Diltiazem and verapamil reduce the loss of adenine nucleotide metabolites from hypoxic hearts

The present study was undertaken to elucidate possible mechanisms for a protection of myocardial cells from hypoxia-induced derangements in cardiac function and metabolism by calcium antagonists. For this purpose, rabbit hearts were perfused for 20 min under hypoxic conditions in the presence of 312 ng/ml diltiazem or 125 ng/ml verapamil, and then for 45 min under reoxygenated conditions. Metabolic changes in the myocardium and the perfusate were examined throughout. Hypoxia induced a marked decline in myocardial high-energy phosphates and an immediate release of ATP metabolites, such as adenosine, inosine and hypoxanthine, from the perfused heart. These changes were effectively depressed by diltiazem and verapamil. Hypoxia and subsequent reoxygenation resulted in a release of creatine phosphokinase from the heart, which was completely inhibited by the treatment with either diltiazem or verapamil. Myocardial calcium contents were increased by 20 min-hypoxic perfusion. Both diltiazem and verapamil are capable of preventing hypoxia-induced increase in the transmembrane flux of cellular components, which may be beneficial for the preservation of substances necessary for the ATP regeneration after hypoxia and for the inhibition of calcium overload in cardiac cells.     

Calcium antagonists and myocardial infarction

In vitro and in vivo studies have demonstrated many similarities between the three calcium antagonists verapamil, nifedipine, and diltiazem in relation to protection of the myocardium during hypoxia. Important clinical differences exist between the three drugs when they are used during or after an acute myocardial infarction with the purpose of preventing death and reinfarction. The balance between the negative inotropic and the vasodilator properties and concomitant treatment with beta blockers may explain the results of clinical trials with the three calcium antagonists. Patients not treated with beta blockers. Nifedipine has been demonstrated to be no better than placebo both during and after an acute myocardial infarction. No placebo-controlled studies exist with diltiazem. Verapamil had no effect during the acute phase of a myocardial infarction. After a myocardial infarction, verapamil improved survival and reduced the reinfarction rate, an effect primarily found in patients without heart failure in the coronary care unit. Patients also treated with beta blockers. Nifedipine prevents the development of myocardial infarcts in patients with unstable angina. Diltiazem probably prevents reinfarction in the first two weeks after non-Q-wave infarction. Secondary prevention with diltiazem after an acute myocardial infarction had no overall effect on death or cardiac events (i.e., reinfarction or cardiac death). Subgroup analysis demonstrated in diltiazem-treated patients, compared with placebo-treated patients, a significant reduction of cardiac events in patients without and a significant increase of cardiac events in patients with heart failure. At present no indications exist for nifedipine during or after a myocardial infarction; further studies are needed with diltiazem, and verapamil may be used in secondary prevention of death and reinfarction.     

Differential cardiovascular effects of calcium channel blocking agents: potential mechanisms

The three major calcium channel blocking agents, diltiazem, nifedipine and verapamil, inhibit calcium entry into excitable 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 evaluated at equieffective vasodilator doses. All three drugs increase coronary blood flow in a dose-dependent fashion (nifedipine greater than diltiazem = verapamil), and produce a negative inotropic effect in vitro in isolated atria and ventricles, also in a dose-dependent manner (verapamil greater than nifedipine greater than diltiazem). However, in conscious dogs nifedipine increases, verapamil decreases and diltiazem has little effect on the inotropic state. A-V conduction is slowed by diltiazem and verapamil but not by nifedipine in anesthetized dogs and in conscious dogs as judged from the P-R interval in the electrocardiogram. Heart rate is slowed in pentobarbital-anesthetized animals but is accelerated in conscious dogs (nifedipine greater than verapamil greater than diltiazem). Nifedipine also appears to interfere significantly with the arterial baroreceptor reflex by an apparent vagolytic action that is less evident with diltiazem and verapamil. Diltiazem, and possibly verapamil and nifedipine as well, appears to retard myocardial damage that accompanies ischemia. The mechanisms and sites of action of these drugs are presumed to be at the cell membrane; however, intracellular sites may also be involved.     

