 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 Blood vessel without

endothelium 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
Endothelial cell

COX NOS EDHF

PGI2 NO Gap junction

Hyper-
polarisation
contraction
relaxation

Direct agonist
Vascular smooth muscle cell
 Vascular smooth muscle cell direct contractants

Ligand-gated
cationic channel
NA, AII, TP, ET1, 5-HT
++
Ca ATP agonist

L-type voltage- P2X GPCR PLC

gated channel IP3

[Ca++] i ++
Ca SR

contraction
Smooth muscle contraction mechanism

[Ca++] i
++
Ca
SR
Ca++ Calmodulin

MLCK → 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*
PDE
cGMP 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 blood vessels

Verapamil > 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 NOS

ET1 ETB 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)