.

RESPIRATORY MECHANIC

INSPIRATION

Inspiratory neurons discharge↓

Nerves to e inspiratory muscles r excited↓

In quiet breathing, e inspiratory muscles contract↓

Increase in intrathoracic volume n reduce e intrapleural pressure (2.5 mm Hg reduces to 6.0

mm Hg relative to atmospheric)↓

Lungs expanded↓

Intrapulmonary pressure decreased↓

Atmospheric pressure > Intrapulmonary pressure↓

Air enters e lungs causing a rise in 1 PuLP.

EXPIRATION

Discharge of neurons is stopped↓

E lung recoil pulls e chest back to e expiratory position, where e recoil pressure of e lungs n

chest wall balance each other.↓

In forced expiration, some muscles contracts in order to increase intrapulmonary pressure n

drawn inhaled air outward.↓

1 PuLP rises from 6 mm Hg to 2.5 mm Hg.↓

Air is draining out of e lung causing fall in 1 PuLP, which also decreases during expiration.

VARIOUS LUNGS’ VOLUMES

LUNG VOLUMES. The volumes of air contained in the lungs at different phases of the

respiratory cycle are important in assessing lung function. The most important being the TV and the vital capacity.

DEFINITIONS1. Total lung capacity (TLC) = Total volume of the respiratory system

when fully expanded by voluntary effort. (3-6 liters) related more to height & weight. It can be divided into parts that participate in gas exchange (alveolar volume) and those that do not (dead space).

2. This alveolar volume can be further divided into that which can be measured at the lips (vital capacity) and that which remains in the lung after a maximal expiration (residual volume).

3. Tidal volume (TV) = the volume of air that moves into or out the lungs with each inspiration or expiration (500 mls).

4. Inspiratory reserve volume (IRV) = that volume of air inspired with a maximal inspiratory effort in excess of the TV

5. Expiratory reserve volume (ERV) = the volume of air expelled by an active expiratory effort after passive expiration.

6. Residual volume (RV) = Volume of air left in the lung after a maximal expiratory effort.

7. Vital capacity = the largest volume of air that can be expired after a maximal inspiration. Index of pulmonary function with respect to the strength of the resp. muscles and other aspects of pulmonary function.

These volumes changes little with body position unlike the functional residual capacity. FRC (the volume left in the lungs after a normal expiration).

TRANSPORT OF RESPIRATORY GASESPORTIONS EXPLANATION

OXYGEN TRANSPORT

OXYGEN DELIVERY TO

TISSUES- The O2 delivery system in the body consists of the lung and the cardiovascular system.- Oxygen delivery to a particular tissue depends on :

1. the amount of O2 entering the lungs2. and the adequacy of pulmonary gas exchange3. the capacity of blood to carry O2

4. the blood flow to the tissue5. the ability of tissue to utilize oxygen

- 99% percent of the O2 which dissolves in the blood combine with oxygen-carrying protein-' Haemoglobin ' - in the red cells. Thus the presence of Hb increases O2-carrying capacity of the blood 70 fold.- The amount of O2 in the blood, in turn, is determined by

1. the amount of dissolved O2

2. the amount of Hb in the blood3. the affinity of Hb for O2

OXYGEN-HAEMOGLOBIN BINDING

- Since haemoglobin is a protein made up of 4 subunits, the haemoglobin molecule can be presented as Hb4, and it actually reacts with 4 molecules of oxygen to from Hb4O8.

Hb4 + O2 ↔ Hb4O2

Hb4O2 + O2 ↔ Hb4O4

Hb4O4 + O2 ↔ Hb4O6

Hb4O6 + O2 ↔ Hb4O8

- The reaction is rapid, requiring less than 0.01 second. (Each of 4 iron atom can bind reversibly one oxygen molecule. The iron stays in the ferrous state, so that the reaction is oxygenation, not an oxidation)- The deoxygenation (reduction) of Hb4O8 is also very rapid.- The quaternary structure of haemoglobin determines its affinity for oxygen; by shifting the relationship of its 4 components of polypeptide chain, the molecule fosters either oxygen uptake or oxygen delivery.- The movement of e chains is associated with a chain in position of e heme moieties, which assume a relaxed or R state that favors oxygen bonding or a tense or T state that decrease oxygen binding.

FACTORS- E factors:

1. Temperature: A fall in temperature increases Hb’s affinity towards oxygen. Thus, e curve shifts to e Lt. which results in a lower PO2 needed to bind a given amount of oxygen.

2. pH: A fall in pH decreases Hb’s affinity towards oxygen. Thus, e curve shifts to e Rt. which results in a higher PO2 needed to bind a given amount of oxygen.

3. 2,3-diphosphoglycerate: Very plentiful n formed from 3-phosphoglyceradelhyde, which is a product of glycolysis via Embden-Meyerhof Pathway. It is a highly charged anion that binds to e beta chains of deoxyhaemoglobin. 1 mole of 2,3-DPG bind to 1 mole of deoxyhaemoglobin. In thin equilibrium, an increase in [2,3-DPG] shifts e curve to e Rt., lowering HG’s affinity towards oxygen. Thus, a higher PO2 is needed to bind a given amount of oxygen. Factors affecting its concentration:

<<↑ concentration: thyroid hormone, growth hormone, androgens, present in high altitude, n exercise>>

OXYGEN-HAEMOGLOB

IN DISSOCIATIO

N CURVE

- Definition: E curve relating percentage saturation of e O2 carrying power of Hb to e P O2.

- Has a sigmoid-shaped.E reaction:

Hb takes up a small amount of O2 n e R state is favored n additional uptake of O2 is facilitated↓

E 2 beta-chain move closer together↓

Combination of e 1st heme increases e affinity of e 2nd heme for O2.↓

Same thing goes to e combination of 3rd n 4th heme with O2.↓

E affinity of Hb is increased- E fully saturated Hb contains 1.39 ml of O2 in 1 gm. However, blood normally contains small amount of inactive derivatives n e measured value in vivo is lower.- Normal Hb concentration in blood = 15 g/dL. Thus, 1 dL 100% saturated blood contains 20.1 mL O2.

AMOUNT OF OXYGEN

DELIVERED

- When blood is fully saturated (100%) with oxygen: 1 gm of Hb carries 1.34 mL of O2.Systemic arterial blood Venous blood

Total O2 content 19.8 mL 19.8 mLSaturation 97% 75%

In 15 g/dL Hb 19.5 mL 15.2 mLAmount of oxygen transferred Amount of O2 removed by tissue = 19.5 mL – 15.2 mL = 4.6 mL/dL

in one minute.Amount of O2 transferred to e tissues in minute = 250 mL.

