Calcium antagonists. Clinical use in the treatment of arrhythmias

Calcium antagonists have recently emerged as a class of drugs for the treatment of angina, hypertension and certain cardiac arrhythmias. Verapamil is the prototype calcium antagonist and has the most clearly defined antiarrhythmic properties. Other agents in the class include D-600 (gallopamil), tiapamil, nifedipine, and diltiazem. The antiarrhythmic effects of these compounds can be correlated with their electrophysiological properties which may differ significantly among different compounds and also between isolated tissues in intact animals and man. As a class they do not increase the effective refractory period of the atria, ventricle, His-Purkinje fibres or the accessory pathways in the heart. The dominant effect is slowing of conduction in the AV node with the prolongation of the AV nodal refractory period. The most marked changes are produced by verapamil, the least with nifedipine which is devoid of antiarrhythmic actions. Verapamil and its congeners as well as diltiazem terminate paroxysmal supraventricular tachycardia and slow the ventricular response in atrial flutter and fibrillation. They are also of prophylactic value in preventing recurrences of paroxysmal supraventricular tachycardia and controlling the ventricular response in atrial flutter and fibrillation during long term oral therapy. Their value in ventricular arrhythmias is uncertain but they are unlikely to be effective except in those complicating coronary artery spasms. The relative merits and potencies of various calcium antagonists in different arrhythmias need further studies.     

Electrophysiological effects of bepridil and its quaternary derivative CERM 11888 in closed chest anaesthetized dogs: a comparison with verapamil and diltiazem.

1. The electrophysiological effects of bepridil, its quaternary derivative, CERM 11888 (methylpyrrolidinium bromide) (both 2.5 mg kg-1 i.v.) and those of verapamil and diltiazem (0.2 mg kg-1 i.v.) were studied in closed chest anaesthetized dogs at doses used in clinical studies. 2. The four drugs caused a bradycardia with the following order of potency: bepridil greater than CERM 11888 greater than diltiazem greater than verapamil. 3. All the compounds slowed conduction in the AV node, increased the refractory period (RP) and decreased Wenckebach rates with the following order: verapamil much greater than diltiazem greater than bepridil greater than CERM 11888. 4. Verapamil and diltiazem did not affect conduction or the RP in atria while bepridil weakly slowed the former and markedly increased the latter. CERM 11888 caused a lengthening of RP but this was a delayed effect. 5. In the ventricle, bepridil and CERM 11888 caused a small increase in the QRS and a more pronounced increase in the RP. Both compounds increased QTc but did not modify HV. Verapamil and diltiazem had no significant effects at the ventricular level. 6. Our results confirm that the main sites of action of calcium antagonists are the SA and AV nodes. Bepridil has a broader spectrum of activity and also acts at the atrial and ventricular levels. A comparison of the effects of bepridil with those of its quaternary derivative suggests the involvement of an intracellular action in the electrophysiological effects of bepridil.     

In-vitro Negative Chronotropic and Inotropic Effects of a Novel Dihydropyridine Derivative,CD-832, in the Guinea-pig: Comparison with Calcium-channel Antagonists

The effects of CD-832 (4R-(-)-2-(nicotinoylamino)ethyl-3-nitroxypropyl-1,4-dihydro-2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxylate), a novel dihydropyridine derivative, on guinea-pig isolated myocardial preparations have been compared with those of Ca²⁺-channel antagonists. All ten compounds induced concentration-dependent negative chronotropic effects on preparations of isolated right atria and negative inotropic effects on isolated right ventricular papillary muscles. The order of potency for the negative chronotropic effect was CD-832 > nicardipine = gallopamil > clentiazem > nifedipine = efonidipine > amlodipine = semotiadil > verapamil > diltiazem; that for the negative inotropic effect was nicardipine = gallopamil > nifedipine > verapamil > CD-832 > diltiazem > clentiazem > efonidipine = semotiadil > amlodipine. The ratio of the EC50 (the concentration of Ca²⁺ antagonist having 50% of the maximum effect) for the negative inotropic effect divided by the EC50 for the negative chronotropic effect, considered to be an index of selectivity for negative chronotropic effect, was higher for CD-832, amlodipine, efonidipine and semotiadil than for the other Ca²⁺ antagonists. The ratio for CD-832, nifedipine, nicardipine, efonidipine, amlodipine, verapamil, gallopamil, diltiazem, clentiazem and semotiadil was 11·4, 0·29, 0·87, 35·4, 37·1, 0·65, 0·87, 0·92, 7·11 and 30·0, respectively. These findings indicate that CD-832 and the newly developed Ca²⁺ antagonists including amlodipine, efonidipine, semotiadil and clentiazem were selective for a negative chronotropic effect rather than for a negative inotropic effect. This ‘chrono-selective’ effect of these drugs might be of benefit in the treatment of cardiovascular disorders.     

