Comparative study of coronary vasodilator and cardiac effects of nitrendipine by use of isolated, blood-perfused dog heart preparations

The coronary vasodilator and cardiac effects of 3-ethyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate (nitrendipine, Bay e 5009) were compared in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node and papillary muscle preparations of dogs with i.a. administration. In all preparations nitrendipine increased (coronary) blood flow. In SA node preparations nitrendipine reduced sinus rate but the reduction remained only about 13% of the basal value even at the highest dose. The dose estimated to produce a 15% (nearly a half maximum) decrease in sinus rate was about 8 times the dose which doubled coronary blood flow. In AV node preparations nitrendipine prolonged AV conduction time when injected into the artery supplying the AV node but the prolongation remained only about 12% of the basal value even at the highest dose. The dose estimated to produce a 15% (nearly a half maximum) increase in AV conduction time was about 11 times the dose which doubled coronary blood flow. When injected into the artery supplying the His-Purkinje ventricular system of AV node preparations, nitrendipine was entirely ineffective on AV conduction. In paced papillary muscle preparations nitrendipine reduced force of contraction. The reduction, however, remained less than 50% of the basal value even at the highest dose. The dose estimated to reduce force of contraction by half was about 11 times the dose which doubled coronary blood flow. Nitrendipine was entirely ineffective on ventricular beating rate of spontaneously beating papillary muscle preparations. These results indicate that nitrendipine is highly vasoselective, and warrant its high efficacy as an antianginal drug.     

Separation of the coronary vasodilator from the cardiac effects of PN 200-110, a new dihydropyridine calcium antagonist, in the dog heart

Coronary vasodilator and cardiac effects of PN 200-110 were compared by use of isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. PN 200-110 was administered intraarterially. In all preparations PN 200-110 produced an increase in coronary blood flow. In SA node preparations, the drug produced a decrease in sinus rate and atrial standstill as well, but only in large doses. The dose that produced a 15% (nearly half-maximum) decrease in sinus rate was about three times the dose that doubled coronary blood flow. In AV node preparations, the drug produced an increase in AV conduction time and, in large doses, second- or third-degree AV block only when it was injected into the artery supplying the AV node. The dose that produced a 15% (nearly half-maximum) increase in AV conduction time was approximately 12 times the dose that doubled coronary blood flow. In paced papillary muscle preparations, the drug produced a decrease in the force of contraction. However, the dose that produced a 50% decrease in the force of contraction of the papillary muscle was approximately 14 times the dose that doubled coronary blood flow. These effects of PN 200-110 were of long duration. The drug was entirely ineffective in changing the rate of ventricular automaticity. The order of selectivity of PN 200-110 was as follows: coronary blood flow greater than SA nodal automaticity greater than AV nodal conduction greater than ventricular muscle contraction. This cardiovascular profile of PN 200-110 is slightly different from that of PY 108-068, a compound closely related to PN 200-110 in chemical structure.     

Coronary vasodilator compared to cardiac effects of PY 108-068, a new dihydropyridine vasodilator, on isolated, blood-perfused dog-heart preparations

We evaluated coronary vasodilator and cardiac effects of PY 108-068 on isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. PY 108-068 was administered intra-arterially (i.a.). PY 108-068 increased (coronary) blood flow in all preparations. In SA node preparations, the drug produced a decrease in sinus rate and, in large doses, atrial standstill. In AV node preparations, the drug produced an increase in AV conduction time. Large doses caused second- or third-degree AV block, but only when injected into the artery supplying the AV node. The doses producing a 15% (nearly half maximum) decrease in sinus rate or a 15% (nearly half maximum) increase in AV conduction time were two to three times the doses that doubled coronary blood flow. In paced papillary muscle preparations, the drug produced a decrease in the force of contraction. However, the dose required to reduce the force of contraction of the papillary muscle by 50% was about 30 times the dose that doubled coronary blood flow. The drug was entirely ineffective on rate of ventricular automaticity. We conclude that PY 108-068 is not likely to produce reflex tachycardia when administered systemically in coronary vasodilator doses.     

Inotropic versus chronotropic, dromotropic, and coronary vasodilator actions of DPI 201-106, a novel positive inotropic agent, in the dog heart

Inotropic versus chronotropic, dromotropic, and vascular effects of DPI 201-106 were assessed in isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. DPI 201-106 was administered intraarterially. In paced papillary muscles the drug produced an increase in developed tension. In spontaneously beating papillary muscles the drug slightly decreased the beating rate. In SA node preparations the drug decreased sinus rate, and atrial standstill ensued from the highest dose. In AV node preparations the drug affected AV conduction only when administered into the AV node artery, and in high doses second- or third-degree AV block occurred. In all preparations the drug increased blood flow. DPI 201-106 at the dose that produced a 50% increase in the force of contraction of ventricular muscle increased coronary blood flow by 8.4%, AV conduction time by 7.6%, and decreased sinus rate by 2.6%, indicating its high selectivity for force. When infused into the AV node artery, the drug in high doses produced dose-dependent prolongations of both the AV nodal conduction time and the functional refractory period of the AV node, which were pronounced with elevation of the pacing rate. These effects of DPI 201-106 are very similar to those of calcium channel blockers.     