At cardiac output 5.5 L/min

CARBON DIOXIDE TRANSPORT

FATE OF CARBON DIOXIDE

- The CO2 disposal system in the body consists of the cardiovascular system and the lungs. The various fates of CO2 in the plasma and the red cells are summarized in the following table:

FATE OF CARBON DIOXIDE

Form Arterial BloodmL/dL

Venous BloodmL/dL

\Amount AddedFrom Tissue mL/dL

(1) Dissolved (in plasma and RBC)(2) As carbamino compounds (with

Hb and with plasma protein)(3) As HCO3- (in plasma and RBC)

2.62.6

43.8

3.03.4

46.3

0.40.8

2.5

Total 49.0 52.7 3.7

- E most important means of CO2 transport is as bicarbonate ion (60%). It occurs in RBC.

1) CO2 combines with water to form carbonic acid in e presence of carbonic anhydrase.CO2 + H2O ↔ H2CO3

↓2) Some of e acid molecules spontaneously dissociate into a proton n bicarbonate ion.

H2CO3 ↔ H+ + HCO3-

↓HCO3

- diffuses into plasma n transported to e lungs where e reversible reaction occurs.

CHLORIDE SHIFT

<< Definition: E inward shift

of chloride ions in

exchange for e outflux of CO2

– generated HCO3

- >>

As e reaction catalyzed by carbonic anhydrase proceeds, H+ + HCO3- start to accumulate within RBC in

systemic circulation.↓

HCO3- diffuses down e concentration gradient out of RBC into plasma through HCO3

- - Cl- carrier.↓

E outflow of negatively charged HCO3- is not accompanied by outward diffusion of positive ions

↓As a result, an electrical gradient is established

↓Cl- diffuses in down e electrical gradient to restore e electrical neutrality.

↓E accumulated H+ in RBC becomes bound to Hb to become HHb n unloads oxygens.

↓At lungs, e process becomes reversible n CO2 + H2O are reformed.

- Haldane effect is e fact that removal of oxygen from Hb increases e ability of of Hb to pick up CO2 n CO2 – generated H+.

REGULATION OF RESPIRATIONPORTIONS EXPLANATION

TYPES OF REGULATIO

N

- 3 Types:1. Neural control2. Chemical control3. Reflex control

NEURAL CONTROL

BRAIN STEM (INVOLUNTARY)- Place where respiratory centre is located.- Consists anatomically diffused but functionally integrated collections of neurons.- Activity of these neurons integrates e activity of respiratory muscles n r made up 3 main groups of neurons.

1. Medullary Respiratory Centre. Composed of:

a) Dorsal Respiratory Group (inspiratory centre): discharges impulses to e inspiratory muscles.

b) Ventral Respiratory Group (expiaratory centre): Quiescent during normal breathing because ventilation is then achieved by active contraction of e inspiratory muscles (mainly diaphragm followed by passive relaxation of chest wall to its equilibrium position). However, in forceful breathing, it becomes active as a result of expiratory cells.

There is no universal agreement on how e intrinsic rhythmically is brought about medullary centre.

2. Apneustic Centre (Lower pontine level). It is so named because if e brain of an experimental animal is sectioned just above this site,

prolonged inspiratory gaps (apneuses) interrupted by expiratory effort is seen. It discharges impulses continuously to e inspiratory centre, which has an excitatory effect. Its role in normal human is not exactly known.

3. Pneumotaxic Centre (upper pontine level). Inhibits or switch off inspiration. Its role is fine-tunning of respiratory rhythm because a normal rhythm can still exist in e

absence of this centre.

CORTEX- CENTRAL CONTROL OF BREATHING (VOLUNTARY)- Breathing is under voluntary control to a considerable extent.- Limbic system n hypothalamus: these areas can affect breathing in some states like rage n fear.

CHEMICAL CONTROL

PERIPHERAL CHEMORECEPTORS- Fast responding monitors of e arterial blood.- Found in:

a) carotid bodies at e bifurcation of e common carotid arteryb) aortic bodies above n below aortic arch

- Respond to:a) e decrease in arterial PO2 n pHb) e increase in arterial PCO2

- Responsible for hyperventilation that occurs as a result of hypoxamaemia.- In their absence, severe hypoxaemia depresses respiration, presumably through e direct effect on e respiratory centre.

CENTRAL CHEMORECEPTORS- E most important receptor r those situated near e ventral surface of e medulla in e vicinity of e exists of 9th n 10th cranial nerves.- Surrounded by brain extracellular fluid n response to changes in its hydrogen ions concentration:

a) Increase in [H+]: stimulates ventilation.b) Decrease in [H+]: inhibits ventilation.

- E effects of carbon dioxide is mainly due to its movement into e CSF n brain interstitial fluid where it increase [H+] n stimulates receptors sensitivity to H+.

REFLEX CONTROL

LUNG RECEPTORSa)Hering-Breuer reflex (Pulmonary Stretch Receptors).

Lies within airway smooth muscle. E main reflex is a slowing of respiratory rate due to an increase in expiratory time. Probably important in newborns.

b)Irritant receptors (Irritant Reflex). Stimulated by inhaled dust, noxious gas, cold air pass through e trachea n large airway. Results in reflex of vasoconstriction followed by cough & hyperpnoea. Probably plays a role in bronchoconstriction seen in asmathic attack as a result of their response to

histamine.c) J. receptors

Situated in interstitial tissue b/w pulmonary capillaries and alveoli. Stimulated by capillary distension. Responsible for increased frequency of breathing during exercise and in pulmonary venous

congestion.

OTHERSa)Nose and upper airway receptors: Respond to mechanical n chemical stimulation n responds include

sneezing, coughing, n bronchoconstriction.b)Joint and muscle receptors: Impulses from moving limbs are believed to be caused in hyperventilation

associated with exercise especially in early state.c) Arterial Baroreceptors:

↑ BP ® reflex hypoventilation or apnea through stimulation of peripheral chemoreceptors.

↓ BP ® hyperventilation (results from hypotension).d)Pain and temperature.

Pain ® a period of apnea followed by hyperventilation. Heating of skin ® hyperventilation.

VENTILATION: PERFUSION RELATIONSHIP OF E LUNGSPORTIONS EXPLANATION

OVERVIEW1. Diffusion: how gas gets across the alveoli.2. Ventilation: Perfusion Relationship: how matching of the gas and blood determines gas

exchange.3. Gas transports to the periphery: how gases are moved to the peripheral tissue.

PARTIAL PRESSURE

- Definition: e pressure exerted by any one gas in a mixture of gases is equal to the total pressure times the fraction of total amount of gas it represents. For example :

Composition of dry air1. O2 = 20.98% (21)

2. N2 = 78.06%3. CO2 = 0.04%

>> Thus, partial pressure of oxygen = 20.98% x 760 mm Hg = 159.6 (160 mm Hg at sea level).(Remark : The water vapor in most climate reduces these percentages and therefore to the partial

pressure to a certain degree)

BLOOD SUPPLY OF

LUNGS

- Lung receives blood via1. Bronchial Circulation 2. Pulmonary Circulation

. Bronchial arteries arise directly from the aorta and supply down to the level of terminal bronchioles.