Profile of coronary vasodilator and cardiac actions of bepridil revealed by use of isolated, blood-perfused heart preparations of the dog

We investigated the coronary vasodilator and cardiac actions of bepridil in various isolated, blood-perfused dog heart preparations. Intra-arterial bepridil increased blood flow in all preparations. In sinoatrial (SA) node preparations bepridil decreased sinus rate and produced atrial standstill in large doses. In paced atrioventricular (AV) node preparations, bepridil injected into the posterior septal artery (which supplies the AV node) increased AV conduction time (i.e., AV nodal conduction time) and in large doses produced second- or third-degree AV block. In the same preparations, bepridil in large doses injected into the anterior septal artery (which supplies the His-Purkinje ventricular system) prolonged AV conduction time (i.e., intraventricular conduction time). In paced papillary muscle preparations, bepridil reduced force of contraction only in large doses. In spontaneously beating papillary muscle preparations, bepridil decreased the rate of automaticity and the force of contraction as well. The order of effectiveness of bepridil on the above cardiovascular variables is as follows: coronary blood flow greater than AV nodal conduction greater than SA nodal automaticity much greater than ventricular automaticity ventricular muscle contraction much greater than intraventricular conduction. The results indicate bepridil to have a pharmacological profile different from that of verapamil, diltiazem, nifedipine, nicardipine, or KB-944.     

The effects of verapamil on the electrophysiology of the intact immature mammalian heart

The electrophysiologic effects of intravenous verapamil were compared in six intact neonatal puppies ages 3-15 days and in adult dogs. Utilizing standard intracardiac recording and programmed stimulation techniques, sinus and AV nodal function and atrial and ventricular refractory periods were determined following incremental intravenous doses of 0.075 mg/kg, 0.15 mg/kg, and 0.30 mg/kg of verapamil. In the neonate, intravenous verapamil resulted in a significant increase of the sinus cycle length (37 +/- 6%) but no changes occurred in either the percent sinus node recovery time or the corrected sinus node recovery time. The atrial effective refractory period was prolonged by verapamil (32 +/- 12%). Concerning atrioventricular (AV) nodal function, verapamil produced a small but significant prolongation of resting AH interval (50.5 +/- 2.4 ms (control) versus 57.3 +/- 4.7 ms post 0.30 mg/kg) and a dose-related prolongation of the paced cycle length resulting in AV nodal Wenckebach (170 +/- 12.8 ms control, 190 +/- 10.3 ms post 0.075 mg/kg, 215.8 +/- 13.0 ms post 0.15 mg/kg and 246.7 +/- 22.8 ms post 0.30 mg/kg). The effective refractory period (ERP) and functional refractory period (FRP) of the atrioventricular node (AVN) were prolonged in a dose-dependent fashion (ERP-AVN: 75 +/- 19% increase, FRP-AVN: 42 +/- 14% increase). Retrograde conduction, present in all six neonates, was completely abolished in four of six subjects and significantly prolonged in one other puppy by verapamil. No changes in ventricular refractory periods were observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Heart rate-dependent atrioventricular nodal conduction and the effects of calcium channel blocking drugs: comparison of verapamil and nifedipine

