Cvs Vasodilators



The effects of digoxin and dopamine on the oxygen consumption, lactate production and haemodynamic performance of an isolated, perfused, working guinea-pig heart.



digoxin improves the haemodynamic performance of the heart without altering its metabolism and therefore increases its efficiency…. dopamine improves the haemodynamic performance of the heart at the expense of increased aerobic and anaerobic metabolism.



Zannad E, Eur J Pharmacol (1982 ) Jul 9; 81(2):263-71

Cardiovascular Pharmacology  Drugs

and blood vessels  Drugs and the heart  Major clinical indications:     

Hypertension Angina pectoris Cardiac failure Atherosclerosis Cardiac arrythmias

Drug action on blood vessels Prof John Finberg Pharmacology Department Rappaport Faculty of Medicine

Cardiovascular pharmacology

 Control of intracellular calcium

concentration is a major target in drug action on the CV system

Determination of contraction of vascular smooth muscle in vitro

Endothelium dependent and independent vascular effects

Blood vessel with endothelium

Blood vessel without endothelium

Endothelium dependent and independent vascular effects Lumen

Endothelial cell

Vascular smooth muscle cell Extracellular space

Endothelium-dependent vasodilators  Acetylcholine  Histamine  Endothelin  5-HT  Bradykinin  Substance P

Shear stress; Agonists, eg: ACh, BK, Hist, 5-HT, Substance P, ATP, ATII

Endothelial cell

GPCR

[Ca++]i ↑ eNOS → eNOS L-Arg → NO

Vascular smooth muscle cell

Agonist, shear stress

COX

PGI2 contraction

NOS

Endothelial cell

EDHF Gap junction Hyperpolarisation

NO relaxation

Direct agonist

Vascular smooth muscle cell

Vascular smooth muscle cell direct contractants Ligand-gated cationic channel

Ca

++

L-type voltagegated channel

NA, AII, TP, ET1, 5-HT

ATP

agonist

P2X

GPCR PLC IP3

[Ca++] i

Ca

++

contraction

SR

Smooth muscle contraction mechanism

Ca

++

[Ca++] i

Ca++ Calmodulin MLCK →

SR

MLCK*

Myosin LC →

Myosin LC-P*

Actin-myosin crossbridges contraction MLCK = Myosin light chain kinase Myosin LC = myosin light chains

Smooth muscle relaxation: NO NO

GC → GC* cGMP

PDE

GMP

MLCP → MLCP* Myosin LC-P* → Myosin LC relaxation

MLCP = Myosin light chain phosphatase

Smooth muscle relaxation: agonists K

PGI2

+

Adren

ANP

IP, β 2

GC → GC* cGMP

cAMP

MLCP → MLCP*

MLCK

Myosin LC-P* → Myosin LC relaxation

MLCP = Myosin light chain phosphatase

Vasodilators: Organic Nitrates  Amyl nitrite: Brunton found it effective for

angina

 Nitroglycerin: converted enzymatically and

non-enzymatically to NO; veins>arteries

 Sodium nitroprusside: converted directly

(non-enzymatically) to NO; veins = arteries

Alfred Nobel 1833-1896 Discoverer of DYNAMITE (nitroglycerin + kieselguhr) Suffered from angina pectoris but refused to take nitroglycerin

Sodium nitroprusside (SNP)

Organic nitrates R-NO2

Non-enzymatic

Enzymatic + non-enzymatic Thiols SH → RSNO

NO

R-SNO

Calcium channels 

1: voltage-operated   



Blocked by dihydropyridines etc Opened by Ca++ agonist drugs eg BayK-8644 Blockade shows use-dependence

2: receptor-operated   

Opened by agonist eg ATP Incompletely blocked by BayK-8644 Blockade does not show use-dependence

Voltage dependent Ca2+ channels •

L-type (long-conducting, cardiac, smooth and striated muscle, neuronal)