. Respiratory bronchioles, alveolar ducts, alveolar sacs and alveoli receive oxygen by diffusion from the alveoli and nutrients from venous blood in pulmonary circulation.

. Bronchial vein drains into superior vena cava ® Rt. atrium ® systemic circulation.(Some of the bronchial venous blood enters pulmonary vein which contains oxygenated blood)

PULMONARY GAS

TRANSFER

- Diffusion Capacity, DC or transfer factor: e amount of gas which cross the alveolar membrane per minute per mm Hg difference in partial pressure gradient between the alveolus and blood in the pulmonary capillary.

1. Dif. Cap. of O2 = 20 - 30 ml/min./mmHg2. Dif. Cap. of CO2 = 500 mL/min./mmHg

Factors affecting gas transfer: Directly proportionate to: Indirectly proportionate to:

1) Partial pressure gradient. 1) Molecular weight of diffusion gas.

2) Area of diffusion. 2) Length of diffusion path.

3) Membrane permeability. 4) Gas solubility. 5) Amount of hemoglobin. 6) Rate of uptake of gas by hemoglobin. 7) Temperature (to a limit)

VENTILATION – PERFUSSION

RATIO

- Alveolar ventilation brings oxygen into e lung n remove carbon dioxide from it (Mixed venous blood is vise versa).- E alveolar PO2 n PCO2 are determined by e relationship b/w alveolar ventilation n perfusion called VA/QC.- Normal values at rest:

1. Ventilation = 4 – 6 L/min2. Perfusion = 5 L/min3. VA/QC = 4/5 = 0.8

- If a group of alveoli is unventilated, but receive normal perfusion, e VA/QC will be less than 0.8.- If a group of alveoli is unperfused, but receive normal ventilation , then PO2 < 100 mm Hg n PCO2 > 40 mm Hg.

REGIONAL DIFFERENT IN

UPRIGHT LUNG

- The lower regions receive better ventilation n perfusion than the upper (compliance n gravitational effects).- E perfusion gradient is much steeper than e ventilation gradient, thus, e ventilation-perfusion ratio is

higher in apical region than in basal region. As a result, e alveolar PO2 is higher n e alveolar PCO2 is lower in e upper portions of e lung than they r in lower region.

VENTILATION – PERFUSION RELATIONSHIP Ventilation Perfusion

Upper Lungs - Intrapleural pressure > negative

- Greater transmural pressure gradient

- Alveoli larger n < compliant- Less ventilation

- Lower intravascular pressures- Less recruitment n distention

- High resistance- Less blood flow

Lower Lungs - Intrapleural pressure < negative

- Smaller transmural pressure gradient

- Alveoli smaller n > compliant- More ventilation

- Greater intravascular pressures

- More recruitment n distention- Low resistance

- Greater blood flow

VENTILATION - Refer to “Respiration” table -

REGIONAL DIFFERENT IN

- The lower regions receive better ventilation n perfusion than the upper zone (in an upright lung).- The dependent parts of the lung have greater ventilation than non-dependent part (in supine position). - Base of the lung has a small resting volume and it expands well on inspiration (ie more compliance).

VENTILATION - Gravity effect. - E above points show that e inspired gas is directed towards e dependent parts of e lungs (base of an upright lung). This is determined by e compliance of different parts of e lung:

Base of e lung has a small resting volume n it expands well on inspiration (> compliance).Apex of e lung has a larger resting volume n only a small volume change is observed on inspiration.

- Different part of e lung are on different part of e compliance curve -

ABNORMALITIES

1. TACHYPNOEA: an increase in the rate of ventilation.2. HYPERNOEA: an increase in ventilation in proportion to an increase in CO2 production.3. HYPERVENTILATION: an increase in ventilation out of proportion to CO2 production.4. HYPOVENTILATION: decrease in ventilation that leads to a rise in PCO2.5. DYSPNOEA: a subjective sensation which is unpleasant or distressing.

RESPIRATIONPORTIONS EXPLANATIONOVERVIEW - Definition: It is the sum of processes by which an organism meets its requirement for oxygen and

eliminates carbon dioxide.- Principle Purpose: E exchange of oxygen n carbon dioxide b/w blood n respired gases. - 2 types:

1) External: The absorption of oxygen and removal of carbon dioxide from the body as a whole.2) Internal: The gaseous exchanges (oxygen and carbon dioxide) between the cells and their fluid

medium.

FUNCTIONAL ANATOMY

1.Upper Respiratory Tract: - Anterior nares → Vocal fold.2.Lower Respiratory Tract: - Vocal fold → Alveoli (divides 23x).

- Trachea, bronchi up to terminal bronchioles (1st 16 branches) is known as conducting zone.- Respiratory bronchioles, Alveolar ducts, Alveolar sacs (last 7 branches) r known as respiratory

unit.3.Alveoli:

- 300 millions (in both lungs)- 70 m2 ( functional area)- Type I cell (primary lining flat cells): flat cells with large cytoplasmic extension.- Type II cell (granular pneumocytes): thicker and secrets surfactant.

4.Respiratory Pumps:- Chest wall and respiratory muscles- Respiratory centre in the brain- The nerve that connect the brain to the muscle

DEAD SPACES

- Anatomical DS: Volume of air occupying the space from the external nares to the terminal bronchioles (150 mL). It is e space in e conducting zone of airway occupied by gas that doesn’t exchange with blood in pulmonary vessels.- Physiological DS: Volume of air (gas) not equilibrating with blood. i.e, wasted ventilation (Any increase in dead space volume effectively decreases alveolar ventilation).

- Normally, both DS are identical. Pathalogically, physiological DS may be increased due to some of e alveoli which may be ventilated n no gas exchange in it -

BREATHING - E lungs are stretched following e 1st cry at birth n at full inspiration.- Ventilation is brought about by variation in e size of e thoracic cavity which is followed by e movement of e lungs.- E pressure in e space b/w lungs n chest wall (intrapleural pressure) is subatmospheric.

RESPIRATORY RATE

- At rest, a normal adult breathes in 10 – 18 times/min.- Respiration rate varies with age:

At birth 40 – 601st year 25 – 35

2 – 4 years 20 – 305 – 14 years 20 – 25

VENTILATION

- Describes e movement of air in n out e lung.1) Alveolar Ventilation: Volume of air involved in gas exchange each minute.

. (Tidal volume – Dead space volume) x Respiratory rate

. (500 mL – 150 mL) x 12 (average)

. 350 x 12 = 4200 mL/min2) Pulmonary Ventilation: Volume of air entering e lungs each minute.