Cardiotrophin-1 (CT-1) can protect the adult heart from injury when added both prior to ischaemia and at reperfusion

OBJECTIVES: To determine whether the cytokine cardiotrophin-1 (CT-1) can protect the adult heart against ischaemia/reperfusion when added either prior to ischaemia or at reperfusion. BACKGROUND: CT-1 has previously been shown to protect cultured embryonic or neonatal cardiocytes from cell death. To assess the therapeutic potential of CT-1, it is necessary to determine whether this effect can be observed in adult cardiac cells both in culture and most importantly in the intact heart. METHODS: We examined the protective effect of CT-1 both in cultured adult rat cardiocytes and in the rat intact heart. In both cases, the cardiac cells were exposed to hypoxia/ischaemia followed by reoxygenation/reperfusion and CT-1 was administered either prior to hypoxia/ischaemia or at reoxygenation/reperfusion. RESULTS: CT-1 has a protective effect in reducing ischaemic damage in the intact heart ex vivo as assayed by infarct size to area at risk ratio (20% compared to 35%). Similar protective effects against cell death were noted in adult cells in vitro. Both in vitro and ex vivo CT-1 can exert a protective effect when added at the time of reoxygenation/reperfusion as well as prior to the hypoxic/ischaemic stimulus (cell death reduced from 50 to 20% in TUNEL assay, infarct size to zone at risk ratio reduced from 35 to 20%). These protective effects are blocked by an inhibitor of the p42/p44 MAPK pathway. CONCLUSION: CT-1 can protect adult cardiac cells both in vitro and in vivo when added both prior to or after the hypoxic/ischaemic stimulus. The potential therapeutic benefit of CT-1 when added at the time of reperfusion following ischaemic damage is discussed.     

Quin2 microfluorometry and effects of verapamil and diltiazem on calcium release from rat aorta smooth muscle cells in primary culture

We investigated the effects of the Ca2+ antagonists diltiazem and verapamil on release of Ca2+ from intracellular store sites of rat aorta vascular smooth muscle cells in primary culture. Using the microfluorometry of Ca2+-indicator dye quin2, relative changes in cytosolic Ca2+ concentration could be measured. In the presence of 1 mM extracellular Ca2+, both diltiazem (IC50, 0.31 microM) and verapamil (IC50, 0.47 microM) dose-dependently inhibited elevations in the cytosolic Ca2+, as induced by depolarization of the plasma membrane with high extracellular K+. In the absence of extracellular Ca2+, caffeine and high extracellular K+ induced transient and dose-dependent elevations of the cytosolic Ca2+, and these elevations were not inhibited by either diltiazem or verapamil. Norepinephrine also induced a transient and dose-dependent elevation of cytosolic Ca2+ in the absence of extracellular Ca2+. However, this elevation was inhibited by verapamil and diltiazem (when the norepinephrine concentration was 10(-5) M, IC50 for verapamil and diltiazem was 4.0 and 24.9 microM, respectively). Thus, while verapamil and diltiazem may have no direct effect on the release of Ca2+ from the depolarization- and the caffeine-sensitive intracellular Ca2+ storage sites, the agents do seem to inhibit the adrenoceptor-mediated Ca2+ release mechanism in vascular smooth muscle cells.     

Termination and suppression of idiopathic left ventricular tachycardia by diltiazem

Idiopathic left ventricular tachycardia is known to be responsive to verapamil in many cases. However, the role of other calcium-channel blockers, such as diltiazem, in treating this specific type of ventricular tachycardia is unknown. We report a case of idiopathic left ventricular tachycardia in a patient with a structurally normal heart, which was terminated and suppressed in the electrophysiology laboratory by a single dose of diltiazem intravenously, and was subsequently suppressed long-term with sustained-release diltiazem. Our finding suggests that idiopathic left ventricular tachycardia may be managed effectively with diltiazem in both the acute and chronic settings.     

Cardiotrophin-1 can protect cardiac myocytes from injury when added both prior to simulated ischaemia and at reoxygenation

OBJECTIVE: The cytokine cardiotrophin-1 (CT-1) has previously been shown to protect cultured cardiocytes from cell death induced by serum removal or hypoxia when administered prior to the damaging stimulus. We wished to test whether a similar protective effect could be observed if CT-1 was added after the ischaemic period and to investigate the signalling pathways involved in the protective effect when CT-1 is given prior to or after ischaemia. METHODS: We therefore examined the protective effect of CT-1 in cultured rat cardiocytes exposed to simulated ischaemia followed by reoxygenation when CT-1 was administered either prior to simulated ischaemia or at reoxygenation. RESULTS: We show that CT-1 can exert a protective effect against the damaging effects of simulated ischaemia/reoxygenation both when added after the simulated ischaemia at reoxygenation (P<0.05 in trypan blue, TUNEL and annexin V assays) or when added prior to the simulated ischaemia (P<0.05). In both cases, these protective effects are blocked by an inhibitor of the p42/p44 MAPK pathway (P<0.05 in all assays). CONCLUSION: CT-1 can protect cardiac cells when added either prior to simulated ischaemia or at the time of reoxygenation following simulated ischaemia and these effects are dependent upon its ability to activate the p42/p44 MAPK pathway. Hence CT-1 may have therapeutic potential when added at the time of reperfusion following ischaemic damage.     

