NEBIVOLOL UNA ALTERNATIVA DIFERENTE EN EL MANEJO DE LA HTA

Y FALLA CARDIACA

DRA. BALKIS ROLONG CAROJefe de Recuperación CV y Rehabilitación Cardiovascular O.Clínica General del Norte

FELLOWSHIP: Insuficiencia Cardiaca –Prevención y Rehabilitación Cardiovascular MD.FAMILIAR

PROFESORA POSTGRADO MD INTERNA Y ANESTESIA FUSM

Hypertension and NO

Haemodynamic progressionof hypertension

• Early hypertension:Increased CO with relative increased SVR

• Established hypertension:Decreased CO and increased SVR

• Late hypertension:Decreased CO (25%) and markedly increased SVR (25%)

Houston MC. Primary Care Clin North Am 1991; 18:713-753.

2

Optimal approach to reduce high blood pressure

• Reduce SVR

• Preserve CO

• Improve arterial compliance

• Maintain organ perfusion

Houston MC. Primary Care Clin North Am 1991; 18:713-753.

3

Haemodynamic effects of mainantihypertensive classes

Calcium channel blockersACE-inhibitorsAngiotensin II (Ang-II) receptor blockers

• reduce SVR, preserve COand improve arterial compliance and perfusion

-blockers• initially they increase SVR, while in chronic therapy they

decrease SVR and riduce CO

Diuretics

• reduce SVR, CO and perfusion, and worsen arterialcompliance

Houston MC. Primary Care Clin North Am 1991; 18:713-753. Rachel RE. Conn’s Current Therapy 2000.

4

Structure of vascular endothelial cells

Transcellular

Junction-associated actinfilament system: actin, myosin and others

Basal lamina

Stress fibre (basal): actin and myosin-containing contractile fibrils

Para-cellular

Focal contact: integrins, talin, vinculin, alpha-actin and others

6

Main functions of endothelium

• Regulation of vasodilation and constriction

• Regulation of vascular permeability

• Regulation of leucocyte and platelet-vessel

wall interaction

• Vascular remodelling

Lüscher TF, Vanhoutte PM. The Endothelium: Modulator of cardiovascular function. CRC Press 1990, Boca Raton.

7

Endothelium-derived vasoactive factors

Adapted from Lüscher and Noll. In: Braunwald E. Heart Disease, 5th ed. Saunders; Philadelpia 1997.

8

Endothelium: physiological condition

Contracting factors:

• Endothelin 1

• Thromboxane A2

• Prostaglandin H2

Cosentino F, Lüscher TF. Eur Heart J 1995; 16:4-12.

Relaxing factors:

• NO

• Prostacyclin

• Endothelium-derivedhyperpolarizing factor

(EDHF)

9

Endothelium: impaired vascular function

Contracting factors:

• Endothelin 1• Thromboxane A2

• Prostaglandin H2

Relaxing factors:

• NO• Prostacyclin

• Endothelium-derivedhyperpolarizing factor

(EDHF)

• Ageing• Menopause

• Hypertension• Diabetes

• Hypercholesterolaemia

Cosentino F, Lüscher TF. Eur Heart J 1995; 16:4-12.

10

L-arginine/NO pathway

Endothelial cell

Vascular smoothmuscle cell

eNOS

L-arginine

NO

citrulline

GTP cGMP

NO

Relaxation (vasodilation)

Guanilatecyclase

Ignarro LJ et al. J Cardiovasc Pharmacol 1999; 34:876-884. Napoli C, Ignarro LJ. Nitric Oxide 2001; 5:88-97.

11

L-arginine/NO pathway inhibition

Endothelial cell

Vascular smoothmuscle cell

Constriction(vasoconstriction)

L-NMMA eNOS

L-arginine

NO (-)

citrulline

(-) NO(-) cGMP

Tousoulis D et al. J Am Coll Cardiol 1997; 25:1256-1262.

12

The NO system in thepathogenesis of hypertension

Decreased NO production; basal and after stimulation

Decreased endothelial vasodilationin response to acetylcholine

Increased vascular resistance

Essential hypertensionCalver A et al. J Hypertension 1992; 10:1025-31.

14

Nebivolol: pharmacological and therapeutic profile

Haemodynamicprofile

1-adrenoceptor antagonism

• Antihypertensive efficacy

• Tolerability profile

NebivololNebivolol

Endothelium-inducedNO-mediated effects

15

Nebivolol and NO release: endothelium induced effects

• Anti-proliferative effectIgnarro, Brehm

• Anti-oxidant activityDe Groot, Troost, Cominacini

• Anti-atherosclerotic activityBrehm, Napoli, Lüscher, Falciani, Kuroedov

• Endothelium-NO-dependent vasodilationIgnarro, Lüscher, Balligand, Broeders

20

Nebivolol: anti-proliferative effect

Arginine

Ornithine

Putrescine

Polyamines for Cell Growth

Spermidine Spermine

arginase

ODC

NO

NO

NebivololNebivolol

NOS

Ignarro LJ. Ann Rev Pharmacol Toxicol 1990; 30:535-560.