. (Tidal volume) x Respiratory rate

. 500 mL x 12 = 6000 mL/min >>> This value is known as total ventilation or minute volume which is sufficient for e basal need of e body. If e need of oxygen increases, hyperventilation results (exercise).

RESISTANCE- Airway resistance

related to lung volume,

bronchomotor tone and the thickness of

the mucosal layer and radius of airway-ANS influences on smooth muscles of

airway.

- Divided into:1) Elastic resistance i.e resistance offered by elastic tissues of the chest wall and the lungs2) Nonelastic resistance or viscous resistance i.e resistance offered by nonelastic tissues of

the chest wall and the lungs3) Airway resistance i.e resistance to air flow offered by the respiratory passages

- E flow of air into n out of lungs is opposed by e frictional resistance of e airway n to a lesser extent by e inertia of e gas.- 2 flows:1) Laminar flow: associated with less resistance than transitional or turbulent flow, occurs at low flow

rate n in e smaller bronchi.2) Turbulent flow: occurs in e larger airways n at branches in e bronchial tree.

COMPLIANCE It indicates the degree of stiffness of the lungs. Definition: Compliance is the change in lung volume per unit change in airway pressure. It is slightly

greater when measured during deflation than measured during inflation. Compliance = V/P L/cm water. Normal value: 0.2 L/cm water (0.09-0.26 L/cm water). Compliance is decreased in pulmonary congestion and interstitial pulmonary fibrosis. It is increased

in emphysaema. Compliance Line: E slop of e line that result from plotting e airway pressure against lung volume.

INSPIRATORY MUSCLES

1) Diaphragm: main muscle of inspiration. Its movement account for 75% of e change in e intrathoracic volume during quite breathing. It is innervated by phrenic nerve from C3, C4, n C5.

2) External intercostals muscle: run obliquely downward n forward from rib to rib. Contraction causes increased AP diameter of e chest. Innervated by intercostals nerves.

3) Accessory muscle: Scalene (1st 2 ribs) n sternocleidomastoid muscle (sternum). Help to elevate e thoracic cage in deep laboured breathing. Little activity during quite breathing.

4) Minor muscles: alae nasi (flaring of nose) n small muscles of head n neck.

EXPIRATORY MUSCLES

1) Internal intercostals muscle: run obliquely downward n posteriorly from rib to rib. Contraction pulls rib cage downward n inward.

2) Anterior abdominal wall muscles, rectus abdominis n transverse abdominis: most important n aid expiration by pulling e rib cage downward n inward n by increasing e intraabdominal pressure pushes e diaphragm up.

RENAL TUBULARPORTIONS EXPLANATION

OVERVIEW - E ultrafiltrate on reaching e tubule is modified by e process of secretion n reabsorption to produce e final product, urine.- E transport of substances across is governed by e body’s need.

FUNCTIONS - Tubular reabsorption: absorption of substances needed by the body from tubule BACK into the blood.- Tubular secretion: secretion of substances to be eliminated from the body INTO the tubule.- Establishment of medullary osmotic stratification (LOH).- Concentrating n diluting filtrate (LOH).- Determining e final tonicity of urine to be excreted (DCT n CD).

TUBULAR ABSORPTIO

N

- E tight junctions in tubular structure prevent substances except water from moving b/w cells, thus, they need to across e cells n face 5 distinct barriers: Luminal membrane, cytosol, basolateral membrane, interstitial fluid, n capillary wall.- This is called transepithelial (across e epithelium) transport. 2 types of transportation:- Active transport: Movement of solute AGAINST a concentration gradient and requires energy from metabolism (1 or > of e steps are active).

a) Primary active transport.b) Secondary active transport (Facilitated diffusion).c) Pinocytosis.

- Passive transport: Movement of solute that does not require energy (All 5 steps are passive). a) Diffusion: Movement of solute DOWN a gradient either in concentration and electrical

potential difference.b) Solvent drag (convection): E process of solute being dragged with water proportional to

hydrostatic oncotic pressure or osmotic pressure.

ACTIVE TRANSPOR

T

a) Primary active transport.- Features: Requires energy, unidirectional, n has limitations due to transport maximum.- Additional features to help reabsorption: Extensive brush border on both the luminal and basolateral side of the epithelial cell in PCT, n high numbers of mitochondria.- Example: Na+/K+ ATPase on the basolateral membrane.b) Secondary active transport.- Definition: Active transport of one substance is coupled to e transport of other substances AGAINST e concentration gradient. - Example: Na+- Glucose symport, Na+- Amino acid symport, Na+- H+ antiport, n Na+- K+ antiport.- This transport does not require energy directly from ATP but energy is obtained from e simultaneous facilitated of Na+ DOWN its electrochemical gradient.c)Pinocytosis.- A mechanism to reabsorb large molecule such as protein.- Requires energy.- Most of e processes take place in proximal tubule.

PASSIVE TRANSPOR

T

- Osmosis is e diffusion of water across membranes. - Molecules diffuse from areas:

1) Of high concentration to areas of low concentration = DOWN their concentration gradient2) Of difference electrical gradient.

- Influenced by permeability of capillary n tubular epithelium.- Examples: Urea, Chloride, n water.

TRANSPORT MAXIMUM

- E limit for substances that are actively transported in tubule which is due to saturation of transport systems is called transport maximum or tubular maximum, Tm.- E.g: Glucose >>Normally glucose does not appear in urine as all filtered glucose is reabsorbed in PCT. When e filtered load exceeds e capability of tubules to reabsorbed, urinary excretion of glucose occurs.- Substances that are passively reabsorbed do not demonstrate transport maximum because e rate of transport is determined by :

1) Electrochemical gradient for diffusion2) E permeability of membrane3) E time required for e fluid containing e substance to remain within e tubule.

- Tm for actively reabsorbed substances: Glucose 300-350mg/min, Phosphate 0.10 mM/min, Sulfate 0.06 mM/min, Amino acids 1.5 mM/min, Urate 15 mg/min, Lactate 75 mg/min, Plasma protein 30 mg/min.- Tm for actively secreted substances: Creatinine 16 mg/min, Paraminohippuric acid (PAH) 80 mg/min.

REGULATION

a) Glomerulotubular balance. Rate of reabsoprtion increases when GFR is increase. Help to :

1)Prevent overloading of the distal tubular segment.2)Prevent excessive changes in GFR.

b) Physical forces of peritubular capillary and renal interstitial fluid. Peritubular capillary:

1)Hydrostatic pressure = opposes reabsorption.2)Colloid osmotic pressure = favours reabsoprtion.

Interstitial fluid:1)Hydrostatic pressure = favors reabsorption.2)Colloid osmotic pressure = opposes reabsoprtion.

Peritubular capillary:1)Hydrostatic pressure is increased by: - Increase arterial pressure. - Increase resistance in the afferent

and efferent.2)Colloid osmotic pressure is increased by

c) Effect of arterial pressure on urine output. High arterial pressure will :

1)Increase sodium and water urinary excretion.