Verapamil protection of ischemic isolated rabbit heart: dependence on pretreatment

Verapamil may protect ischemic myocardium by several mechanisms: prevention of Ca overload as a direct effect of blocking Ca influx through slow channels, coronary vasodilatation, decreased contractility, or cardioplegia produced by high doses. We manipulated the experimental situation to ask whether the first mechanism alone could be protective. We studied isovolumically contracting rabbit hearts perfused at 37 degrees C, paced at 150/min, and maximally vasodilated by dipyridamole. Hearts were subjected to 60 min of low flow ischemia followed by 60 min reperfusion. Two groups were exposed to verapamil 0.5 microM beginning either 2 to 4 min before ischemia or 10 min after the onset of ischemia (when pressure development had ceased) and continuing until reperfusion. Developed pressure recovered during reperfusion to 70 +/- 4% of its initial value in hearts treated with verapamil before ischemia compared to 40 +/- 5% for control hearts and 35 +/- 11% for hearts treated with verapamil 10 min after the onset of ischemia. There was significant preservation of phosphocreatine at 10 min of ischemia and of ATP at 60 min in the early verapamil group compared to the other two. When verapamil was present before ischemia, pressure development during early ischemia was reduced to about 50% of control. Consequently there was substantial sparing of high energy phosphates and enhanced recovery of mechanical function. If verapamil was added 10 min after the onset of ischemia, when it no longer could affect cardiac work, there was no protection. Therefore, in the isolated rabbit heart, verapamil had an important protective effect only by reducing contractility of ischemic myocardium.     

Effect of calcium channel blocker diltiazem on cytoprotection and prostaglandin and sulfhydryl production by rat gastric epithelial cells

The calcium channel blockers verapamil and diltiazem protect gastric mucosa against exogenous injury in vivo. Whether this protection is mediated by systemic factors, such as blood flow, is due to inhibition of gastric acid secretion, or is associated with stimulation of endogenous protective agents such as prostaglandins or sulfhydryls, is unknown. We have evaluated whether diltiazem protects rat gastric epithelial cells in tissue culture (a model which excludes the influence of systemic factors) against damage induced by sodium taurocholate, indomethacin, or ethanol. Further we have assessed the effect of diltiazem on prostaglandin and sulfhydryl production. 51Chromium release assay and phase contrast microscopy have been used to assess cell damage. Sodium taurocholate, indomethacin, and ethanol-damaged cultured cells in a dose-dependent manner. Pretreatment with diltiazem did not prevent the drug-induced damage. Diltiazem did not increase PGE2 and 6-keto PGF1a production by cultured cells nor did it affect the cellular level of endogenous sulfhydryls. In conclusion, the calcium channel blocker diltiazem is not directly protective to rat gastric mucosal cells in vitro. Diltiazem does not stimulate prostaglandin production by gastric cells nor does it increase the cellular level of protective sulfhydryls.     

Effects of diltiazem on reperfusion-induced arrhythmias in vitro and in vivo

The effects of the calcium antagonist, diltiazem, on myocardial injury during ischemia and reperfusion were studied both in vitro, in the isolated rat heart, and in vivo, in a closed-chest pig model. In the isolated rat heart, administration of diltiazem before or at the onset of ischemia resulted in a dose-dependent reduction of the incidence and duration of ventricular fibrillation. This reduction was associated with a dose-dependent reduction in overflow of ATP catabolites (adenosine, inosine, hypoxanthine and xanthine). Both changes were significant at concentrations of 3 X 10(-7) M diltiazem and higher. When 3 X 10(-7) M diltiazem was administered upon reperfusion no effect on the incidence of ventricular fibrillation and on ischemia induced total purine overflow was observed. However, the duration of ventricular fibrillation and purine overflow at 5 min after reperfusion were significantly reduced. In the pig experiments all untreated animals (n = 8) showed accelerated idioventricular rhythm (AIVR) upon reperfusion which lasted for 22 +/- 5 min after which sinus rhythm returned. Only two out of five treated animals (450 micrograms/kg/2 h) had an AIVR. Upon reperfusion both groups showed a substantial rise in noradrenaline concentration in the coronary sinus blood, but after 5 min this was significantly less in the treated group. Creatine kinase-kinetics were not altered by diltiazem, but the maximum creatine kinase level was significantly reduced. Within 4 days after the acute experiment 50% of the untreated animals died suddenly, whereas no sudden deaths occurred in the diltiazem group (P less than 0.05). Seven days after the acute experiment, sustained ventricular tachycardia could be induced with programmed electrical stimulation in three out of four surviving untreated pigs. In none of the diltiazem treated pigs was ventricular tachycardia inducible. The results of this study show that the calcium antagonist diltiazem can beneficially influence the events during ischemia and during reperfusion, both in vitro and in vivo; this benefit is associated with a reduction of ATP catabolism, creatine kinase release and noradrenaline overflow. Furthermore, diltiazem reduces electrical instability in the chronic phase of myocardial infarction.     

