ANS receptors

8/7/2019 ANS receptors

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y Vascular smooth muscle. Activation of vascular smooth muscle receptors

causes vasoconstriction, leading to an increase in peripheral resistance and in

blood pressure. Alpha 1 antagonists are used in the treatment of hypertension

because of their properties as peripheral vasodilat ors.

y Mydriasis. Mydriasis is mediated by both alpha 1 and 2 activation.

y Genitourinar y tract smooth muscle. Alpha 1A receptors are located at the

external sphincter of the bladder. Blockade of alpha 1A receptors decreases tone

in the smooth muscle of the bladder neck and prostate, thus improving urinary

flow. Tamsulosine is used for the treatment of benign prostatic hyperplasia

because of its ability to selectively block alpha 1A receptors.

Alpha 2 receptors

Although alpha 2 receptors are found on both presy naptic neurons andpostynaptic cells, they work mainly as autoreceptors to mediate feedback

inhibition of sympathetic transmission.

In addition to neurons, alpha 2 receptors are located in other regions, like

pancreatic beta cells and platelets.

The diagram below shows how when activated, these receptors act as inhibitory

autoreceptors (they inhibit norepinephine release from adrenergic neurons) and

as inhibitory heteroreceptors (they inhibit acetylcholine release from cholinergic

neurons).

In addition, activation of alpha 2 receptors on pancreatic beta cells membranes

inhibits insulin release.



Drugs affecting alpha receptors

Alpha 1 agonists



Because of their properties as vasoconstrictive agents they are used to reduce

edema and inflammation. Common decongestant drugs include naphazoline,

phenylephrine and propylhexedrine.

Alpha 1 antagonists

These drugs act by causing vasodilation and decreased peripheral resistance,

therefore they are used in the treatment of hypertension ( prazosin). Treatment of

benign prostatic hyperplasia is another clinical use of alpha 1 antagonists:

tamsulosin is a subtype-selective alpha 1A receptor that has more specificity

toward smooth muscle in genitourinary tract; thus tamsulosin has lower incide nce

of orthostatic hypotension.

Alpha 2 agonists

By activating central alpha 2 receptors, alpha 2 adrenergic agonists inhibit

sympathetic outflow from CNS. Clonidine is used for the rteatment of

hypertension and symptoms associated with opioid withdrawal. Alpha-

methyldopa is a precursor to the alpha 2 agonist alpha -methylnorepinephrine, it is

the drug of choice for the treatment of hypertension during pregnancy.

Alpha 2 antagonists

Yohimbine blockade of alpha 2 receptors leads to increased release of

norepinephrine with susequent stimulation of cardiac beta 1 receptors and

peripheral vasculature alpha 1 receptors. Yohimbine was used in the past to treat

erectile dysfunction.

Beta receptors are a subtype of adrenergic receptor (adrenoceptor), their

activation triggers a sympathomimetic (adrenergic) response. This article

overviews the characteristics related to their physiology and pharmacological

aspects. In addition, a related article discu sses alpha receptors.

Contents:

- Structure and general characteristics

- Location and physiology of Beta 1 Adrenergic Receptors

- Location and physiology of Beta 2 Adrenergic Receptors

- Weight control Beta 3 Adrenergic Receptors



Structure and general characteristics

Beta receptors are G-protein coupled receptors, they act by ac tivating a Gs

protein. Gs activates adenylyl cyclase, leading to an increase in levels of

intracellular cAMP. Increased cAMP activates protein kinase A, which

phosphorylates cellular proteins.

Beta receptors are characterized by a strong response to isopro terenol, with less

sensitivity to epinephrine and norepinephrine. The rank order in terms of potency

is the following:

isoproterenol > epinephrine > norepinephrine

Beta receptors are subdivided into three subgroups, beta 1, 2, and 3. This

division is mainly based on their affinities to adrenergic agonists and antagonists.

Beta 1 receptors

Beta 1 receptors are located mainly at the heart and the kidney, their main effects

are depicted below.