2)Decrease reabsorption of sodium and water.

3)Reduced angiotensin II.d) Hormonal control. Aldosterone-increase sodium reabsortion

and increase potassium secretion. Angiotensin II-increase sodium and water

reabsorption. ADH – increase water reabsorption. ANP- decrease sodium and water

reabsorption. Parathyroid Hormone-increase calcium

reabsorption.e) Sympathetic nervous system. Increase activity of sympathetic nervous

- Increased systemic plasma colloid. - Increase filtration fraction (GFR/RFP).

system: Decrease sodium and water EXCRETION by

constricting both afferent and efferent which will reduce GFR.

Increase sodiun REABSORPTION in the PCT n thick ascending limb LOH.

Increase angiotensin II and renin

RENAL HANDLING OF WATERPORTIONS EXPLANATIONOVERVIEW 1) Concentrating Power: can concentrate e urine up to 5-folds e plasma osmolality.

2) Diluting Power: can dilute e urine up to 10-folds.- Thus, there is less concentrating power than diluting power, n loss of concentrating power is an early sign of renal failure.

NORMAL VALUES

- Normal plasma osmolality: 280 – 296 mosm/L.- Normal urine osmolality: 30 mosm/L (high flow rate) or 1400 msom/L (slow rate).- Amount of water filtered at glomerulus: 180 L/day.- Amount of urine excreted: 0.5 – 1.5 L/day.- Thus, 99% of filtered water is reabsorbed.

PCT - 65% of water is reabsorbed here.- This absorption occurs regardless of water load in e body n not subjected to regulation.- PCT is very permeable to water because of e presence of many “always open” water channel called Aquaporins-1.- Thus, water moves passively out of tubule along e osmotic gradients set up by active transport of solutes.- Water reabsorption is also aided by e plasma-oncotic pressure exerted by concentrated protein plasma in e peritubular capillaries (after ultrafiltration, concentration of plasma protein is increased). This pressure tends to pull water towards it osmotically.- As a result, the tonicity at this part is remained isotonic.

LOH LOH – Countercurrent Multipliers Vasa Recta – Countercurrent Exchangers

- E countercurrent multiplier multiplies e osmolality of e tubular fluid resulting in e establishment of e corticopapillary osmotic gradient which is maintained by e countercurrent exchanger.- Descending Limb:

Permeable to water n impermeable to solutes.

Thus, water diffuses out of LOH into interstitium along e concentration gradient, leaving hypertonic tubular fluid.

At e same time, isotonic fluid enters LOH from PCT n hypotonic fluid leaves PCT into DCT.

E process will be repeating for many times, n as a result, a gradient of osmolality is formed from to e bottom of LOH.

- At e bottom of LOH, urea enters n causes e tubular fluid to be > concentrated (hypertonic) n contributes to e osmotic gradient.- Ascending Limb:

Permeable to solutes n impermeable to water. Sodium leaves e tubule along a concentration

gradient leaving behind water. As a result, fluid leaving LOH is hypotonic to e

interstitium. In e case of dehydration, e tubular fluid is isotonic.

- The repeating of e whole process generates e corticopapillary osmotic gradient along e LOH n CD n that is why LOH is known as countercurrent multiplier.

- E countercurrent exchanger maintains e e corticopapillary osmotic gradient (concentration of solutes like urea n sodium in e interstitium).- Vasa recta is straight artery supplying LOH which has a hairpin construction n is permeable to both salts n water.- It loops back LOH through e concentration gradient in reverse n allows e its blood content to leave e medulla n enter e renal vein essentially isotonic to incoming arterial artery.- As blood passed down e descending limb of VR, equilibrating with e progressively increasing concentration of interstitium, it picks up salts n loses water.- then, as blood flows up e ascending limb, salts diffuse back into interstitium n water reenters VR.- This passive exchange of solutes n water b/w e 2 limbs of VR is known as countercurrent exchange.- This process doesn’t established concentration gradient, rather it prevents e dissolution of e gradient.- As a result, e incremental gradient of hypertonicity in e medulla is preserved at e same time e medullary tissues are nourished.

DCT - 5% of water is reabsorbed here.- E extent of reabsorption here is subjected to direct hormonal control, depending on e body’s state of dehydration.- E process is controlled by aldosterone because it is relatively permeable to water, further diluting e urine.- As a result of e action of LOH n vasa recta, e tonicity here is hypotonic.

CD - 15% of water is reabsorbed here.- Divided into 2 parts: cortex n medullary.- E main control of water reabsorption here is ADH hormone or vasopressin (produced in posterior pituitary gland). However, its action is only established by e presence of Aquaporin-2 which r stored in vesicles. ADH acts by causes a rapid insertion of these channels into luminal membrane with e presence of vasopressin V2 receptor, cAMP, protein kinase A, n dyneins (molecular molecule).- In e presence of ADH, CD becomes > permeable to water, n reabsorption occurs down e concentration gradient osmotically.- However, when e level of ADH decreases, e amount of water reabsorbed is also reduced.- E maximum levels of ADH can concentrate urine up to 1200 msom/L by e end of e CD. Beyond e point, no further modification occur, n e tubular fluid is called urine.- Even though ADH conserves body fluid, it cannot completely halt e production of urine because a minimum volume of urine must be excreted with solute wastes.

FACTORS AFFECTINF

[URINE]

1) ADH: exerts a major control over urine concentration. Its absence can result in a urine volume equal to 13% of filtered fluid – 23 L.

2) Dietary protein: protein breakdown results in e formation of urea. Urea contributes to e osmolality of e medullary interstitium.

3) GFR: a low GFR presents a small volume of fluid to e countercurrent system, with a decline in flow rate in e loops. E osmotic gradient is therefore greater.

4) Hypokalaemia: for unknown reasons, low plasma potassium level is associated with low concentrating power.

5) Certain drugs: eg – Non-steroidal anti-inflammatory drugs (NSAID) used over a long period of time in high dose may cause a loss of concentrating power. Lithium, a drug used in psychiatry also causes a reversible loss of concentrating power.

APPLIED PHYSIOLOG

Y

- Diabetes Insipidus (DI):2 types: a) Nephrogenic DI: Defect in ADH receptor. b) Central DI: Defect in ADH production. Effect: polyuria – large amount of urine excreted because of lost of renal concentrating power.- Diabetes Mellitus (DM):2 types: a) Type 1 DM: Defect in e production of insulin. b) Type 2 DM: Defect in insulin receptor.Effects: polyuria – large amount of urine n glycosuria – presence of glucose in urine because of renal fails to reabsorb glucose n a large amount of water accompanies glucose to avoid too concentrated urine.

Chemicals released that induce AA vasoconstriction

Stimulation of macula densa to release

vasoactive chemical

↑ Arterial BP

↑ Driving pressure into glomerulus

↑ Glomerular

capillary pressure.