An exercise hemodynamic comparison of verapamil,diltiazem, and amlodipine in coronary artery disease

Summary A prospective, randomized study compared the effects of equivalent intravenous doses of three slow calciumchannel blockers (verapamil, diltiazem, and amlodipine) on rest and exercise haemodynamics in 30 ischemic heart disease patients. Following a stable control period during which rest and exercise (supine bicycle) hemodynamics were assessed, equivalent hypotensive doses of each compound were administered over 20 minutes and rest/exercise parameters were assessed 10 minutes later. At rest all agents similarly reduced systemic blood pressure; the fall in systemic vascular resistance and the increase in cardiac indices was ranked: amlodipine > diltiazem > verapamil. The heart rate increase for amlodopine differed from verapamil and diltiazem (+19.4% vs. +1.5% vs. –7%; p<0.01).On exercise, similarly greater falls in the systemic vascular resistance index followed amlodipine, compared with verapamil and diltiazem (p<0.05). Only amlodipine significantly reduced the exercise pulmonary artery occlusion pressure (PAOP). Exercise cardiac stroke volume improved after diltiazem and amlodipine. In terms of cardiac performance, both amlodipine and diltiazem produced an improvement, whereas verapamil depressed cardiac pumping activity. Thus, hemodynamic differences between slow-calcium-channel blocking drugs may be demonstrated in humans. These differences would be compatible with a predominant peripheral vascular site of action for amlodipine, in contrast with mixed cardiac and peripheral sites for diltiazem and verapamil.     

Calcium antagonists in heart failure

Clinical experience with calcium antagonists in congestive heart failure has, to date, been mainly restricted to the use of nifedipine but there is either no or only a limited extent of information available on diltiazem and verapamil. In patients with acute and chronic congestive heart failure, single-dose administration of nifedipine was seen to lead to a decrease in systemic vascular resistance, left ventricular filling pressure and ventricular volumes as well as to an increase in stroke volume, ejection fraction and mean velocity of circumferential fiber shortening. These favorable effects could not be detected in eight patients during a three-week treatment phase with 80 mg nifedipine daily: resting blood pressure, cardiac volumes, echocardiographically-dimensions and exercise tolerance were unchanged as compared with placebo. In patients with ischemic heart disease and impaired ventricular function, in addition to an improvement in systolic function, single-dose nifedipine administration led to favorable effects on diastolic function with a shift of the diastolic pressure-volume relationship downward and to the diastolic pressure-volume relationship downward and to the left. In patients with severe aortic regurgitation, the observed increase in effective cardiac output affected by nifedipine was primarily attributable to an increase in heart rate. In the presence of an initially-elevated systemic vascular resistance, the regurgitation fraction decreased. In pulmonary hypertension, favorable hemodynamic effects have been reported after acute administration of verapamil as well as diltiazem and nifedipine. In individual cases, promising results in patients with primary pulmonary hypertension have been reported during long-term therapy with nifedipine provided that a favorable initial response could be documented.     

Comparative clinical electrophysiologic effects of diltiazem, verapamil and nifedipine: a review

The slow channel blocking agents--diltiazem, verapamil and nifedipine--have generated clinical interest for the treatment of a variety of cardiovascular disorders. These agents, despite a similar basic mechanism of action, produce disparate clinical cardiac electrophysiologic effects in human beings. In usual doses, the acute administration of diltiazem slows heart rate. Verapamil and nifedipine, however, increase heart rate. Although diltiazem and verapamil produce equivalent slowing of atrioventricular (A-V) nodal conduction, verapamil prolongs A-V nodal refractoriness to a greater degree. In contrast, nifedipine facilitates A-V nodal conduction and shortens A-V nodal refractoriness. Knowledge of these differences may aid in the appropriate selection of specific slow channel blocking agents in specific clinical situations.     

