Antiarrhythmic and hemodynamic effects of calcium channel blocking agents during coronary arterial reperfusion (original) (raw)
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Circulation, 1984
The calcium channel-blocking drugs verapamil, diltiazem, and nifedipine are being used with increasing frequency in patients with angina pectoris due to coronary artery disease. Although each of these agents possesses negative inotropic potential, their relative effects on myocardial function in relation to their vasodilator potencies are unknown. We undertook to study this in 20 conscious dogs that had partial occlusions of their circumflex coronary arteries during therapy with placebo, verapamil, nifedipine, or diltiazem. Myocardial blood flow was measured by use of microspheres, and left ventricular function was measured by radionuclide angiography. Drug effects were compared at doses causing equal decreases in mean arterial pressure and coronary vascular resistance of nonischemic myocardium. Global ejection fraction and ejection fraction of the ischemic region were significantly decreased by verapamil (p < .01) and increased by nifedipine (p < .001); diltiazem caused no significant changes. Verapamil significantly increased peak diastolic filling rate (p < .001); nifedipine also increased diastolic filling rate, but only at doses that markedly decreased mean arterial pressure and coronary vascular resistance. The effect of diltiazem on diastolic filling rate was not significantly different than placebo. For doses causing an equal decrease in mean arterial pressure, verapamil decreased heart rate (p < .001), and diltiazem and nifedipine increased heart rate (p < .001). We conclude that the relative potencies of these three calcium channel-blocking agents on left ventricular systolic and diastolic function during myocardial ischemia are different when compared with their relative vasodilator potencies. These differences may have important clinical implications.
Calcium-channel blockers: possible mechanisms of protective effect on the ischemic myocardium
~-'1'8ll_v of Cincinnati College u{ 1.\1edicine, Cincinnati. Ohio \'a:-;cular Effects of Cakium-Channt>l Blockers Pre:-<=·tne-fl(>W relationships in the circumflex and left anterior de;;cendinF: eoronar:-arteries CorP nary arterial m·dusion pressures and back now of blood from lT~nplete\y ueduded coronary artt>ries l~t•J.(itllt:JIIlnw rlislrihutit•n actions, actions in ischemia, and finally, a summary of potential mechani:-:;m:;. CALCIUt\1 ANTAGONISTS A.:"JD ISCHEMIC MYOCAHDIL'~, . . t 193 VASCULAR EFFECTS OF CALCIUM·CHANNEL BLOCKERS All the divt:rse chemical agents that are loosely clas:->ified as Ca:!+ antagonists are· p'ut.ent relaxers of vascular smooth muscle and act probably by inhibiting some Ca 1 --dependent event. For example, in porcine coronary artery strips in vitro, nifedipine I> 10_, Ml, verapamil (> w-' M), and diltiazem (> 10-' MJ exert relaxant actions . Coronary flow in dogs is increased by nifedipine (11) and diltiazem (8). Coronary collateral flow to the ischemic myocardium is increased by verapamil (13) and diltiazem (8). Interestingly these agents appear to have different effects depending on whether the vessel is activated by a receptor-mediated pathway or by a voltage-dependent (e.g., KCI) site or sites . The vascular effects of diltiazem and nisoldipine on coronary blood flow can be den10nstrated in dogs with separately controlled and perfused circumflex and left anterior descending coronary arteries (Ftg. 3). Dogs were anesthetized with pentobarbital sodium (30 mg/kg iv), anticoagulated with heparin sodium (5,000 L USP/kg iv), and artificially respired. The chest was opened in the left 5th intercostal space, and a pericardia} cradle was cohstructed to support the hear·t. The left carotid artery was connected to the left circumflex coronary artt>ry, :mel the femoral artery to the left des{'ending coronary artery. Coronal',\' flow in both aneries was kept conswnL and independent. by in-line adjustable fin~er pu111ps. Ml•an l'OI'O!Hll)' perfusion pressureH were made equal to Lht• s.vstemil' systolic arterial blood pres:-;ure. Control coronary flows ranged be· twe!!ll .:to and HO ml/min. Contractile force of the lefl ventricle was recorcil'd from a sLrain ~au~e sulurt~d to the anterior wall close to Lhe apex of the hearL · Hearl ratt•, elertrocardiogram, aortic pressure, coronary pressures, coronary.· flows, contractile force, lefl ventricular pres.-;ure (LVP), and the dP/dt of the LVP were recorded on a Grass P7 polygraph. The flows were measured by Biotronex electromag-netic flowmeters. This permitted us to change flow and; or pressure in one or both of the perfused areas. \Ve cot 1 tld stop anlegrade flow and collect retrograde blood to assess collateral flow during complete coronary t'HL 2. Potential sites of action, of Ca~· anta..:onist. Site I, Pxterior of sar· l'Oh·mma; sill':!. inside sarcolemma (po:>· sihlv via ralmudulin oceupam·.v and/or phospholipids); site :J, on innl'r surfal'e of . .;;arcolemma; site 4, mitoehomirial membrane; site 5, san:oplasmic reticulum; site G, t ruponin, t ropomyu;-;in. actin, and tll,\'osin.
