Comparative effects of verapamil, diltiazem and felodipine during experimental digitalis-induced arrhythmias

We compared the abilities of three different calcium (Ca2+) entry blockers, verapamil, diltiazem and felodipine to abolish ouabain-induced ventricular ectopy (100 X ectopic/total beats, VE) in anesthetized, closed-chest dogs. Ventricular tachycardia (VT) was produced in anesthetized, bilaterally vagotomized, closed-chest dogs by an average dose of 65 +/- 19 micrograms/kg ouabain. 30 min after establishing VT, either verapamil (25-50 micrograms/kg + 5-10 micrograms/kg/min), diltiazem (50-100 micrograms/kg + 20-50 micrograms/kg/min), felodipine (3 micrograms/kg + 0.3 micrograms/kg/min) or saline was administered for another 30 min. Verapamil, at the higher dose utilized, practically abolished ouabain-induced VT (97 +/- 3 to 8 +/- 19% VE); diltiazem was moderately effective (96 +/- 4 to 50 +/- 8% ectopy) at 100 micrograms/kg, and felodipine exerted no antiarrhythmic effects in this model. All three Ca2+ entry blockers lowered mean aortic pressure, felodipine lowering this parameter most prominently. Thus, these structurally and electrophysiologically dissimilar Ca2+ entry blockers differed in their abilities to abolish the digitalis glycoside-induced arrhythmias in vivo. The superiority of verapamil may be related to its multiple, additional electrophysiologic effects.     

Calcium entry blocking activity of dilazep in dog coronary artery

Calcium entry blocking activities of adenosine and its potentiating compounds (dipyridamole, lidoflazine and dilazep) were studied in potassium (100 mmol/l) depolarized, dog, large coronary artery strips, in comparison to nifedipine, verapamil and diltiazem. Apparent pA2 values were calculated by using concentration-response curves for calcium before and 30 min after the addition of each dilator drug. The order of potency (using both pA2 and IC50 values) for the calcium entry blocking effect was: nifedipine greater than verapamil greater than diltiazem greater than lidoflazine greater than dilazep. Dipyridamole and adenosine had negligible calcium entry blocking activities (about 10,000 times less potent than verapamil). The calcium entry blocking activity of verapamil (using pA2 values) was 39.8 times less potent than nifedipine, and 3.6, 21.4 and 97.7 times more potent than diltiazem, lidoflazine and dilazep, respectively. The maximum relaxations induced by adenosine (3.7 X 10(-4) mol/l) and dipyridamole (5 X 10(-5) mol/l) were less than 20% that of 3 X 10(-4) mol/l papaverine. However, the other test drugs caused 80-90% relaxation under similar conditions. The relaxing effect of adenosine was inhibited by 8-phenyltheophylline (adenosine receptor antagonist) and potentiated by EHNA (an adenosine deaminase inhibitor), while dilazep-induced relaxation was not affected by these drugs. These findings suggest that the calcium entry blocking effect of dilazep in dog, large coronary artery strips is not mediated through adenosine.     

Calcium entry blocking activity of adenosine potentiating compounds in guinea pig taenia coli

Calcium entry blocking activities of adenosine and its potentiating drugs, dilazep, lidoflazine and dipyridamole, were studied in potassium (100 mM)-depolarized guinea pig taenia coli, and compared with nifedipine, verapamil and diltiazem. The potency ratio of calcium entry blocking effect of nifedipine, diltiazem, lidoflazine and dilazep to verapamil was 158.5, 1/1.1, 1/15.8 and 1/81.3, respectively. Dipyridamole and adenosine had negligible calcium entry blocking effects.     

Rapid desensitization of central beta-adrenoceptors in rat after subacute treatment with imipramine and calcium entry blockers.