22

Effect of different -blockers on cell proliferation and metabolic activity

Nebivolol

Carvedilol

Metoprolol

Propranolol

10

30

50

70

90

110

130

150

Co 0.1 1 2 4 6 8 10

Pro

life

rati

on

(% c

on

tro

l)

-blocker (µmol/l)

BrdU-ELISA

0

20

40

60

80

100

120

140

Co 0.1 1 2 4 6 8 10

-blocker (µmol/l)

MTT-TEST

Brehm BR et al. J Cardiovascular Research 2001; 49:430-439.

*** *

**

*

*

**

*

*

*

**

*

*

*****

* p<0.01

(n=6)M

eta

bo

lica

cti

vit

y(%

co

ntr

ol)

23

Nebivolol: vasodilationin healthy volunteers

Effects of nebivolol and atenolol administered intra-arterially in two distinctoccasions, at equimolar doses, for 6 minutes on forearm blood flow

Nebivolol 0 18 88.5 177 354 (g/min)Atenolol 0 10 50.0 100 200 (g/min)

Nebivolol

Incr

ease

in F

BF

(%

)

Atenolol

-20

20

60

100

*

*

*

* p<0.01

Cockroft JR. J Pharmacol Exp Ther 1995; 274(3):1067-1071.

31

Nebivolol: decreases systemicoxidative stress

Troost R et al. Br J Clin Pharmacol 2000; 50:377-379.

8-i

so

-PG

F2

(pm

olm

mo

l-1c

rea

tin

ine

)

0

10

20

30

40

50

60

70

Placebo Nebivolol

55.3

42.3

24% reduction

* p<0.05

*

24

Nebivolol: inhibits in vitrohuman platelet aggregation

Falciani M et al. J Cardiovasc Pharmacol 2001; 38:922-929.

% a

gg

reg

ati

on

100

75

50

25

0

-6 -5 -4

% a

gg

reg

ati

on

120

100

80

60

40

-9 -8 -7 -6 -5 -4

NebivololCarvedilolPropranolol

*††*††

††

Log [antagonist]Nebivolol log [M]

NebivololNebivolol+L-arginineNebivolol+L-NMMA

ADP: aggregating agentValues represent mean ± SEM of n=5 experiments

* p<0.050 * p<0.05 nebivolol vs. propranolol† p<0.05 nebivolol vs. carvedilol† † p<0.01 nebivolol vs. carvedilol

**

*

**

*

26

0

10

20

30

40

50

60

70

80

90

100

Plaque reduction and improvementof endothelial dysfunction

Kuroedov A et al. ESC Vienna 2003.

Surface covered byplaques (% vs control)

Relaxation to 10-4 M acetylcholine (% vs control)

Control

Nebivolol

Atenolol*

* *

*

* p<0.05

27

*p<0.05

**

p<0.001

(n=12)

Tzemos N et al. Circulation 2001; 104:511-514.

Nebivolol: vasodilation inhypertensive patients

Placebo

Nebivolol

Atenolol50

0

40

0

30

0

20

0

10

0

0

Acetylcholine, nmol/min

25 50 100

**

**

*

*

L-NMMA, µ mol/min

0

-10

-20

-30

-40

-50

-60

-70

1 2

4

**

*

*

*

35

0

30

0

25

0

20

0

15

0

10

0

50

0

Sodium Nitroprusside, nmol/min

4.2 12.6 37.8

*

F

BF

%

33

Nebivolol blood lipid profile

Predel HG et al. J Hum Hypertens 2001; 15:715-721.

0

50

100

150

200

250

TotalCholesterol

(mg/dl)

LDLCholesterol

(mg/dl)

HDLCholesterol

(mg/dl)

LDL/HDL Triglycerides(mg/dl)

* p=0.0074

Before treatment at rest

After treatment at rest(Nebivolol 5 mg)

*(n=18)

85

Tolerability:Nebivolol vs Amlodipine

Mazza A. et al. Blood Pressure 2002; 11:182-188.

Nebivolol(n=81)

Amlodipine(n=87)

0

5

10

15

20

25

30

Total AEs Oedema Headache Flushing Dizziness Bradycardia

**

*

*

* p<0.05

** p<0.036

N.

of

dru

g r

elat

ed a

dve

rse

even

ts74

CONCLUSIONES LA DISFUNCION ENDOTELIAL DEBE SER CONSIDERA COMO

UN OBJETIVO EN EL TTO ANTIHIPERTENSIVO

NEBIVOLOL UNICO CON PROPIEDADES BENEFICAS Y DIRECTAS SOBRE ENDOTELIO A TRAVES DE VASODILATACION MEDIADA POR LA VIA DEL OXIDO NITRICO AUN EN PRESENCIA DE DISFUNCION ENDOTELIAL

IMPACTO NEUTRO A NIVEL METABOLICO

BIEN TOLERADO Y EFICAZ COMPORTAMIENTO HEMODINAMICO

DISMINUCION RESISTENCIA VASCULAR SITEMICA SIN AFECTAR GASTO CARDIACO

IMPACTO EN MORBIMORTALIDAD EN FALLA CARDIACA

“Hace 50 años teniamos pocos tratamientos para tratar las

enfermedades cardiovasculares, pero existía la relación Médico-Paciente, ahora

tenemos el conocimiento y existen tratamientos muy

eficaces pero no los utillizamos.Acercar este conocimiento a nuestros pacientes debe ser

una prioridad medica y social.”

Salim Yusuf