Heart

- Increase in chronotropy (heart rate) and inotropy (force of contraction)

Tachycardia results from a Beta 1 mediated increase in the rate of phase 4

depolarization of sinoatrial node pacemaker cells. The inotropic effect is mediated

by increased phosphorylation of Ca ++ channels, including calcium channel s in

the sarcolemma and phospholamban in the sarcoplasmatic reticulum

- Increase in AV- node conduction velocity

Beta 1 stimulated increase in Ca entry increases the rate of despolarization of AV

node cells.

Kidney

Beta 1 receptors are present mainly on yuxtaglomerular cells, where receptor

activation causes renin release.

Beta 2 receptors

In this section Beta 2 receptors will be studied in two diagrams. The first

highlights effects after Beta 2 activation in two systems (respiratory and

reproductive), this is viewed separately because of the clinical relevance of Beta



2 agonists in clinical practice. The second figure shows the remaining

sympathomimetic effects elicited by Beta 2 receptor activation in other systems.

Bronchial smooth muscle

Beta 2 receptor activation promotes bronchodilation, this physiological property

is enhanced by inhaled Beta 2 agonists used in the treatment of asthma and

COPD. Some drugs under this category include: salbutamol (albuterol in the US),

salmeterol, formoterol and terb utaline.

Uterine contraction

Drugs that bind to Beta 2 receptors (Beta 2 agonists) are used in the treatment of

premature labour, this clinical application illustrates how Beta 2 receptors

mediate tocolysis on the uterine muscle. Ritodrine is an example of a tocolytic

drug.



Bladder detrusor muscle: adrenergic activation of Beta 2 receptors at the

bladder promotesrelaxation. Bladder constriction is activated by the

parasympathetic system, therefore drugs that activate muscarinic receptors such

as bethanechol are used in the treatment of urinary retention.

Eye ciliar y muscle : this muscle controls eye accomodation and regulates the

flow of aqueous humour. Its sympathetic innervation is mediated by Beta 2

receptors.

GI tract: adrenergic activation of the gastrointestinal tract produces a slowing of

peristaltic movements (decreased motility) and secretions. These changes are

mediated by Beta 2 receptors.

Liver: hyperglycemia and lipolysis occur when Beta 2 receptors are activated.

Glucose metabolism is potentiated through gluconeogenesis and glycogenolysis.

Vascular smooth muscle: while Alpha 1 receptors mediate vasoconstriction,

Beta 2 receptors induce vasodilation in muscle and liver.



Beta 3 receptors

It has been recently proposed that Beta 3 receptors are linked to the regulation

of body weight.Located mainly in adipose tissue, Beta 3 receptors promote

lipolysis.

ACETYLCHOLINE RECEPTORS:

A number of drugs target acetylcholine receptors, blockade of these receptors is

associated with anticholinergic ( parasympatholytic) effect, while stimulation

causes activation of cholinergic (parasympathomimetic) effects.

This articles overviews the key concepts on the pharmacology of acetylcholine

receptors, such as:

What happens after acetylcholine is released?

Classification of acetylcholine receptors

Location

Acetylcholine receptors and the autonomic nervous system

Muscarinic receptors

Nicotinic receptors

What happens after acetylcholine is released?

Acetylcholine is released from a presynaptic neuron into the synaptic cleft. Once

in the synaptic gap, acetylcholine can:

- Bind to presynaptic receptors: presynaptic activation or inhibition leads toautomodulation of the presynaptic cholinergic neuron.

- Be degradated by acetylcholinesterase: activity of this enzime on acetylcholine

triggers its degradation into choline and acetyl coenzime A, thus terminating its

effect.



- Bind to postsynaptic receptors: activation of these recep tors by acetylcholine

leads to cholinergic response.

Classification of acetylcholine receptors

The figure below shows the two main families of acetylcholine receptors:

muscarinic and nicotinic. In structural terms, muscarinic receptors are G -coupled

protein receptors, while nicotinic receptors are ligand -gated ion channels. They

can be found on both sides of the synaptic cleft (presynaptic and postsynaptic).

However, for clinical purposes, we are focusing only on postsynaptic receptors.