The subcutaneous (s.c.) administration of isoprenaline to rats produced a dose-dependent increase in water drinking which was effectively antagonized by propranolol. This dipsogenic response was significantly inhibited after the intraperitoneal (i.p.) administration of imipramine (15 mg/kg/day), together with either of the following calcium entry blockers, for four days: diltiazem (15 mg/kg/day), verapamil (10 mg/kg/day), nifedipine (10 mg/kg/day) or nicardipine (15 mg/kg/day). Simultaneous injection of the inhibitor of the synthesis of serotonin, p-chlorophenylalanine (200 mg/kg/day, i.p.), did not affect this attenuation of the isoprenaline-induced response. Similarly, the selective 5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) or the 5-HT2 receptor antagonist, ketanserin, had no significant effect on the attenuation of isoprenaline-induced drinking behaviour. The inhibition of isoprenaline-induced drinking, was, however, effectively attenuated after treatment of the animals with 6-hydroxydopamine (2.5 micrograms) or clonidine (30 micrograms), injected intracerebroventricularly (i.c.v.). These results indicate that the calcium entry blockers accelerate the desensitization of central beta-adrenoceptors possibly by an action on central adrenoceptors of the rat.     

Inhibition by nilvadipine of ischemic and carrageenan paw edema as well as of superoxide radical production from neutrophils and xanthine oxidase.

1. Nilvadipine (FK 235, FR 34235) suppressed ischemia (20 min)-reflow (20 min)-induced paw edema of mice (ED30:0.4 mg/kg i.v. and 2 mg/kg p.o.). Other calcium entry blockers of dihydropyridine-type also suppressed the edema, but 30-fold higher doses were required. 2. Oral dosing of nilvadipine suppressed carrageenan-induced paw edema (ED30:15 mg/kg in rats and 20 mg/kg in mice) at a potency corresponding to that of an anti-inflammatory drug, ibuprofen. Nifedipine, nicardipine and nimodipine resulted in a suppression of 30% only with 100 mg/kg oral dosing in rats. Nitrendipine, diltiazem and verapamil were without effect. 3. Nilvadipine inhibited superoxide radical (O-2production from xanthine oxidase (XOD) both with lactate dehydrogenase + NADH method and cytochrome c method (IC50:90 and 100 micrograms/ml, respectively). Nifedipine and nicardipine showed some inhibition, but the other calcium entry blockers failed to inhibit significantly even at 320 micrograms/ml. As uric acid formation was not reduced by the tested drugs, the inhibitory action might be due to their O-2scavenging effects. 4. Superoxide production of neutrophils from casein-induced peritoneal fluid in rats was most strongly inhibited by nilvadipine when the cells were stimulated by a calcium ionophore, A23187 (IC50:4 micrograms/ml). Inhibition by this drug when stimulated by f-methonyl-leucyl-phenylalanine and phorbol myristate acetate was less effective (IC50:20 and 30 micrograms/ml, respectively). Nifedipine and nicardipine inhibited neutrophil O-2production at higher concentrations (30-200 micrograms/ml) with all stimulants. Inhibitory actions by other drugs were weak. 5. Triggering of atherosclerosis depends largely on the oxidative stress on blood vessels after recently established concept.(ABSTRACT TRUNCATED AT 250 WORDS)     

Verapamil, diltiazem and nifedipine inhibit vascular responses to noradrenaline, acetylcholine and 5-hydroxytryptamine in human saphenous vein

Verapamil (0.02-2 microM), diltiazem (0.22-8.14 microM) and nifedipine (0.29-8.96 microM) produced concentration-dependent relaxation of human isolated saphenous vein. Based on the EC50 values of the calcium entry blockers, verapamil (relative potency = 1) was 7 and 5 times as potent as nifedipine and diltiazem, respectively, in producing relaxation of the human saphenous vein. In addition, verapamil, diltiazem and nifedipine inhibited the vascular responses (i.e. contractions) produced by noradrenaline (0.03-36 microM), acetylcholine (0.05-55 microM) and 5-hydroxytryptamine (0.02-25 microM) and to KCl (10-100 mM). It was concluded that verapamil, diltiazem and nifedipine relaxed the human isolated saphenous vein, verapamil being more potent than diltiazem or nifedipine, and modified the vascular response to vasoconstrictor agents, e.g. noradrenaline, acetylcholine, 5-hydroxytryptamine and KCl. Thus verapamil, diltiazem and nifedipine may inhibit calcium influx through both potential and receptor-operated calcium ion channels.     

