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

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

Zannad E, Eur J Pharmacol (Zannad E, Eur J Pharmacol (1982 1982 ) Jul 9; ) Jul 9; 8181((22):):263-71263-71

Cardiovascular PharmacologyCardiovascular Pharmacology

Drugs and blood vesselsDrugs and blood vessels Drugs and the heartDrugs and the heart

Major clinical indications:Major clinical indications: HypertensionHypertension Angina pectorisAngina pectoris Cardiac failureCardiac failure AtherosclerosisAtherosclerosis Cardiac arrythmiasCardiac arrythmias

Drug action on Drug action on blood vesselsblood vessels

Prof John FinbergProf John Finberg

Pharmacology DepartmentPharmacology Department

Rappaport Faculty of MedicineRappaport Faculty of Medicine

Cardiovascular pharmacologyCardiovascular pharmacology

Control of intracellular calcium Control of intracellular calcium concentration is a major target in drug concentration is a major target in drug action on the CV systemaction on the CV system

Determination of contraction of vascular smooth muscle in vitro

Endothelium dependent and Endothelium dependent and independent vascular effectsindependent vascular effects

Blood vessel with endothelium

Blood vessel without endothelium

Endothelium dependent and Endothelium dependent and independent vascular effectsindependent vascular effects

Vascular smooth muscle cell

Endothelial cell

Lumen

Extracellular space

Endothelium-dependent Endothelium-dependent vasodilatorsvasodilators

AcetylcholineAcetylcholine

HistamineHistamine

EndothelinEndothelin

5-HT5-HT

BradykininBradykinin

Substance PSubstance P

Endothelial cell

Vascular smooth muscle cell

[Ca++]i

eNOS eNOSeNOS

L-Arg NO

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

GPCR

Endothelial cell

Vascular smooth muscle cell

Agonist, shear stress

NOS

NO

EDHF

Gap junctionHyper-polarisation

Direct agonist

contractionrelaxation

COX

PGI2

L-type voltage-gated channel

Ca++

SRCa++[Ca++] i

contraction

GPCR

agonist

IP3

P2X

ATP

Ligand-gated cationic channel

PLC

NA, AII, TP, ET1, 5-HT

Vascular smooth muscle cell direct contractants

SR

Ca++[Ca++] i

contraction

Ca++ Calmodulin

MLCK MLCK*

Myosin LC Myosin LC-P*

Actin-myosin crossbridges

MLCK = Myosin light chain kinaseMyosin LC = myosin light chains

Smooth muscle contraction mechanism

relaxation

MLCP MLCP*MLCP*

Myosin LC-P*Myosin LC-P* Myosin LC

MLCP = Myosin light chain phosphatase

Smooth muscle relaxation: NO

cGMP

GC GC*GC*

NO

GMPPDE

relaxation

MLCP MLCP*MLCP*

Myosin LC-P*Myosin LC-P* Myosin LC

MLCP = Myosin light chain phosphatase

Smooth muscle relaxation: agonists

cGMP

MLCK

cAMP

IP, 2

K+

ANP

GC GC*GC*

PGI2Adren

Vasodilators: Organic NitratesVasodilators: Organic Nitrates

Amyl nitrite: Brunton found it effective for Amyl nitrite: Brunton found it effective for anginaangina

Nitroglycerin: converted enzymatically and Nitroglycerin: converted enzymatically and non-enzymatically to NO; veins>arteriesnon-enzymatically to NO; veins>arteries

Sodium nitroprusside: converted directly Sodium nitroprusside: converted directly (non-enzymatically) to NO; (non-enzymatically) to NO;

veins = arteriesveins = arteries

Alfred Nobel 1833-1896

Discoverer of DYNAMITE (nitroglycerin + kieselguhr)

Suffered from angina pectoris but refused to take nitroglycerin

Sodium nitroprusside (SNP)

NO

Non-enzymatic

Organic nitrates R-NO2

Enzymatic + non-enzymaticThiols SH RSNO

R-SNO

Calcium channelsCalcium channels

1: 1: voltage-operatedvoltage-operated Blocked by dihydropyridines etcBlocked by dihydropyridines etc Opened by Ca++ agonist drugs eg BayK-8644Opened by Ca++ agonist drugs eg BayK-8644 Blockade shows use-dependenceBlockade shows use-dependence

2: 2: receptor-operatedreceptor-operated Opened by agonist eg ATP Opened by agonist eg ATP Incompletely blocked by BayK-8644Incompletely blocked by BayK-8644 Blockade does not show use-dependenceBlockade does not show use-dependence

Voltage dependent Ca2+ channels

1. L-type (long-conducting, cardiac,

smooth and striated muscle, neuronal)2. T-type (Transient)

3. N-type (neuronal)

4. P/Q-type (Cerebral Purkinje cell)

5. R-type (rat brain)

L-type calcium channel structureL-type calcium channel structure

Voltage gated calcium channelsVoltage gated calcium channels

αα1 subunits confer pharmacological 1 subunits confer pharmacological characteristicscharacteristics αα1S skeletal muscle1S skeletal muscle αα1C cardiac, smooth muscle, neuronal1C cardiac, smooth muscle, neuronal αα1D endocrine/neuronal1D endocrine/neuronal

αα1subunits have1subunits have II – – IV domains, each domain IV domains, each domain has S1-S6 segments with SS1 and SS2 short has S1-S6 segments with SS1 and SS2 short loopsloops