↑ GFR

↑ Rate of fluid flow through tubules

↓ Blood flow into glomerulus

↓ Glomerular capillary pressure

to normal.

↓ GFR to normal.

TUBULOGLOMERULAR FEEDBACK MECHANISM

↓ Arterial pressure

↓ GFR

↑ Renin ↓ AA resistance

↑ EA resistance

↑ Angiotensin

↓ Sodium arrival at macula densa

↓ Glomerular OH pressure

↑ Arterial pressure

PERITUBULAR REACTION

↓ Arterial BP

Detection by baroreceptors

↑ Sympathetic activity

Arteriolar vasoconstriction↑ Total Peripheral Resistance

↑ Cardiac output

↑ Arterial BP

Short term adjustment for

↓ Urine volume↓ GFR

↓ Glomerular capillary BP

AA vasoconstriction

Long term adjustment for

↑ Arterial BP

↑ Conservation of fluid n salt

BARORECEPTOR REFLEX INFLUENCE ON E GFR IN

LONG TERM REGULATION OF

ARTERIAL BP.

ACTION OF SMOOTH MUSCLE

MECHANICAL N CHEMICAL REACTIONS

Binding of acetylcholine to muscarinic receptors

↓Increased influx of Ca2+

into e cells↓

Activation of calmodulin-dependant myosin light

chain kinase↓

Phosphorylation of myosin

↓Increased myosin ATPase

activity n binding of myosin to actin

↓Muscle contraction

↓Dephosphorylation of

myosin by myosin light chain phosphate

↓Relaxation or sustained

contraction due to lack of e latch bridge n other

mechanism.

TYPES OF SMOOTH MUSCLE

a) Visceral/unitary Characteristics: has large

sheets, functions in a syntial fashion, n has many low-resistance gap-junction bridge.

b) Multiunit Made up of individual units

w/o interconnecting bridges.Each multiunit has enpassant

ending of nerve fibers.Responds to hormones n

other circulating substances.

MEMBRANE POTENTIAL

- 50

mV

Acetylcholine, parasympathetic stimulation, cold, n stretch

Ephinephrine n sympathetic stimulation

Membrane potential

ACTION POTENTIAL

Resting membrane potential = =90 mV↓

Electrical activity of pacemaker: stimulus↓

Membrane of a ventricular myocardial contractile is excited over -70 mV (threshold potential) generates

action potential.↓

Explosive increase in membrane permeability to Na+ n a subsequent massive Na+ influx (opening of Na+

channels)↓

Rapid depolarization – 2 msec (overshoot)↓

Early rapid repolarization (closure of Na+ channels)↓

Subsequent prolonged plateau – 250 msec (Opening of Ca2+ - Na+ channels – slow inward diffusion of Ca2+ n a

marked decrease in K+ permeability).↓

Late rapid repolarization (inactivation of Ca2+ - Na+ channels – diminishes slow n inward movement of Ca2+ n

activation of K+ channels – promotes rapid outward movement of K+)

↓Inside of e cell: negativeOutside of e cell: positive

- Result in resting membrane potential = -90 mV

CARDIOVASCULAR PHYSIOLOGYPORTIONS EXPLANATIONFUNCTIONS 1) Transportation of respiratory gases, nutrients, hormones, n enzymes to all cells of e body, as

well as transportation of waste materials from cells to e lungs n kidneys for elimination.2) Body temperature regulation: a) Blood vessels constrict to retain body heat. b) Blood vessels dilate to dissipate heat at skin surface.3) Body protection: Protect through immune system, blood cells, n etc.

HEART - Separated into 4 chambers by a single fibrous skeleton which comprises of 4 interconnected rings of dense connective tissue.- 4 chambers: Rt. n Lt. atria n Rt. n Lt. ventricles.- 4 valves: a) Atrioventricular valves: Rt. – Tricuspid, Lt. – Mitral. b) Semilunar valves: Rt. Pulmonary, Lt. – Aortic.

CARDIAC MUSCLE

- 3 types: a) Atrial muscle. b) Ventricular muscle. c) Specialized conducting fibres.- Microscopic appearance: > Striated in appearance like skeletal muscle. > Roughly quadrangular n usually have only a single centrally located nucleus. > Muscle fibers branch n connected to each other by intercalated disk (provide a strong union b/w fibers, maintaining cell-to-cell cohesion, so that e pull of 1 contractile unit can be transmitted along its axis to e next) which contain desmosomes n gap junction (provide low-resistance bridges for e spread of excitation from one fiber to another). > Close contact with large no. of elongated mitochondria.

PROPERTIES OF CARDIAC

MUSCLE

1) Autorhythmicity E ability to generate electrical impulses spontaneously n rhythmically. Under normal resting condition, cardiac muscle can contract n relax continuously n

rhythmically w/o stopping. It contracts w/o extrinsive nerve or hormonal stimulation, but these reactions can cause

increased or decreased discharge.2) Conductivity

E ability of e heart muscle to conduct nerve impulses around its fibers. It is conducted by specialized conducting system.

3) Excitability E ability of heart muscle to respond to a stimulus. Cardiac muscle has extra-long rsting potential.

4) Contractility Cardiac muscle remains contracted (depolarized) longer than skeletal muscle due to

prolonged delivery of calcium ions from sarcoplasmic reticulum n ECF.

EFFECTS OF ECF IN

CARDIAC FUNCTION

1) Decreased temperature of ECF: decreased cellular metabolism, lower heart rate, n strength of cardiac contraction.2) Variation in ECF electrolyte concentration has a direct effect on membrane potential of cardiac cells.- Cardiac muscles are sensitive to ECF calcium concentration.

ABNORMALITIES

a) Hypercalcaemia: cardiac muscles become extremely excitable. Its contraction ism powerful n prolonged (can be fatal, stop in systole).

b) Hypocalcaemia: less excitable→ weak contraction → weak heart beat.

15

4

2

3

+ 40

+ 20

0

- 20

- 40

- 60- 70- 90

2

Membrane Potential (

mv )

1= Depolarization (Na+ entry: Permeability to K+

↓).2 = Early rapid repolarization.

3 =Plateau phase (Ca2+ - Na+ open: Ca2+ influx).4= Repolarization (Ca2+ - Na+ close: Ca2+ influx,

Permeability to K+ ↑).5 = Base Line.

CONTRACTILE RESPONSEACTION POTENTIAL

Urea recycling in renal medulla in CT.

Early part of CT:Is impermeable to urea.

Urea becomes progressively > concentrated (hypertonic to surrounding interstitium) as water is

reabsorbed in e presence of ADH.Last part of CT:

Is permeable to urea.Concentration of urea > than in e surrounding

interstitium n in e tubular fluid in e bottom of LOH.This concentration difference favors e diffusion of urea (reabsorption) into interstitium n into bottom

of LOH.Urea diffusion is increased by e action of ADH.