Effects of calcium entry blockers on calcium-dependent contractions of rat portal vein

1 The effects of six calcium entry blockers belonging to the dihydropyridine (isradipine or PN 200-110, nifedipine, nicardipine), verapamil (D888 or desmethoxyverapamil, D600 or gallopamil) and diltiazem classes were investigated on isometric spontaneous contractions and contractions induced by high-K+ solutions, noradrenaline, acetylcholine and caffeine. 2 The rank order of potency was PN 200-110 greater than nicardipine = nifedipine = D888 greater than D600 greater than diltiazem from experiments on spontaneous contractions and high-K+ induced contractions. With depolarized preparations, the concentration-response curves for nicardipine, PN 200-110, nifedipine and D600 were significantly shifted to the left indicating that the calcium entry blockers show voltage-dependent inhibitory properties. This effect was not significant with D888 and diltiazem. 3 All the calcium entry blockers strongly reduced the noradrenaline (NA)- and acetylcholine (ACh)-induced contractions at concentrations which produced complete inhibition of spontaneous contractions. They had a slight effect on caffeine-induced contractions. 4 In Ca2+-free, EGTA-containing solutions, both ACh, NA and caffeine produced transient contractions, the amplitude of which could be taken as a measurement of the amount of internal calcium present in a drug-sensitive calcium store. The filling of the calcium store was maximal after 10-12 min of calcium loading in 2.1 mM Ca2+, while the depletion was complete after 4-6 min of perfusion in Ca2+-free solution. 5 At concentrations which abolished spontaneous contractions, PN 200-110, nifedipine, D888 and D600 had no appreciable effect on contractions evoked in Ca2+-free solutions by ACh, NA and caffeine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Direct effects of diltiazem, nifedipine and verapamil on peripheral sympathetic nerve function, cardiac impulse conduction and cardiovascular function in anesthetized dogs subjected to ganglionic blockade

The Ca2+ entry blockers diltiazem, nifedipine and verapamil produced dose-dependent increases in atrioventricular conduction time (A-H interval), while decreasing heart rate and mean arterial pressure in anesthetized dogs previously subjected to ganglionic blockade to prevent hypotension-induced reflex changes in sympathetic tone. Nifedipine and verapamil, but not diltiazem, also reduced (P less than 0.05) the tachycardia produced by electrical stimulation of the cardioaccelerator nerve at doses which did not alter the heart rate response to direct beta-adrenoceptor stimulation by isoproterenol (0.1 microgram/kg i.v.). The lowest doses of nifedipine (0.03 mg/kg) and verapamil (0.3 mg/kg) that produced decreases in mean arterial blood pressure were the same as or greater than those which selectivity reduced the tachycardiac effects of low frequency (1 Hz, 25-35 V, 5 ms), but not high frequency (10 Hz, 25-35 V, 5 ms) cardiac nerve stimulation. These data suggest that threshold vasodilator doses of some Ca2+ blockers may selectively reduce low level (or basal) sympathetic neurotransmission and this additional pharmacologic action may contribute to the antihypertensive mechanism. The failure to inhibit the high frequency nerve response may also help to explain the relatively low incidence of orthostatic hypotension associated with the clinical use of Ca2+ blockers as compared to other direct-acting vasodilators.     