We compared the effects of the calcium channel blocking drugs verapamil and nifedipine on atrioventricular (AV) nodal function by His bundle electrocardiography in 24 pigs. AV nodal conduction time was decreased 16% by nifedipine (0.1 mg/kg + 3 micrograms/kg/min; p less than 0.05) and increased 20% by verapamil (0.2 mg/kg + 10 micrograms/kg/min; p less than 0.05). Pretreatment with a beta-adrenoceptor blocking agent (metoprolol, 0.4 mg/kg) prevented the decrease in AV nodal conduction time by nifedipine. Vasodilatation alone (nitroprusside, 20 micrograms/kg/min) produced a 16% decrease in AV nodal conduction time and a 19% decrease in cycle length. Before any of the drugs was given, AV nodal conduction time correlated negatively with the heart rate (rho = -0.65; p less than 0.001; n = 24). beta-Adrenoceptor blockade (metoprolol, 0.4 mg/kg) resulted in a 13% increase in cycle length and an 8% increase in AV nodal conduction time. These results indicate that, even with high concentrations, the effect of nifedipine on the AV node in vivo is primarily a facilitation caused by a baroreceptor reflex. In contrast, verapamil causes a depression of the AV node without such an increase in sympathetic tone.     

Novel method to assess cardiac electrophysiology in the rat: characterization of standard ion channel blockers

The rat continues to be an important tool to assess cardiac electrophysiologic (EP) effects of test agents and to study the distribution/role of ion channels in cardiovascular diseases. However, no data have been described that accurately measure discrete cardiac EP parameters in rats in vivo. Therefore, we developed a method to assess cardiac EP in rats and then profiled several ion channel agents. Briefly, rats were instrumented with endocardially placed electrodes to assess cardiac refractoriness and conduction. Administration of class I agents resulted in a dose-dependent slowing of ventricular conduction. The potassium channel blocker 4-aminopyridine caused significant increases in atrial and ventricular refractoriness. An IKr blocker had little or no effect on atrial and ventricular refractoriness but significantly increased AV nodal refractoriness. Additionally, an IKs blocker had little effect on rat cardiac EP. The L-type blocker diltiazem caused a dose-dependent delay in AV node conduction and an increase in AV node refractoriness. Overall, this study provides normative data that describe the roles of Na, Ca, and K channels in rat cardiac electrophysiology, in vivo. Furthermore, the model provides a method to assess changes in cardiac electrophysiology in the setting of disease by using well-established rat models of induced or genetic cardiovascular disease.     

Cardiac electrophysiologic effects of orally administered DPI 201-106 in conscious canines: effects of pharmacologic autonomic blockade or cardiac transplantation

This study assessed the cardiac electrophysiologic effects of DPI 201-106 (DPI), a novel orally absorbable positive inotropic agent, the administration of which has been associated with electrocardiographic (ECG) QT and T-wave changes. In the intact conscious dog, oral administration of both 8 and 16 mg/kg DPI produced marked sinus cycle length prolongation (8 mg/kg, + 11%; 16 mg/kg, + 9%) within 60 min of DPI administration (p less than 0.05 vs. baseline). DPI also tended to prolong right atrial refractory periods, and increase sinus node recovery time. In addition, DPI exhibited a negative dromotropic effect on the atrioventricular (AV) node, prolonging both AV node effective and functional refractory periods and tending to increase the minimum atrial paced cycle length at which AV conduction of 1:1 was maintained. DPI also significantly increased right ventricular effective refractory period (ERP) at both doses studied and increased ventricular functional refractory period (FRP) at the 16-mg/kg dose. Finally, although DPI administration was associated with QT interval prolongation, this effect was slight when corrected for sinus cycle length (SCL) (QTc, +3%). When administered concomitantly with propranolol and atropine or after surgical cardiac denervation, DPI-induced electrophysiologic changes were largely attenuated or abolished. Thus, findings in this study indicate that the apparent cardiac electrophysiologic effects of DPI are predominantly of neurally mediated origin in this animal model.     

Comparison of Intravenous Diltiazem and Verapamil for the Acute Treatment of Atrial Fibrillation and Atrial Flutter