Protective action of calcium channel antagonist agents against ventricular fibrillation in the isolated perfused rat heart

This study investigates the effect of calcium channel antagonist agents, verapamil, nifedipine and diltiazem on the ventricular fibrillation threshold before and after left main coronary artery ligation in the isolated perfused rat heart.Verapamil 1.5 × 10^?7m and nifedipine 10^?6m decreased, whereas diltiazem 5 × 10^?6m did not alter the ventricular vulnerability to fibrillation in control non-ligated hearts. During acute regional myocardial ischaemia, verapamil 1.5 × 10^?7m, nifedipine 10^?6m and diltiazem 5 × 10^?6m decreased the vulnerability to ventricular fibrillation. In series paced at 230 beats/min both the d(+) and l(?) optical isomers of verapamil 1.5 × 10^?7m displayed equivalent anti-fibrillatory activity during acute regional myocardial ischaemia. Racemic verapamil 1.5 × 10^?7m displayed greater protection than either isomer alone. The mechanism whereby calcium channel antagonist agents mediate protection against ventricular fibrillation appears exceedingly complex due to the heterogeneity of action of these agents, viz. (1 slowing of heart rate; (2) preservation of high energy phosphate; (3) coronary artery vasodilation; (4) reduction in tissue cyclic AMP content; (5) inhibition of transmembrane calcium influx; and (6) nonspecific effects. Factors which appear to be important in mediating protection against ventricular fibrillation are calcium channel antagonism and a non-specific effect which may represent fast channel inhibition. The relationship between coronary flow distribution to the ischaemic myocardium and the anti-fibrillatory activity of calcium antagonist agents needs to be defined.     

Prevention of calcium paradox-related myocardial cell injury with diltiazem,a calcium channel blocking agent

The effect of diltiazem on creatine kinase release and tissue adenosine triphosphate content was investigated during calcium paradox in the isolated perfused rat heart. Creatine kinase loss was minimal during the calcium-free phase, but there was a 100-fold increase in creatine kinase release after reperfusion with normal calcium-containing medium. Diltiazem reduced creatine kinase loss by 35 percent when added to calcium-free medium and by approximately 80 percent when added to both calcium-free and reperfusion media. Adenosine triphosphate content was significantly increased from 2.98 μmol in untreated calcium paradox hearts to 5 μmol/g dry weight in diltiazem-treated hearts. With hyopthermia the calcium paradox injury was completely inhibited if the temperature of calcium-free perfusion was maintained at 15 ° C. Diltiazem appears to exert its protective effect through its ability to prevent the cellular separation and alterations in the gap junctions during calcium deprivation of cells and to limit calcium entry into the cells after reperfusion with calcium-containing medium.     

Enrichment of vital adult cardiac muscle cells by continuous silica sol gradient centrifugation

Summary A major improvement in the isolation of vital adult cardiocytes was achieved by isopycnic preformed continuous silica sol gradient centrifugation after perfusion of the heart with collagenase. Vital rat cardiocytes were enriched to 90–95% vital cells reproducibly and constantly by one- or two-step gradient centrifugations. The isolated cardiocytes were tolerant to calcium concentration up to 0.03 mmol/l, to diluted human serum, and to human complement. Gentamycin (50 g/ml) exerted a cytotoxic effect on myocytes, whereas Penicillium and Streptomycin in concentrations of 50 IU/ml did not induce cytolysis of cital cells. Digoxin 15 ng/ml) decreased the natural decay of myocytes of 20% in 24 hours to 8%.Enriched of vital cardiocytes by silica sol gradient centrifugation following their isolation by perfusion with collagenase may be helpful for investigations depending on a high yield of vital myocardial cells.Supported by DFG-grant MA 780/1     

Prolonged protective effect of the calcium antagonist anipamil on the ischemic reperfused rabbit myocardium: Comparison with verapamil