PREVENTIVE EFFECT OF A NEW CALCIUM ANTAGONIST, MONATEPIL, ON DRUG-INDUCED ISCHAEMIC ELECTROCARDIOGRAPHIC CHANGES IN RATS

1. The preventive effects of monatepil, a new calcium antagonist with α₁-adrenoceptor blocking activity, on ischaemic electrocardiographic changes in rat models of vasospastic angina were evaluated and compared with those of the existing calcium antagonists (diltiazem, verapamil, nicardipine and nifedipine). 2. In order to assess the contribution of the α₁-adrenoceptor blocking action of monatepil to its anti-vasospastic action, the anti-ST depression effect of prazosin, an α₁-adrenoceptor blocker, was also examined. 3. Monatepil given orally (3–30 mg/kg) inhibited vasopressin (0.2 IU/kg, i.v.)-induced ST depression which is considered to indicate ischaemic electrocardiographic changes in a vasospastic angina. This effect of monatepil was more potent and long-lasting than that of diltiazem, and was similar to that of verapamil and nicardipine. At a dose of 30 mg/kg, monatepil produced a significant inhibition, even at 7 h after administration. 4. Monatepil given intravenously (0.3 mg/kg) exerted a significant inhibitory effect on methacholine (16 μg/kg, intracoronary arterial administration; i.c.a.)-induced ST elevation which seems to be caused by coronary vasospasm. This effect was more potent or equipotent to those of the existing calcium antagonists. 5. These results indicate that monatepil produces the preventive effect on the drug-induced ischaemic electrocardiographic changes in rats and suggest that monatepil may have potential for the treatment of vasospastic angina.     

Cardiac versus vascular effects of a new dihydropyridine derivative, CV-4093. In vitro comparison with other calcium antagonists

The effects of CV-4093, a new dihydropyridine derivative, on isolated cardiovascular tissues were compared with those of several dihydropyridine and non-dihydropyridine calcium antagonists. CV-4093 effectively inhibited the contractions induced in canine femoral arteries by high [K+]0 and Bay K 8644, but incompletely relaxed those induced by norepinephrine. CV-4093, 10(-6) M, abolished the electrically induced slow action potentials in guinea-pig papillary muscles partially depolarized by 25 mM K+ solution and attenuated those induced by isoproterenol, histamine and Bay K 8644. The rank order of potency of dihydropyridine and non-dihydropyridine calcium antagonists in canine femoral arteries and veins precontracted with 120 mM [K+]0 was as follows: nisoldipine greater than nicardipine greater than or equal to nifedipine greater than or equal to CV-4093 greater than verapamil greater than or equal to diltiazem. Nisoldipine was the most potent and CV-4093 was the least potent among these drugs in terms of negative inotropic effect in normally polarized papillary muscles and negative chronotropic effect in right atria of guinea pigs. The rank order of potency for these cardiodepressant actions was nisoldipine greater than or equal to nifedipine greater than nicardipine greater than verapamil greater than diltiazem greater than or equal to CV-4093. The duration of action potential in guinea-pig papillary muscles was shortened by nisoldipine and nifedipine, unchanged by nicardipine and CV-4093 and was slightly prolonged by verapamil and diltiazem. These results suggest that CV-4093 is a calcium antagonist with a highly selective vascular effect and little cardiodepressant action, and could be of value for the treatment of hypertension.     

Antihypertensive and cardiovascular effects of the new dihydropyridine derivative methyl (E)-3-phenyl-2-propen-1-yl-1,4-dihydro-2,6-dimethyl- 4-(3-nitrophenyl)pyridine-3,5-dicarboxylate