Study Objectives . To compare the efficacy and safety of intravenous diltiazem and verapamil in controlling ventricular rate in patients with atrial fibrillation or flutter, and to evaluate the effects of these agents on left ventricular systolic function. Design . Prospective, randomized, double-blind, crossover study. Setting . University-affiliated hospital and Veterans Administration hospital. Patients . Seventeen men with atrial fibrillation or flutter with a ventricular rate of 120 beats/minute or higher and a systolic blood pressure of 100 mm Hg or greater. Interventions . Patients received up to two intravenous boluses of either diltiazem or verapamil, followed by an 8-hour continuous infusion if a therapeutic response was achieved (phase I). After a washout period, patients who responded were crossed over to receive the other drug in a similar fashion (phase II). Measurements and Main Results . At the end of each infusion, the patient's ejection fraction was assessed by gated angiography. Of the 17 men initially randomized, 8 successfully completed both phases I and II. In these patients, baseline mean (± SD) ventricular rates before treatment with intravenous diltiazem and verapamil were 138 ± 15 and 132 ± 9 beats/minute, respectively (NS). At 2 minutes after the initial bolus dose, the mean ventricular rate decreased to 100 ± 13 beats/minute in the diltiazem group compared with 114 ± 17 beats/minute in those receiving verapamil (p<0.05). Mean ventricular rates of 96 ± 11 and 97 ± 9 beats/minute were maintained during the 8-hour continuous infusion of diltiazem and verapamil, respectively (NS). On completion of the bolus dose(s) and during continuous infusions, there were no significant differences in blood pressures between the groups. Mean ejection fractions were 35.6 ± 13.6% and 35.5 ± 15.4% in the diltiazem and verapamil groups, respectively (NS). For the 17 patients, the mean maximum percentage decreases in blood pressure were not significantly different between groups. However, three patients developed symptomatic hypotension all of whom were randomized to receive verapamil initially. Conclusion . Intravenous diltiazem and verapamil are comparable in terms of efficacy and effect on systolic function in patients with rapid atrial fibrillation and flutter. However, hypotension may limit therapy with verapamil in some patients.     

Effects of semotiadil (SD-3211), a benzothiazine calcium antagonist, on blood pressure and atrioventricular conductivity in anesthetized dogs.

We investigated the effects of semotiadil (SD-3211), a novel calcium antagonist, on blood pressure and the atrioventricular (AV) conduction time and functional refractory period (FRP) of the AV conduction system (AV conductivity) in anesthetized open-chest dogs. The heart was electrically stimulated at a constant rate. In dogs with an intact nerve supply to the heart, i.v.-injections of semotiadil (0.03 to 0.3 mg/kg) produced a fall of blood pressure in a dose-dependent manner. AV conduction time and FRP were prolonged by rather higher doses (0.3 mg/kg), and second-degree AV block occurred only with the highest dose (1 mg/kg). In dogs with the nerve supply to the heart interrupted, the vasodepressor effects and suppressant effects of semotiadil on AV conductivity were slightly enhanced. The suppressant effects on AV conductivity became marked as pacing rates were increased. These results suggest that semotiadil at appropriate doses produces a vasodepressor effect without affecting AV conductivity even in the heart deprived of nervous control, e.g., the heart with beta-adrenoceptors blocked. The frequency-dependent suppressant effect on FRP of semotiadil is also noteworthy in the treatment of reentrant supraventricular tachycardia that involves the AV node.     

Effects of verapamil on accessory pathway properties and induction of circus movement tachycardia in patients with the Wolf-Parkinson-White syndrome

The electrophysiological effects of 0.2 mg/kg of intravenously administered verapamil (mean plasma level, 51.3 ng/ml) were evaluated using intracardiac recordings and electrical stimulation in 10 patients with the concealed or manifest Wolff-Parkinson-White syndrome. Verapamil produced a minimal effect on both the antegrade and retrograde effective refractory periods of the accessory pathway and the retrograde conduction time over the accessory pathway, but significantly lengthened the intranodal conduction time as well as the effective and functional refractory periods of the atrioventricular (AV) node. Reproducible sustained circus movement tachycardia was initiated in 8 patients before administration of verapamil and in 2 after verapamil. The sustained tachycardia could no longer be initiated in 6 patients because of an increase in AV nodal refractoriness. In 4 patients, atrial echoes were induced at longer premature beat intervals due to a greater AV conduction delay of the atrial impulse. The cycle length of the tachycardia was lengthened in 2 patients, reflecting an increase in the A-H interval after verapamil administration. In conclusion, these results show that verapamil has no apparent effect on either antegrade or retrograde accessory pathway properties and suggest that verapamil does indeed prevent sustained circus movement tachycardia by increasing the AV nodal refractoriness in some patients with the Wolff-Parkinson-White syndrome.     

Effects of the calcium antagonists diltiazem, verapamil and nitrendipine on the contractile responses of guinea-pig isolated ileum to electrical stimulation or carbachol.