• T-type (Transient) • N-type (neuronal) • P/Q-type (Cerebral Purkinje cell) • R-type (rat brain)

L-type calcium channel structure

Voltage gated calcium channels  α1 subunits confer pharmacological

characteristics  α1S skeletal muscle  α1C cardiac, smooth muscle, neuronal  α1D endocrine/neuronal

 α1subunits have I – IV domains, each domain

has S1-S6 segments with SS1 and SS2 short loops

Calcium channel blockers  Phenylalkylamines, eg

verapamil  Dihydropyridines, eg nifedipine  Benzothiazines, eg diltiazem Heart Verapamil >

blood vessels diltiazem

> nifedipine

Ca channel blockade ++

 Channels cycle between resting,

open, inactivated  Affinity for blocking drug depends on state  Blockers show greatest affinity for inactivation state

L-type channels: sub-unit structure and CCB binding sites D

B

P

Endothelins ET1 COX ET1

ETB

NOS

PGI2

ETB

NO contraction

ETA Bosentan: ETA,B antagonist: useful in pulmonary hypertension, but hepatotoxic

Neutral endopeptidase (NEP) inhibitors 

Actions of NEPs :   





Metabolism of atrial natriuretic peptide (ANP), Metabolism of AII Similar function to Endothelin converting enzyme (big ET → ET1)

NEP inhibitors increase ANP → vasodilation; reduce ET → vasodilation; can increase AII → vasoconstriction Candoxatril, orally active NEPI, reduces BP but unpredictable response

Phosphodiesterase inhibitors  Caffeine, aminophylline: general PDE-I  Amrinone, milrinone, PDE3-I, vasodilator

and positive inotropes  Sildenafil (Viagara): PDE5 cyclic GMP inhibitor:  

Increases penile erection, affects color vision, Potential fatal combination with nitrates

Ischemic heart disease Cardiac work ∝ VO2 VO2 ∝ blood flow Increased work → increased demand for blood flow. Demand cannot be met, so get anaerobic metabolism, increased lactic acid production, and ischemic pain (angina pectoris)

Ischemic heart disease 

 

In normal conditions, the increased coronary BF in response to increased cardiac work is mediated by NO In coronary artery disease with plaque formation, this mechanism is non-functional As a result, direct vasodilator drugs, eg dipyridamole, will not increase blood flow to ischemic area, but worsen the situation by causing “ischemic steal”

Stenosis of branch of coronary artery

Rang et al Pharmacology, 5th Edition, p280

“Ischemic steal”

Effect of nitrates

Angina pectoris  Stable angina, treated with beta-blockers,

Ca++ antagonists or nitrates  Calcium antagonists, use verapamil type, reduce VO2 during effort  variant angina, use vasodilator calcium blockers, eg nifedipine, amlodipine (long acting)  Additional treatments include aspirin, statins, diet

Pharmacological treatment of angina pectoris  Organic nitrates: NTG

s/l, or isosorbide dinitrate, isosorbide-5- mononitrate p.o. or s/l  Therapeutic dose, reduce preload + dilation of collateral vessels  Excessive dose, reduces preload + afterload → hypotension and tachycardia (detrimental)  Nitrates also reduce platelet aggregation

Nitrates, side-effects     

Relaxation of other smooth muscle, can relieve chest pain caused by esophageal spasm Can potentiate or precipitate esophageal reflux Headache; tolerance develops Tolerance to therapeutic effect minimised by intermittent dosing regime NBB: nitrates are contraindicated if patient is taking phosphodiesterase inhibitor eg sildenafil (Viagra)!!

Vasodilators         

Nitrates Beta-adrenoceptor agonists Alpha-1 adrenoceptor antagonists Angiotensin antagonists (AT1 antagonists, ACE inhibitors) Calcium channel blockers Potassium channel openers Endothelin antagonists PDE inhibitors Hydralazine (mixed K+ opener and Ca++ antagonism)