The hypotensive and cardiovascular effects of a newly synthetized dihydropyridine derivative, methyl (E)-3-phenyl-2-propen-1-yl-1,4-dihydro-2,6-dimethyl-4-(3- nitrophenyl)pyridine-3,5-dicarboxylate (FRC-8411) were investigated in rats, guinea pigs, and rabbits, in comparison with nifedipine, nicardipine, and diltiazem. In conscious hypertensive rats, FRC-8411 (0.3-3 mg/kg p.o.) was found to be an orally effective antihypertensive agent and its effect lasted for more than 7 h. This effect was gradual and yet much more potent and longer than those of other reference drugs. An accompanied tachycardia was observed after oral administration of FRC-8411 and other dihydropyridine derivatives. In anesthetized rats, FRC-8411 (3-30 micrograms/kg i.v.) also showed a gradual, potent and long-lasting hypotension with a tachycardia. FRC-8411 (up to 3 mg/kg i.v.) had no effect on the PQ interval of the ECG in anesthetized rats. In isolated guinea pig atria, FRC-8411 (10(-9) - 3 X 10(-8) mol/l) showed a negative chronotropic effect, but a higher dose of the drug was needed for induction of the negative inotropic effect. In K+-depolarized rabbit aorta and guinea pig taenia coli, FRC-8411 (3 X 10(-9) - 3 X 10(-7) and 10(-7) - 3 X 10(-7) mol/l) showed a dose-dependent inhibition of the calcium-induced contraction, and its pA2 value was 8.4 and 7.1, respectively. FRC-8411 had a much higher sensitivity to the aorta than the taenia coli, though it was less potent than nifedipine and nicardipine in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular effects of nicardipine in anesthetized open-chest dogs in the absence and presence of beta-adrenergic receptor blockade: a comparison with nifedipine and verapamil

Nicardipine, a new 1,4-dihydropyridine calcium-entry blocker, was assessed for cardiovascular effects against nifedipine and verapamil in anesthetized open-chest beagle dogs, in the absence and presence of beta-adrenoceptor blockade (propranolol 1 mg/kg i.v.). In control conditions, intravenous nicardipine and nifedipine (30 nmol/kg) produced decreases in blood pressure of similar magnitude without evidence of cardiodepression. An equihypotensive dose of verapamil (300 nmol/kg), by contrast, induced long-lasting negative chronotropic and inotropic effects, which, when combined with the effects of propranolol, were so marked as to cause the death of two of five dogs (atrioventricular block). Dihydropyridine derivatives at higher doses (100 nmol/kg) produced different responses: nifedipine depressed cardiac performance significantly more than nicardipine and, in the presence of beta-adrenergic blockade, caused the death of three of six dogs due to cardiovascular failure. In the nicardipine group, on the contrary, cardiac function was adequately preserved even in the presence of beta-blocker, and no animals died. The results of the present study confirm a previous in vitro observation: nicardipine is a calcium-entry blocker devoid of remarkable cardiodepressant effects and particularly selective for the vascular smooth muscle.     

Different antagonism of the positive chronotropic and inotropic responses of the isolated, blood-perfused dog atrium to Bay k 8644 by nicardipine and verapamil

The effects of Bay k 8644, a dihydropyridine calcium agonist, on sinoatrial (SA) node pacemaker activity and atrial contractility and its interaction with the calcium antagonists, nicardipine and verapamil, were investigated in the isolated, blood-perfused dog atrium. Bay k 8644 (0.03-30 micrograms) increased sinus rate and atrial contractility dose dependently. Norepinephrine (NE) and CaCl2 dose dependently increased the sinus rate and contractility but the positive chronotropic effect of CaCl2 was much less than that of the other drugs. The positive chronotropic effect of Bay K 8644 (0.3-1 microgram) was dose dependently depressed by nicardipine at doses of 1-10 micrograms but the inotropic effect was depressed only by a large dose of 10 micrograms. After sinus arrest induced by nicardipine (10-30 micrograms), SA node pacemaker activity was readily restored by Bay k 8644 or NE. Verapamil (1-3 micrograms) also depressed the positive chronotropic effect of Bay k 8644 more effectively than the inotropic effect although it did not attenuate the chronotropic effect of NE. The inotropic interaction could not be evaluated at higher doses of antagonists because of sinus arrest. Propranolol (3 micrograms) suppressed both positive chronotropic and inotropic effects of NE but did not depress the Bay k 8644-induced responses. These results show that the antagonism between Bay k 8644 and calcium antagonists is predominant on SA node pacemaker activity in cardiac tissues.     