The effects of the organic Ca2+ antagonists nitrendipine, verapamil and diltiazem on the cholinergic contractile responses induced by field electrical stimulation or carbachol (0.1 microM) and on contractions evoked by high concentration KCl (30 mM) were studied in isolated preparations from the guinea-pig ileum. The three Ca2+ antagonists dose-dependently suppressed the contractile responses showing the same order of potency (nitrendipine greater than verapamil greater than diltiazem) with the three different types of stimulation. Comparison of the IC50 values of the Ca2+ antagonists for carbachol-, KCl- and electrically-evoked contractions demonstrated that the carbachol-evoked contractions were most sensitive to the inhibitory action of the antagonists tested. The presynaptic inhibitory effect of (Met)enkephalin (10 nM) on the electrically-evoked cholinergic contractions was only slightly potentiated by high concentrations (1 or 10 microM) of nitrendipine and diltiazem and remained unchanged by verapamil. The results suggest that the Ca2+ antagonists tested block mainly the carbachol-activated L-type Ca2+ channels on the smooth muscle cells, while the effects on the N-type Ca2+ channels are insignificant, except for the high concentrations of nitrendipine and diltiazem.     

The effects of slow channel blockers and beta blockers on atrioventricular nodal conduction

The PR interval on the electrocardiogram represents the time that it takes an impulse to travel through the atrium and atrioventricular (AV) conduction system to the ventricles. Normally, activation is slowest in the AV node, and variations in PR interval most commonly parallel changes in AV nodal activation time. The AV nodal conduction time and effective refractory period are rate dependent and, in adult humans, are usually prolonged with increasing atrial paced rates. In addition, alterations in autonomic tone effect AV nodal conduction as well as sinus rate. The effect is usually in the same direction but often to different degrees. In patients with normal AV nodal function, parasympathetic and sympathetic tone are balanced at rest, but in patients with abnormal AV conduction, the effect of the parasympathetic system is more marked. Drugs including the slow channel blockers and beta blockers, affect AV nodal function. Slow channel blockers inhibit the slow inward calcium current, which may prolong conduction and refractoriness in the AV node. However, whereas diltiazem and verapamil have been shown to prolong AV nodal conduction and refractoriness in humans, nifedipine, a potent vasodilator, cannot be used in doses large enough to affect the AV node. The increase in PR interval caused by verapamil is minimal, and at doses of less than 480 mg/d, AV block occurs infrequently. When AV block occurs, it is first degree block in most patients, and it is usually asymptomatic. The electrophysiologic effects of diltiazem are similar to those of verapamil. Beta blockers also have a negative dromotropic effect on the AV node. They prolong the AH interval and AV nodal refractory periods and may lengthen the PR interval. The prolonged PR interval rarely results in more than first degree AV block in patients receiving maintenance therapy. In selected patients, combination therapy with a slow channel blocker and a beta blocker rarely causes second-degree AV block.     

Cardiac versus coronary vasodilator actions of KB-944, a new calcium antagonist, assessed in isolated, blood-perfused heart preparations of dogs

We compared the cardiac and coronary vasodilator actions of a new calcium-antagonistic vasodilator, KB-944, in isolated, blood-perfused heart preparations of dogs. In all preparations KB-944 injected intra-arterially produced an increase in blood flow. In sinoatrial (SA) node preparations KB-944 decreased sinus rate and in large doses produced atrial standstill. In atrioventricular (AV) node preparations KB-944 increased AV conduction time and in large doses produced second- or third-degree AV block only when injected into the artery supplying the AV node. In the same preparations KB-944 had virtually no effect on AV conduction when injected into the artery supplying the His-Purkinje-ventricular system. In papillary muscle preparations KB-944 in medium and large doses depressed force of contraction, the depressant action being greater at high rates of contraction. In the same kind of preparations KB-944 affected automaticity slightly and inconsistently. Depression by KB-944 of SA nodal automaticity and AV nodal conduction occurred pari passu with coronary vasodilation, whereas force of contraction was depressed to a lesser extent in coronary vasodilator doses. In these respects, KB-944 resembles verapamil and diltiazem rather than nifedipine and nicardipine.     