Functions of urea reabsorption:1)Reabsorbed urea contributes to medullary

hypertonicity which is important in renal’s ability to produce hypertonic urine.

2)Urea recycling provides a mechanism for concentrating urea in e excreted fluid while

economizing e loss of water.Process:

Diffusion of urea into interstitium n bottom of LOH[Urea] in these 2 parts

[Urea] in these 2 parts ↑ until it equilibrates with [Urea] in last part of CD.

↓This contributes to medullary osmotic gradient.

↓Pulls water out of tubular fluid in descending LOH

to increase [sodium] n makes e tubular fluid > concentrated .

↓↑ [sodium] causes sodium to diffuse down its

concentration gradient into interstitium from thick n thin limbs of ascending LOH.

↓Thus, e vertical osmotic gradient in insterstitium is

contributed by both urea n sodium.↓

However, as sodium diffuses out into interstitium at ascending limb of LOH, urea remains in e tubular

fluid because LOH is impermeable to urea.↓

As a result, [urea] ↑.↓

Same thing happens in e early part of CD.↓

At e last part of CD, [urea] becomes much greater than e beginning one, n in e presence of ADH, urea

diffuses out into interstitium n bottom of LOH because [urea] is greater than [ ] in interstitium n

bottom of LOH.↓

Cycle repeats n continues.

- This process doesn’t alter e total amount of urea excreted, but it does concentrate urea

in e urine by altering e amount of water reabsorbed -

TUBULOGLOMERULAR FEEDBACK MECHANISM OF AUTOREGULATION

↑ Arterial BP↓

↑ Driving pressure into glomerulus↓

↑ Glomerular capillary pressure↓

↑ GFR↓

↑ Rate of fluid flow through tubules↓

Stimulation of MD cells to release vasoactive chemicals

↓Chemicals released that induce AA vasoconstriction

↓↓ Blood flow into glomerulus

↓↓ Glomerular capillary pressure to normal

↓↓ GFR to normal

BARORECEPTOR REFLEX INFLUENCE ON E GFR IN LONG TERM REGULATION OF

ARTERIAL BP.

↓ Arterial BP↓

Detection by baroreceptors↓

↑ Sympathetic activity → ↑ Cardiac Output ↓ ↓

Generalized arteriolar vasoconstriction → ↑ Total peripheral resistance

↓↓ Urine volume ↓ ↓ GFR ↓↓ Glomerular capillary BP ↓ AA vasoconstriction ↓↑ Conservation of fluid n salt ↓ ↑ Arterial BP ↓Long term adjustment for ↓ ↑ Arterial BP ↑Short term adjustment for

↓ Arterial Pressure↓

↓ Glomerular OH pressure↓

↓ GFR↓

↓ Sodium arrival at macula densa

↓ AA Resistance ↑ Renin ↓↑ Angiotensin II ↓↑ EA Resistance

↑ Arterial pressure

PERITUBULAR REACTION.

REGULATION OF SODIUM

REABSORPTION

Pressure natriuresis and pressure diuresis.

Most powerful mechanism for control of sodium and fluid balance.

Pressure diuresis: increase BP to raise urinary excretion.

Pressure natriuresis: rise in Na+ excretion that occurs with elevated BP.

Both occurs in parallel and are referred to as PRESSURE NATRIURESIS

Sympathetic adrenergic nervesIncrease sympathetic output stimulates Na+

reabsorption in the proximal tubule.This is achieved as norepinephrine interacts

with- adrenergic receptors to stimulate:Na+ / H+ exchanger on the luminal.Na+ / K+ ATPase on the basolateral.

GFRGFR lead to ↑ Na+ reabsorption.

If GFR increases, NaCl delivery to tubules is increased and lead to:

↑ tubular reabsorption of extra Na+ filtered (Glomerulotubular balance).

↑ Na+ in delivery to the distal tubule causes afferent arteriolar constriction:

Macula densa feedback.Constriction of AFFERENT arteriolar will return

GFR towards normal.

AldosteroneProduced in adrenal cortex

Primary site of action is collecting duct. Also acts on the late distal tubule.

Increase sodium reabsorption by:Stimulating Na+/K+ ATPase pump on the

basolateral membrane.Increase Na+ and K+ channels in the luminal

membrane.Increase enzymes in the citric acid cycle that

lead to energy production.

ANPInhibit secretion of aldostrerone.

Inhibit Na+ reabsorption at the medullary collecting duct.

The mechanism of this effect is unknown and EPhysiological significance of Na+ inhibition is

unclear.

Angiotensin II (Ang II)Most powerful sodium retaining hormone

Stimulated when BP is low.Ang II helps increasing BP and ECF through increasing sodium and water reabsorption

through 3 main effects:1) Ang II stimulates aldosterone

2) It constricts the efferent arterioles3) It directly stimulates sodium reabsorption in

the proximal tubules:a) By stimulating Na+/K+ ATPase pump.

b) By stimulating Na+/H+ antiport/exchange.

RENAL HANDLING OF DIFFERENT SUBSTANCESPORTIONS OVERVIEW PCT LOH DCT CD REGULATION

GLUCOSE REABSORPTION

- Easily filtered n all filtered glucose is reabsorbed mostly in PCT n few in DT because normal urine doesn’t contain glucose.- Transported by mean of 2o transport (symport) with Na+.- This process is dependant of insulin.

In PCT n DT:- Glucose concentration in: Tubule < Tubular Cells > Interstitial fluid < Arteriol.- At luminal membrane: a cotransport carrier transfers glucose against a concentration gradient n Na+ down a electro-chemical gradient from lumen into cell. Energy used is established by e Na+-K+ pump.- At basolateral membrane: glucose is transported down its concentration gradient from cell into e interstitial fluid through facilitated diffusion mediated by a passive glucose carrier.- This process requires e presence of Na+ in e lumen, or else, it won’t occur.

- No glucose reabsorbed here because all glucose has been reabsorbed through PCT n

DT.

a) Transport maximum, Tm:- Normally, carriers r not saturated with glucose, but when glucose ↑, they become saturated n results in glycosuria.- Max. amount that can be absorbed is called TmG = 375 mg/min (males) n 300 mg/min (females).b) Renal threshold, RT:- Means: E plasma concentration at which threshold substances 1st appear in urine.Normal value: 180 mg/dL.- ↑ TmG,↑ RT.

SODIUM, Na+ REABSORPTION

1) 70-80% in PCT.2) 5-20% in e LOH.3) 4-10% in DT.4) 2-3% in CD.

- Importance:1) Na+ is e electrolyte present in the

highest concentration in the blood.2) It is filtered and reabsorbed in e largest

amount.3) Its reabsorption consumes lots of

energy.4) Na+ is e major osmole in blood and

determines ECF volumes.