Effect of calcium channel blocking agents on the reductive metabolism of halothane

The effect of calcium channel blocking agents on the reductive metabolism of halothane in liver microsomes of guinea pigs was investigated. The reaction mixture for the measurement of the end products consisted of microsomal suspension, 5 mM NADPH, calcium channel blocking agents (verapamil, diltiazem, nicardipine and nifedipine) and halothane in 0.1 M phosphate buffer (pH 7.4). The reductive metabolism of halothane was inhibited competitively by verapamil, diltiazem and nicardipine. The binding spectra for the interaction of these three drugs with cytochrome P-450 in microsomes were investigated. Verapamil caused the reverse type I difference spectrum and diltiazem caused the type I difference spectrum. However, the change caused by nicardipine was not observed by the presence of its specific spectra. NADPH-cytochrome P-450 reductase activity in microsomes did not change by the addition of these three drugs. These results suggest that these three calcium channel blocking agents inhibit the production of radical intermediates during the reductive metabolism of halothane.     

Protective activity of calcium entry blockers against ouabain intoxication in anesthetized guinea pigs

Several studies have suggested a central role for calcium in the pathogenesis of digitalis-induced arrhythmias. To test this hypothesis, the effects on ouabain-induced arrhythmia of intraarterial pretreatment with the calcium entry blockers nifedipine, flunarizine, verapamil, diltiazem, and bepridil, the calcium entry promotor Bay K 8644, and CaCl2 were compared with those of the currently applied digitalis antidotes phenytoin and lidocaine in urethane-anesthetized (1.5 g/kg i.p.) guinea pigs. Pretreatment with nifedipine (0.03 and 0.1 mg/kg), flunarizine (1 and 3 mg/kg), and phenytoin (10 mg/kg) doubled the time (from 10-20 to 20-40 min) required to provoke toxic ECG changes. Verapamil, diltiazem, and bepridil caused a slight but significant reduction of ouabain toxicity. Pretreatment with CaCl2 (10 mg/kg) enhanced all toxic effects of ouabain. None of the above-mentioned pretreatments as such changed the ECG parameters. Bay k 8644 (0.03 and 0.1 mg/kg) enhanced the effects of ouabain on ventricular rhythm, but abolished the ouabain-induced impairment of AV conduction. Bay k 8644 as such increased heart rate (from 318 +/- 11 to 376 +/- 6 beats/min at 0.1 mg/kg) and shortened the PR interval. The negative inotropic effects of the calcium entry blockers were quantified in electrically paced (3 Hz) guinea pig isolated left atria 15 min after pretreatment with ouabain (3 X 10(-7) M). The rank order of potency for the negative inotropic effect was nifedipine greater than verapamil greater than bepridil greater than diltiazem greater than flunarizine. In conclusion, nifedipine, flunarizine, and phenytoin showed obvious and equally effective protection against ouabain-induced arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of glucose-induced insulin secretion by calcium channel blocking drugs in-vitro but not in-vivo in the rat

The organic calcium channel blocking drugs darodipine, nicardipine, diltiazem and verapamil inhibited glucose-induced (8.3 mmol L-1) insulin secretion by rat isolated islets in a concentration-dependent manner. The IC50 values (mumol L-1) for nicardipine, diltiazem and verapamil were 0.0025, 1.94 and 3.6, respectively. There were no significant differences between the potencies of any one drug when compared at two different glucose concentrations (27.8 and 8.3 mmol L-1). Isolated islets were also responsive to the calcium channel activating drugs BAY K 8644 and CGP 28392, which enhanced glucose-induced insulin secretion and prevented the inhibitory effect of verapamil. BAY K 8644 was more potent than CGP 28392. In the anaesthetized rat, neither verapamil (1 mg kg-1 i.v. 10 min before glucose) nor nicardipine (0.2 mg kg-1 i.v.) modified the glucose or insulin response to intravenous glucose whilst producing marked cardiovascular effects. The plasma concentrations of nicardipine (3.9 X 10(-8) M at 10 min post injection) were similar to those producing effects in-vitro whereas the plasma concentrations of verapamil (5 X 10(-7) M) were lower. It thus appears that the islet B cell calcium channel is less sensitive to calcium channel blocking drugs in-vivo than in-vitro. Moreover, in-vivo, the cardiovascular system is more sensitive to these drugs than are the islet B cells, although the potencies of the calcium channel blocking drug in isolated islets are similar to those reported for cardiac muscle and vascular smooth muscle in-vitro.     