Effects of S-1389 (711389-S), a new antiarrhythmic agent, on the conduction in perfused guinea pig hearts

In the His bundle and ventricular electrograms of Langendorff-perfused guinea pig hearts driven at a cycle length of 450 or 700 msec, S-1389 (711389-S), a new antiarrhythmic agent, above 3 x 10(-7) or 10(-6) M increased the basal conduction times in the following order: His-Purkinje system greater than ventricular and atrial muscles greater than atrioventricular (AV) node. Slowing of the ventricular and AV nodal conduction of extrasystoles with variable coupling intervals was also caused by S-1389. S-1389 above 10(-6) or 3 x 10(-6) M significantly prolonged the functional and/or effective refractory periods of the AV node and ventricle. Disopyramide (3 x 10(-6)-3 x 10(-5) M) also produced similar effects, but they were much less potent than those of S-1389. Although disopyramide did not produce the rate-dependent increases in the atrial and AV nodal conduction times and in the AV nodal refractory period, S-1389 increased these parameters rate-dependently.     

Paradoxical effect of calcium on some cardiovascular effects of verapamil in the rat

The ability of calcium infusions to reverse some cardiovascular effects of verapamil was tested in anesthetized rats and on isolated rat atria. Intravenous infusions of 1.88 mg/kg verapamil increased the cycle length (CL), lengthened the PR interval (PRi), and decreased the mean arterial pressure (Pa). After these effects were stabilized, a series of infusions of calcium chloride (338 mumol/kg each) were performed. Calcium on the one hand promoted the return of Pa to its basal value; on the other hand, it failed to reverse the effect of verapamil on AV conduction and the first infusion of calcium produced an additional increase in CL of 55 +/- 16 ms. This paradoxical effect of calcium was prevented by previous infusion of atropine (0.2 mg/kg). On isolated atria, the increase of calcium concentration in the media ([Ca2+]0) from 1.0 to 6.0 mM increased the concentration frequency by approximately 40 beats/min, both in atropinized and in nonatropinized preparations. After verapamil, however, the same increase in [Ca2+]0 decreased atrial rate in 50 +/- 15 beats/min in nonatropinized atria. The results obtained indicate that extra calcium can overcome the hypotensive effect of verapamil, whereas it paradoxically increases its negative chronotropic effect and fails to reverse its effect on AV conduction. This paradoxical effect of calcium can be prevented, both in vivo and in vitro, by atropine blockade of muscarinic receptors.     

Electrophysiologic effects of verapamil metabolites in the isolated heart.

The electrophysiologic effects of the metabolites of verapamil are unknown and may contribute to the observed differences between intravenous and oral verapamil. We examined the electrophysiologic effects of verapamil and its metabolites (norverapamil, N-dealkylverapamil (D617), and N-dealkylnorverapamil (D620)) at estimated, free therapeutic concentrations, in the retrogradely perfused, isolated rabbit heart. Verapamil at 5 and 10 ng/ml significantly prolonged anterograde (11 and 27%, respectively) and retrograde (10 and 25%, respectively) atrioventricular (AV) nodal block cycle lengths. Anterograde and retrograde AV nodal conduction times and refractory periods were also prolonged. Norverapamil at 100 ng/ml had qualitatively similar effects equivalent to 20-50% that observed with verapamil at 10 ng/ml. D620 had small but statistically significant effects on some AV nodal parameters. D617 had no effect. The combination of verapamil plus its principal metabolite, norverapamil, had additive effects. None of the compounds had any measurable effect on atrial conduction, His-Purkinje conduction, or atrial refractoriness. Ventricular refractoriness was significantly prolonged only by norverapamil. In conclusion, some of the metabolites of verapamil have important electrophysiologic AV nodal effects and may contribute to the clinical effects observed during chronic oral verapamil dosing.     

