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)