Location of acetylcholine receptors

Acetylcholine is a key neurotransmitter acting on a wide number of functions andtissues. This figure shows the three main locations of acetylcholine receptors:

CNS receptors

(muscarinic and nicotinic): cholinergic neurotransmission at the CNS level is

thought to regulate sleep, wakefulness, and memory. Two clinical situations

depict the role of acetylcholine in CNS:

- Acetylcholinesterase inhibitors are used in the treament of Alzheimer¶s disease

and other dementias. Inhibition of the enzime that catalyzes acetylcholine



degradation (acetylcholinesterase) produces an increased concentration of

acetylcholine at the synaptic cleft, thus potentiating cholinergic

neurotransmission. Examples of these drugs include donepezil and rivastigmine.

- Drugs that possess anticholinergic properties may cause acute encephalopathy,

such as delirium or a confusional state. Some over -the-counter medications such

as diphenidramine (an antihistamine) can cause cholinergic blockade that may

lead to a decompensation of underlying cognitive, functional and behavioral

deficits (particularly in patients with Alzheimer¶s disease).

Autonomic receptors: they are present both in adrenergic and cholinergic

transmission. They are discussed in the next section.

Neuromuscular junction: acetylcholine receptors at the neuromuscular

junction are exclusively nicotinic, they belong to the N N subtype.

Acetylcholine receptors and the autonomic nervoussystem

Acethylcholine acts on central and peripheral nervous systems ( the lat ter is

divided into somatic and autonomic). The autonomic nervous system (ANS)

exerts its actions through its two antagonic branches: sympathetic ( adrenergic)

and parasympathetic (cholinergic).

Looking the diagram below we can see that both sympathetic a nd

parasympathetic branches are modulated at the preganglionic level by the

neurotransmitter acetylcholine. This molecule binds nicotinic receptors at the

autonomic ganglia to trigger the release of norepinephrine (if a sympathetic

synapse is stimulated) or acetylcholine that binds to tissue muscarinic receptors,

which will produce a parasympathetic or cholinergic response.



Muscarinic receptors

Muscarinic receptors bind both acetylcholine and muscarine , an alkaloid present

in certain poisonous mushrooms (it was first isolated in Amanita muscaria).

Cholinergic transmission (acetylcholine-mediated) that activates muscarinic

receptors occurs mainly at autonomic ganglia, organs innervated by the

parasympathetic division of the autonomic nervous system and in the central

nervous system.

All muscarinic receptors are G-protein coupled receptors. Binding studies have

identified five subclasses of muscarinic receptors: M 1,M2, M3, M4, and M5. The

image below shows their locations:



M1, M4 and M5 receptors: CNS. These receptors are involved in complex CNS

responses such as memory, arousal, attention and analgesia. M1 receptors are

also found at gastric parietal cells and autonomic ganglia.

M2 receptors: heart. Activation of M2 receptors lowers conduction velocity at

sinoatrial and atrioventricular nodes, thus lowering heart rate.

M3 receptors: smooth muscle. Activation of M3 receptors at the smooth muscle

level produces responses on a variety of organs that inc lude: bronchial tissue,

bladder, exocrine glands, among others.

Nicotinic receptors

Unlike muscarinic receptors (which are G-protein coupled receptors), nicotinic

receptors are ligand-gated ion channels. When bound to acetylcholine , these

receptors undergo a conformational change that allows the entry of sodium ions,

resulting in the depolarization of the effector cell.

Nicotinic receptors can be divided as the diagram shows:



N1 or NM receptors: these receptors are located at the

neuromuscular junction, acetylcholine receptors of the N M subtype are the only

acetylcholine receptors that can be found at the neuromuscular junction.

N2 or

NNreceptors: as mentioned before, nicotinic receptors play a key role in

the transmission of cholinergic signals in the autonomic nervous systems.

Nicotinic receptors of the NN subtipe can be found both at cholinergic and

adrenergic ganglia, but not at the target tissues (e.g, heart, bladder, etc). These

receptors are also present in the CNS and adrenal medulla.

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ANS receptors