Calcium channel blockersCalcium channel blockers Phenylalkylamines, eg verapamilPhenylalkylamines, eg verapamil Dihydropyridines, eg nifedipineDihydropyridines, eg nifedipine Benzothiazines, eg diltiazemBenzothiazines, eg diltiazem

HeartHeart blood vessels blood vessels

Verapamil >Verapamil > diltiazem diltiazem > nifedipine> nifedipine

CaCa++++ channel blockade channel blockade

Channels cycle between resting, Channels cycle between resting, open, inactivatedopen, inactivated

Affinity for blocking drug depends on Affinity for blocking drug depends on statestate

Blockers show greatest affinity for Blockers show greatest affinity for inactivation stateinactivation state

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

D B

P

EndothelinsEndothelins

NOS

NO

COX

PGI2ETBET1

ETB

ETA

contraction

ET1

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

Neutral endopeptidase (NEP) Neutral endopeptidase (NEP) inhibitorsinhibitors

Actions of NEPs :Actions of NEPs : Metabolism of atrial natriuretic peptide (ANP),Metabolism of atrial natriuretic peptide (ANP), Metabolism of AMetabolism of AIIII Similar function to Endothelin converting enzyme (big Similar function to Endothelin converting enzyme (big

ET ET ET1) ET1)

NEP inhibitors increase ANP NEP inhibitors increase ANP vasodilation; vasodilation; reduce ET reduce ET vasodilation; can increase A vasodilation; can increase AII II vasoconstrictionvasoconstriction

Candoxatril, orally active NEPI, reduces BP but Candoxatril, orally active NEPI, reduces BP but unpredictable responseunpredictable response

Phosphodiesterase inhibitorsPhosphodiesterase inhibitors

Caffeine, aminophylline: general PDE-Caffeine, aminophylline: general PDE-II Amrinone, milrinone, PDE3-Amrinone, milrinone, PDE3-II, vasodilator , vasodilator

and positive inotropesand positive inotropes Sildenafil (Viagara): PDE5 cyclic GMP Sildenafil (Viagara): PDE5 cyclic GMP

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

Ischemic heart diseaseIschemic 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 diseaseIschemic heart disease

In normal conditions, the increased coronary BF In normal conditions, the increased coronary BF in response to increased cardiac work is in response to increased cardiac work is mediated by NOmediated by NO

In coronary artery disease with plaque formation, In coronary artery disease with plaque formation, this mechanism is non-functionalthis mechanism is non-functional

As a result, direct vasodilator drugs, eg As a result, direct vasodilator drugs, eg dipyridamole, will not increase blood flow to dipyridamole, will not increase blood flow to ischemic area, but worsen the situation by ischemic area, but worsen the situation by causing “ischemic steal”causing “ischemic steal”

Stenosis of branchof coronary artery

Rang et al Pharmacology, 5th Edition, p280

“Ischemic steal”

Effect of nitrates

Angina pectorisAngina pectoris

Stable angina, treated with beta-blockers, Stable angina, treated with beta-blockers, Ca++ antagonists or nitratesCa++ antagonists or nitrates

Calcium antagonists, use verapamil type, Calcium antagonists, use verapamil type, reduce VOreduce VO2 2 during effortduring effort

variant angina, use vasodilator calcium variant angina, use vasodilator calcium blockers, eg nifedipine, amlodipine (long blockers, eg nifedipine, amlodipine (long acting)acting)

Additional treatments include aspirin, Additional treatments include aspirin, statins, dietstatins, diet

Pharmacological treatment of Pharmacological treatment of angina pectorisangina pectoris

Organic nitrates: NTG s/l, or isosorbide Organic nitrates: NTG s/l, or isosorbide dinitrate, isosorbide-5- mononitrate p.o. or dinitrate, isosorbide-5- mononitrate p.o. or s/ls/l

Therapeutic dose, reduce preload + Therapeutic dose, reduce preload + dilation of collateral vesselsdilation of collateral vessels

Excessive dose, reduces preload + Excessive dose, reduces preload + afterload afterload hypotension and tachycardia hypotension and tachycardia (detrimental)(detrimental)

Nitrates also reduce platelet aggregationNitrates also reduce platelet aggregation

Nitrates, side-effectsNitrates, side-effects

Relaxation of other smooth muscle, can relieve Relaxation of other smooth muscle, can relieve chest pain caused by esophageal spasmchest pain caused by esophageal spasm

Can potentiate or precipitate esophageal refluxCan potentiate or precipitate esophageal reflux Headache; tolerance developsHeadache; tolerance develops Tolerance to therapeutic effect minimised by Tolerance to therapeutic effect minimised by

intermittent dosing regimeintermittent dosing regime NBB: nitrates are contraindicated if patient is NBB: nitrates are contraindicated if patient is

taking phosphodiesterase inhibitor eg sildenafil taking phosphodiesterase inhibitor eg sildenafil (Viagra)!!(Viagra)!!

VasodilatorsVasodilators

NitratesNitrates Beta-adrenoceptor agonistsBeta-adrenoceptor agonists Alpha-1 adrenoceptor antagonistsAlpha-1 adrenoceptor antagonists Angiotensin antagonists (AT1 antagonists, ACE Angiotensin antagonists (AT1 antagonists, ACE

inhibitors)inhibitors) Calcium channel blockersCalcium channel blockers Potassium channel openersPotassium channel openers Endothelin antagonistsEndothelin antagonists PDE inhibitorsPDE inhibitors Hydralazine (mixed K+ opener and Ca++ antagonism)Hydralazine (mixed K+ opener and Ca++ antagonism)