The American Journal of Cardiology, 1982
The effects of dlltlazem, nisoldiplne (a nifedipine derivative) and verapamil on electrical and mechanical activity were s.tudied in isolated canine Purkinje fibers and in Isolated human atrial appendage. The actions of these three drugs on atrioventricular (A~V) conduction and coronary resistance were studied in open chest dogs In which autonomic effects were minimized by alpha and beta teceptor blockade, bilateral vagotomy and atrial pacing after' crushing of the sinus node •.
Differential cardiovascular effects of calcium channel blocking agents: Potential mechanisms
The American Journal of Cardiology, 1982
The three major calcium channel blocking agents, diltlazem, nifedlpine and verapamil, inhibit calcium entry Into eX,"itable cells. Despite this apparent common action at the cell membrane, these drugs produce quantitative and frequently qualitative differences in cardiovascular variables (for example, heart rate, atrioventricular [A-V] conduction and myocardial inotropiC state) when evaluat.ed at ~quieHective vasodilator doses. All three drugs increase coronary blood flow in a dose-dependent fashion (nlfedipine > dlltlazem = verapamill, and produce a negative Inotropic effect in vitro In isolated atria and ventricles, also in a dose~ dependent manner (verapamil > nlfedipine >dittiazem). However, in conscious dogs nifedipine increases, verapamil decreases and diltiazem has little effect on the inotropiC state. Ax V conduction is slowed by diltlazem and verapamil but not by nifedlpine in~"esthetized dogs and In conscious dogs as judged from the P .. R interval·ln the electrocardiogram, Heart rate is slowed in pentobarbital"anesthetized anlma.ls but is accelerated in conscious dogs (nifedipine > verapamil > diltiaze~). Nifedipine also appears to interfere significantly with the arterial baroreceptor reflex by an apparent vagolytic action that is less evident with diltiazem and verapamil. Oiltiazem, and possibly verapamU and nifedipine as well, appears to retard myocardial damage that accompanies ischemia. The mechanisms and sites of action of these drug~ are presumed to be at the cell membrane; however, .intracellular sites may also be involved.
Effects of intravenous verapamil on cardiac arrhythmias and on the electrocardiogram
American Heart Journal, 1975
Numerous compounds of varying potencies are now available for the control of clinical and experimental cardiac arrhythmias.* Many of the new agents, such as beta-adrenergic receptor blocking drugs and amiodarone,3 have anti-angina1 as well as antiarrhythmic properties. Another such compound is verapamil, whose antiarrhythmic action appears to be markedly different from that of other compounds.', * It was originally considered to be a potent coronary dilator" and was subsequently found to be effective in the treatment of angina pectoris.6 Its antiarrhythmic actions, well demonstrated in experimental animals,'-'0 have recently been confirmed in a number of preliminary clinical studies,"-" although its complete spectrum of therapeutic use remains to be fully evaluated. The exact mechanism of action of verapamil is also not completely understood. However, the drug has aroused great interest because of the possibility that its salutary effects in arrhythmias may be related to the property of specifically and selectively inhibiting depolarizing calcium currents in the heart.', I". l5 In this report, we present the results of our studies of its effect after intra
Calcium-Channel Blockers Preserve Coronary Endothelial Reactivity After Ischemia-Reperfusion
The Annals of Thoracic Surgery, 1997
Calcium-channel blockers have been reported to improve myocardial recovery after ischemia-reperfusion, but their effects on coronary blood flow regulation remain to be defined. Experiments were designed to evaluate the effects of calcium antagonists on coronary artery vasoregulation exposed to ischemia-reperfusion. Three groups of hearts (n = 6) were pretreated with a 10-minute infusion of either diltiazem, verapamil, or nifedipine at concentrations of 10(-9) mol/L to 10(-6) mol/L and exposed to 30 minutes of no-flow ischemia and 45 minutes of reperfusion. Another group (n = 6) received no pretreatment and was used as control. Endothelium-dependent and -independent relaxations were tested by assessing coronary flow increase to 5-hydroxytryptamine (10(-6) mol/L) and sodium nitroprusside (10(-5) mol/L) infusion, respectively. Left ventricular pressure, its first derivative, and coronary basal flow were recorded before and after ischemia as well as during calcium antagonist infusion. Endothelium-dependent relaxation after ischemia was significantly improved with all three drugs in a dose-dependent fashion; nifedipine was found to be the more potent. Endothelium-independent relaxation was also significantly preserved with calcium antagonists regardless of the type, whereas left ventricular hemodynamics were not. During perfusion, nifedipine was found to have the most negative inotropic effect and to be the most potent vasodilator on the coronary circulation. Diltiazem was the less effective drug on both left ventricular hemodynamics and coronary circulation. This study indicates that preischemic infusion of calcium antagonists enhance endothelium-dependent and -independent coronary artery relaxation in the isolated rat heart model in a dose- and drug-dependent fashion. This can be achieved at low doses without affecting left ventricular hemodynamics and should contribute to preserve coronary artery autoregulation.
The American Journal of Cardiology, 1977
The effects of various drugs on delayed activation of the ischemic myocardium and the incidence of ventricular arrhythmias were studied in 34 open-chest anesthetized dogs. The left anterior descending coronary artery was occluded for 6 minutes before and 6 minutes and 42 minutes after administration of aprindine (2.55 mg/kg body weight), quinidine (8 mg/kg) and verapamil (0.2 mg/kg) and during infusion of isoproterenol (0.2 #g/rain). The time intervals from the onset of the QRS complex to the major deflection of the bipolar electrograms recorded within the normal and ischemic zones were measured at cycle lengths of 500, 400 and 300 msec and were correlated with the development of ventricular arrhythmlas. At a cycle length of 500 msec, aprindine increased by 19.5 msec the delay in activation Ume produced by coronary ligaUon alone (P <0.05), whereas verapamii reduced by 10 msec the extent of isohemia-induced conduction delay (P <0.05). The delay in activation time in the ischemic zone was not significantly altered by quinidine or isoproterenol. The incidence of ventricular arrhythmias was increased by aprindine (from 1 in 11 to 8 in 11 dogs), decreased by verapamil (from 3 in 7 to 0 in 7 dogs)and was not changed by quinidineor isoproterenol. Thus, delayed activation of the ischemic myocardium appears to play an important role in the genesis of early arrhythmias due to myocardial ischemia, and drugs that significantly depress conduction in the ischemic myocardium may predispose to the development of ventricular arrhythmia whereas those that improve conduction may be protective. Contrary to their effects on slow channel'dependent conduction, verapamil improved and isoproterenol worsened conduction during ischemia.
International Journal of Medical Research & Health Sciences, 2013
Background: Calcium channel blockers block voltage dependent L-type of calcium channel and thus reduce the frequency of opening of these channels in response to depolarization. The result is a marked decrease in transmembrane calcium current associated with long lasting relaxation of vascular smooth muscle, reduction in contractility in cardiac muscle, decrease in pacemaker activity in the SA node and decrease in conduction velocity in the AV node. Among Calcium channel blockers verapamil, is cardio selective, nifedipine is vascular smooth muscle selective, while diltiazem exhibits intermediate selectivity. Methods: In the present study, the effect of two Ca ++ channel blocker, Verapamil and Diltiazem were compared on the isolated frog heart by using adrenaline & calcium chloride as standard on frog heart contractility. Results and conclusion: Adrenaline and calcium chloride increased the amplitude of contraction of isolated perfused frog heart. The L-type of Ca 2+ channel blockers verapamil and diltiazem produced dose dependent (2µg, 4µg, 8µg, and 16µg) reduction in the amplitude of contraction produced by calcium chloride in isolated perfused frog heart. There was no statistical significant difference (p > 0.05) between the inhibitory effect of diltiazem and verapamil on calcium chloride induced contraction of isolated frog heart.