Effect of tiapamil in the Wolff-Parkinson-White syndrome

The effect of tiapamil was studied in 9 patients with the Wolff-Parkinson-White syndrome using programmed stimulation of the heart. Before the drug, sustained orthodromic tachycardias could be initiated in 7 patients and antidromic tachycardia in 2 by premature atrial and/or ventricular stimulation. An intravenous bolus of tiapamil, 2 mg/kg, terminated the tachycardia in 7 out of 8 cases by a block in the atrioventricular (AV) node. Tiapamil lengthened the effective refractory period of the AV node in the only patient in whom it could be measured and the atrial effective refractory period in 1 out of 9 cases, but the drug had no influence on antegrade or retrograde refractory periods of the accessory pathway or on that of the ventricle. The AV nodal conduction time (A-H interval) was prolonged. Following tiapamil, it was not possible to initiate the tachycardia in 4 cases, in 2 patients the tachycardia zone widened, and in 3 it was unaltered. In the latter cases, the cycle length of the tachycardia was increased. Tiapamil appears to be useful for the termination of tachycardia and also for its prevention in some cases. In others, it may facilitate the inhibition of tachycardia. The delayed AV nodal conduction during sinus rhythm augments the area of ventricular preexcitation, which may facilitate the electrocardiographic localization of the accessory pathway.     

Nifedipine, diltiazem, bepridil and verapamil uptakes into cardiac and smooth muscles

Vogel et al. (1979; J. Pharmacol. Exp. Ther. 210, 378) reported that one calcium antagonist, bepridil, exerted an effect internally as well as its effect on blocking Ca2+ entry in cardiac muscle. Therefore, the uptakes of tritiated nifedipine, diltiazem, bepridil, and verapamil by cat ileal smooth muscle, chick embryonic ventricular muscle, and rabbit papillary muscle were investigated. It was found that the uptakes of verapamil and bepridil by the muscles were much higher than those of nifedipine and diltiazem. The uptake of bepridil was substantially greater than that of verapamil; thus, the order of uptake was: bepridil greater than verapamil much greater than nifedipine greater than diltiazem. The cardiac muscles accumulated at least 2-fold greater amount of calcium antagonists than the smooth muscle. The amount of a given calcium antagonist accumulated by a muscle was not a function of the ability of that calcium antagonist to inhibit Ca2+ uptake into the muscle, since nifedipine and diltiazem were more potent in depressing Ca2+ uptake, but had the smallest uptakes. The calcium antagonists were more effective in depressing Ca2+ uptake into smooth muscle than into cardiac muscle. Calculation indicates that internal drug concentration at steady state for both cardiac and smooth muscles was either equal to (diltiazem) or much higher than the drug concentration in the medium (bepridil and verapamil). It is concluded that bepridil and verapamil enter and accumulate in the muscle cells, whereas nifedipine and diltiazem permeate more slowly into the muscles. The ability of all four drugs to enter the muscle cells confers the possibility that these calcium antagonists may exert secondary actions on internal sites of the muscle, such as the sarcoplasmic reticulum.     

Pharmacological profile of semotiadil fumarate, a novel calcium antagonist, in rat experimental angina model.

1. The aim of the present study was to determine whether antianginal efficacy of semotiadil fumarate (SD-3211), a structurally novel calcium antagonist, is distinct from those of diltiazem, nifedipine and nisoldipine. 2. First, the duration of the inhibitory effects of semotiadil was compared with that of other Ca2+ antagonists in rat experimental angina evoked by vasopressin. Semotiadil (10 mg kg-1, p.o.) was effective for at least 9 h in the anginal model and those effects of semotiadil were longer-lasting than those of diltiazem (30 mg kg-1, p.o.), nifedipine (10 mg kg-1, p.o.), and nisoldipine (3 mg.kg-1, p.o.). 3. Second, the selectivity of actions of these Ca2+ antagonists for the coronary arteries and myocardium was evaluated in rat isolated perfused hearts. Diltiazem (10(-6) M) reduced cardiac contractility without inhibiting the elevation of perfusion pressure evoked by acetylcholine. Semotiadil (10(-7) M) significantly suppressed cardiac contractility and inhibited the coronary response to acetylcholine. In contrast, nifedipine (3 x 10(-9)-3 x 10(-8) M) and nisoldipine (3 x 10(-10)-10(-8) M) did not reduce cardiac contractility at concentrations which significantly inhibited the increase in perfusion pressure to acetylcholine. 4. The selectivity of semotiadil for coronary artery and myocardium is intermediate between diltiazem and dihydropyridines tested in the present study. 5. These findings suggest that semotiadil has an advantage of diltiazem, nifedipine, and nisoldipine in the treatment of angina with regard to long-lasting action and selectivity for coronary artery and myocardium.