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.     

Tissue selectivity of the novel calcium antagonist sesamodil fumarate in isolated smooth muscles and cardiac muscles

The effects of the novel Ca2+ antagonist sesamodil fumarate (JAN), (+)-3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4- methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H- 1,4-benzothiazine hydrogen fumarate (SD-3211), on isolated smooth muscles and cardiac muscles were investigated and compared with those of diltiazem, verapamil, nifedipine and nicardipine. Ca2+ antagonistic activity of SD-3211 (pA2 = 8.42) was more potent than that of diltiazem and verapamil, but less potent than that of nifedipine and nicardipine in isolated pig coronary artery. The inhibition of Ca2(+)-induced contraction by SD-3211 was not reversed by drug washout, whereas that by diltiazem was easily reversed by drug washout. SD-3211 produced a concentration-dependent relaxation (EC50 = 5.7 x 10(-8) mol/l) of KCl-contracted pig coronary artery. The order of potency of the various compounds correlated with their respective Ca2+ antagonistic activities. SD-3211 antagonized KCl-induced contraction, but not that induced by A23187, in the rabbit aorta. On the other hand, negative inotropic and chronotropic effects of SD-3211 on the guinea pig right atria approximated those of diltiazem and verapamil. These results suggest that SD-3211 exerts a potent and long-lasting Ca2+ antagonistic effect on isolated arteries, possessing pharmacological properties diverse from those of known Ca2+ antagonists with respect to tissue selectivity, i.e., it is more vasoselective than diltiazem and verapamil, and more cardioselective than nifedipine and nicardipine.     

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.     

Interaction between calcium and slow channel blocking drugs on atrial rate

The relationship between extracellular calcium concentration and the chronotropic effect of prenylamine, verapamil and nifedipine was studied in isolated spontaneously beating rat atria. The three slow channel blocking drugs produced a concentration-dependent decrease in atrial rate, though with different relative potencies. The order of potency for decreasing atrial rate, independently of the calcium level (1.0, 3.0, 6.0 or 9.0 mmol/l) was: verapamil greater than nifedipine greater than prenylamine. Increasing calcium from 1.0 to 6.0 and 9.0 mmol/l increased atrial rate from 251 +/- beats . min-1 to 265 +/- 6 beats . min-1 and 285 +/- 9 beats . min-1 (mean +/- 1 standard error) respectively (P less than 0.05). Despite their positive chronotropic effect high calcium levels failed to reverse the negative chronotropic effect of the slow channel blockers. Furthermore, the negative chronotropic effect of both verapamil and nifedipine was enhanced at high calcium levels. Raising calcium from 1.0 to 6.0 mmol/l in the presence of verapamil (1 X 10(-7) mol/l) or nifedipine (3 X 10(-7) mol/l) increased 2-fold the negative chronotropic effect of the calcium channel blockers. In addition, the concentration-effect curves for verapamil and nifedipine shifted to the left by 0.50 +/- 0.14 and 0.50 +/- 0.16 log units, respectively, when calcium increased from 1.0 to 6.0 mmol/l. The data show that increasing calcium may produce positive or negative chronotropic effects depending on whether or not the calcium channels are blocked. This paradoxical effect of calcium ions can be produced either by opposite chronotropic effects on automatic cells or by shifting the pacemaker activity to a group of cells which respond in a different way to an increment of calcium.