Summary To assess whether pretreatment with the calcium antagonist anipamil protects the heart against ischemic and reperfusion damage and to establish how long the protection persists after cessation of the therapy, rabbits were injected subcutaneously twice daily for 5 days with 2 mg/kg body weight of this drug. The heart was then isolated 2, 6, or 12 hours after the last injection and was perfused by the Langendorff technique during a control period and 90 minutes of total ischemia (37°C), followed by 30 minutes ofreperfusion. Diastolic and developed pressure was monitored; coronary effluent was collected and assayed for creatine phosphokinase (CPK); mitochondria were harvested and assayed for respiratory activity, ATP production, and calcium content; and tissue concentration of adenosine triphosphate (ATP) and creatine phosphate were determined. The data obtained with anipamil were compared with those obtained with verapamil administered to the rabbit at the same dose and following the same procedure.Pretreatment with anipamil induced a negative inotropic effect under normoxic conditions; reduced the rate and extent of depletion of ATP and creatine phosphate during ischemia, with an incomplete restoration of the nucleotides after reperfusion; maintained mitochondrial function and calcium homeostasis during ischemia and reperfusion; reduced the rate of CPK release; and improved the recovery of ventricular function on reperfusion. The protective effects of anipamil persisted for as long as 12 hours after the last administration. In contrast, the protective and negative inotropic effects of verapamil were no longer apparent in heart isolated 6 or 12 hours after the last dose of the drug.It is concluded that anipamil pretreatment provides a protection against some of the deleterious effects of myocardial ischemia and reperfusion and that this effect is substantially longer than that of verapamil. The protective effect of anipamil (like that of verapamil) is probably secondary to a reduction of the rate of ATP hydrolysis during ischemia, although alternative mechanisms of action cannot be excluded.     

A protective effect of coenzyme Q10 on the adriamycin-induced cardiotoxicity in the isolated perfused rat heart

Experiments were undertaken to determine if pretreating the animal with coenzyme Q₁₀ (CoQ) protected the cardiac muscle of the isolated heart from the acute toxic injury induced by perfusion with adriamycin.CoQ (15 mg/kg/day) or vehicle alone was injected intraperitoneally into male rats for 7 days. Two hours after the last injection, the hearts were excised and perfused by Langendorff's technique. Perfusion with various concentrations of adriamycin (5, 10, 20, 30 or 50 μg of adriamycin/ml of perfusate) induced a dose-dependent decline in the contractile tension development and a dose-dependent elevation in the resting tension. When adriamycin in perfusate was 10 μg/ml or less than that, the coronary flow rate remained almost constant during the perfusion. No significant recovery in the contractile tension development and the resting tension was obtained by subsequent perfusion without adriamycin. The contractile tension development of the CoQ-pretreated hearts was significantly greater than that of the vehicle-pretreated hearts both during the perfusion with adriamycin (10 μg/ml) for 60 min and during the subsequent adriamycin-free perfusion for 30 min. After 60 min of perfusion with adriamycin, the cardiac stores of ATP, total adenine nucleotide and nicotinamide adenine dinucleotide in the CoQ-pretreated group were significantly higher than those in the vehicle-pretreated group.These results indicate that exogenous CoQ protects the cardiac muscle from the deterioraion in mechanical function induced by adriamycin. Better mechanical function of CoQ-pretreated hearts was attributable to relatively higher ATP stores presumably due to lesser loss of adenine nucleotide pool from the cardiac cells.     

Should calcium antagonists be used after myocardial infarction? Ischemia selectivity versus vascular selectivity

Summary The use of calcium antagonists for postinfarct cardioprotection remains controversial. Several major trials have failed to show benefit, despite positive expectations based on promising experimental data. A clue to the problem with the calcium antagonists was provided by the diltiazem trial, in which an adverse effect in the presence of congestive heart failure masked a benefit in those without heart failure. Accordingly, the most recent trial, DAVIT-II, was carried out in patients in whom preexisting left ventricular failure had been excluded. One of the interesting byproducts of that study was the possibility that verapamil prevented postinfarct sudden death, which implies a potential antiarrhythmic mechanism. It is proposed that cytosolic calicum overload could play a role in ischemic ventricular fibrillation. Experimentally, calcium antagonists are most effective antifibrillatory agents when catecholamine stimulation is combined with acute ischemia, as would be the situation in the acute phase of myocardial infarction. This potential benefit of calcium antagonists may be offset in the presence of congestive heart failure because left ventricular dilation is directly arrhythmogenic. The ideal calcium antagonist, aimed at preventing postinfarct ischemic arrhythmias, but without a significant negative inotropic effect, could be based on 1 of 2 principles. First, the agent could be highly selective for the ischemic but not the nonischemic zone of the myocardium (ischemic-selective agent). Second, the agent could be highly vascular selective, so that left ventricular dilation would be avoided. A comparative study of these two types of calcium antagonists should be undertaken in postinfarct patients.