- On luminal (apical) membrane: [Na+] in e lumen is higher than in e cell, passive diffusion can occur

1) Na+/Glucose co-transport (symport)

2) Na+/Amino acid co-transport

3) Na+/Cl- co-transport4) Na+/H+ antiport

- On basolateral membrane: [Na+] in e cell is lower than in e interstitium, active transport is needed

1) Na+/K+ ATPase

1) Descending:- Impermeable to NaCl.Na reabsorption does not occur.2) THIN Ascending:- Permeable to NaCl.Na+ reabsorption is through passive diffusion.3) THICK Ascending:- On basolateral membrane: active transport through Na+/K+ ATPase.- On luminal membrane: co-transport with Cl-.

- On basolateral membrane: Active transport.- On luminal membrane:

1) Na+/Cl- co-transport

2) Na+/H+ antiport.

3) Na+/K+ antiport.

** In late distal tubule, Na+ is reabsorbed in exchange of either K+ or H+ whichever is in higher concentration under e influence of aldosteron.

- PLEASE REFER TO E NEXT PAGE -

BICARBONATE REABSORPTION

- 85-90% of filtered bicarbonate is reabsorbed in the PCT. The rest is reabsorbed by DT and CD.

- Filtered HCO3- cannot cross the luminal membrane INTO the cells.- It combines with H+ (under the influence of carbonic anhydrase, CA) to produce CO2 and H2O.- CO2 is lipid soluble, so it can diffuse into cell. E reverse reaction occurs catalyzed by CA to produce HCO3-.- HCO3- crosses the basolateral membrane via Na+/ HCO3- symport.

H+ SECRETION- The maximum

concentration gradient for H+ in tubular fluid is

when the pH in the tubular reaches 4.5

- Fate of H+:H+ needs to be removed from its original form or buffered or neutralized. It reacts with buffers:1) Reaction with filtered bicarbonate system HCO3- :

Both the cells in PCT n DCT secrete H+.

H+ is secreted from intracellular dissociation of H2CO3 which is catalyzed by enzyme

H+ is relatively independent of Na+ H+ is secreted by

1) Primarily, ATP driven proton pump2) H+ / K+ ATPase

Aldosterone influence the pump to increase H+ secretion

- Factors Affecting Acid Secretion:1) Intracellular PCO2 In respiratory acidosis, PCO2 is high, more H2CO3 is available to buffer hydrion (H+ + HCO3- H2CO3 → CO2 + H2O) ► more acid secretion

(limiting pH)- There will be no

further secretion of H+ beyond this point.- Consequences of

inhibition of H+ secretion:

1) Increase [H+] in plasma causing

metabolic acidosis.2) Urine will be too

acidic.- So, H+ has to be dealt

that with so that [ ] gradient is maintained n

that H+ continues to occur.

Titratable acidityRepresent the H+ which is buffered by alkali that must be added to urine to return its pH to 7.4. It

is mostly by H+ buffering by phosphate.

H+ + HCO3- H2CO3 → CO2 + H2OTakes place in prox tubule where there is carbonic anhydrase to facilitate CO2 + H2O formation.2) Reaction with disodium hydrogen phosphate/ dibasic phosphate to form monobasic phosphate.H+ + Na+ Na+ HPO42- → Na+ H2PO4-This mostly takes place in DT and CD where phosphate is greatly concentrated by the reabsorption of water.3) Reaction with ammoniaH+ + NH3 → NH4+Occurs in DT.

CARBONIC ANHYDRASE. For 1 H+ secreted into

luminal tubule, 1 Na+ and 1 HCO-3

In PCT, H+ is secreted through Na+ / H+ exchange (20 active transports).

The I cells (similar to parietal cell in GIT) secrete acid and contain abundant of carbonic anhydrase

I cells contain Band 3, an anion exchange protein which functions as a Cl- - HCO3- exchanger for the transport of HCO3- to the interstitial fluid.

2)K+ concentrationLoss of K+ enhances acid secretion, because ↓ K+ causes intracellular acidosis.3)Carbonic anhydrase levelIf carbonic anhydrase is inhibited, H2CO3 ↓ thus acid secretion is reduced.4) AldosteroneAs it enhances tubular reabsorption of Na+, acid secretion is enhanced.

POTASSIUM, K+ REABSORPTION N

SECRETION

- K+ balance is mainly by secretion that takes place in e distal tubule and e collecting ducts.- 90% is excreted by e kidney and e remaining 10% is lost in e stools.- K+ is regulated precisely as e cell f(x) is sensitive to changes in ECF [K+] (98% of [K+] is in e cell).- K+ excretion depends on :a) E rate of K+ filtration.b) E rate of K+ reabsorption in the tubule.c) E rate of K+ secretion by e tubule.

- Most of the filtered K+ is reabsorbed in the PCT.- Only 10% of filtered K+ reaches e distal tubule. Reabsorption is by active transportation via Na+ / K+ ATPase at e:

a) E PCT.b) E thick ascending limb of e

LOH.

- Secretion mostly occur at distal tubule and collecting duct- Cells that secrete K+ are called principal cells.- Secretion involves 2 step process:

1) Active transport of K+ into the cell2) Passive diffusion of K+ from the cell

into tubular fluid-The primary factors that control potassium secretion by the principal cells of late distal tubule and collecting duct are:

1) The activity of Na+/K+ ATPase pump2) The electrochemical gradient for K+

secretion from blood to tubular lumen3) The permeability of luminal membrane for

K+- Regulation is important to tightly regulate the plasma [K+] concentration to keep it within the normal range of 3.5 to 5.5 mEq/L- Cells are sensitive to changes in ECF [K+]. Both hyperkalemia and hypokalemia have undesirable effects.

-Takes place in DCT n CD.- When K+ intake is reduced or if there are extrarenal K+ losses, e kidneys adapt by excreting less K+ in the urine.1) Increase ECF potassium [ ].- 1 of e most important mechanism.- 3 mechanisms where ECF [K+] will ↑ secretion:a) Stimulates Na+/K+ ATPase pump. b) Increase K+ gradient from interstitium to intracellular fluid, prevent backleakage.c) Stimulates aldosterone secretion by adrenal cortex, which further stimulates K+ secretion (feedback mechanism)2) Aldosterone stimulates K+ secretion- Increase the permeability of luminal membrane for potassium.- Same with how it stimulates Na+ reabsorption.- Stimulating Na+/K+ ATPase pump on the basolateral membrane.- Increase Na+ and K+ channels in the luminal membrane.- Increase enzymes in the citric acid cycle that lead to energy production.3) Increase Distal Tubular Flow RateOccurs in:

a) Volume expansion.b) High sodium intake.

c) Diuretic drug treatment.- Conversely decrease tubular flow rate as in sodium depletion ↓ K+ secretion.