Cardiovascular profiles of the calcium antagonists nisoldipine and nifedipine in the blood-perfused dog heart

The coronary vasodilator and cardiac effects of nisoldipine (Bay k 5552) were compared with those of nifedipine in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node and papillary muscle preparations of dogs with i.a. administration. Principally all preparations received both nisoldipine (0.01-10 micrograms) and nifedipine (0.3-3 micrograms). In all preparations both drugs increased (coronary) blood flow, and in this respect they were nearly equipotent. In SA node preparations nisoldipine reduced sinus rate and produced atrial standstill in large doses. Nifedipine also reduced sinus rate in the dose range tested. In this respect, too, both drugs were nearly equipotent. The ratio of the dose that produces a 15% (nearly half-maximum) decrease in sinus rate to the dose that doubles coronary blood flow was about 7 for nisoldipine and about 9 for nifedipine. In AV node preparations both nisoldipine and nifedipine prolonged AV conduction time and produced second- or third-degree AV block in large doses only when injected into the artery supplying the AV node but not into the artery supplying the His-Purkinje-ventricular system. In suppressing AV nodal conduction both drugs were nearly equipotent. The ratio of the dose that produces a 15% (nearly half-maximum) increase in AV conduction time to the dose that doubles coronary blood flow was about 3.3 for nisoldipine and about 5 for nifedipine. In paced papillary muscle preparations both nisoldipine and nifedipine reduced the force of contraction. In this respect, too, both drugs were nearly equipotent. The ratio of dose that reduces the force of contraction by half to the dose that doubles coronary blood flow was about 5 for both of them.(ABSTRACT TRUNCATED AT 250 WORDS)     

Profile of cardiac and coronary vasodilator effects of MS-857, a novel cardiotonic agent, assessed in isolated, blood-perfused heart preparations of the dog

MS-857 is a novel orally active nonglycoside and nonsympathomimetic cardiotonic agent. Cardiovascular properties of MS-857 were assessed in isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparation of the dogs. MS-857 (0.3-100 nmol) was injected intraarterially (i.a.). In paced papillary muscles, the drug produced a dose-dependent increase in developed tension. In spontaneously beating papillary muscles, MS-857 was ineffective on the ventricular automaticity. The drug increased sinus rate in SA node preparations and shortened AV conduction time by accelerating AV nodal conduction in AV node preparations. In all preparations, MS-857 increased coronary blood flow. The drug produced no arrhythmia in all doses tested. At doses which MS-857 produced a 50% increase in developed tension of papillary muscle, the drug also produces coronary vasodilatation with minimal chronotropic and dromotropic effects. In having such a cardiovascular profile, MS-857 resembles both milrinone and MCI-154 among few cardiotonic agents.     

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.     

Cardiac and coronary vasodilator effects of the novel cardiotonic agent, MCI-154, assessed in isolated, blood-perfused dog heart preparations

MCI-154 is a potent nonglycoside and non-sympathomimetic cardiotonic agent with a pyridazinone structure. We assessed its cardiac and coronary vasodilator effects by use of isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. The drug (1-100 nmol) was injected intraarterially. MCI-154 increased the force of contraction of paced and unpaced papillary muscles but failed to affect the rate of automaticity of the latter. It increased sinus rate and shortened AV conduction time by accelerating AV nodal conduction, but in all doses examined it produced no arrhythmias. In all preparations, it increased blood flow. All the effects were long-lasting (1-2 h). MCI-154, however, was not homogeneously effective on these cardiovascular variables. The drug was nearly equieffective in producing a positive inotropic effect and coronary vasodilatation, but less effective in producing positive chronotropic and dromotropic effects. In having such a cardiovascular profile, MCI-154 most resembles milrinone among new cardiotonic agents, although unlike milrinone, its main mechanism of cardiotonic action is believed to be the sensitization of the contractile proteins to Ca2+. Whatever mechanisms are involved, the revealed cardiovascular profile of MCI-154 justifies its clinical trial in the treatment of heart failure.     

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.     

Are the cardiovascular effects of gentamicin similar to those of calcium antagonists?

Cardiac and coronary vasodilator effects of gentamicin (GM) were investigated in isolated, blood-perfused papillary muscle, sino-atrial (SA) node and atrioventricular (AV) node preparations of dogs. GM (0.3-100 mumol) was injected intraarterially. GM produced an increase in coronary blood flow in all preparations. In paced papillary muscle preparations, GM reduced the force of contraction. In spontaneously beating papillary muscle preparations, GM decreased the rate of automaticity and the force of contraction. In SA node preparations, GM decreased the sinus rate. In AV node preparations, GM injected into the posterior septal artery (which supplies the AV node) increased AV conduction time and in large doses, produced third-degree AV block. In the same preparations, GM 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) and reduced the amplitude of ventricular bipolar electrograms. The order of potencies of GM on the above cardiovascular variables is as follows: Coronary blood flow greater than or equal to ventricular muscle contraction greater than ventricular automaticity greater than SA nodal automaticity greater than AV nodal conduction greater than intraventricular conduction. This cardiovascular profile is different from those of organic calcium-antagonists, but rather similar to that of manganese ions, reflecting its own mechanism of action.     

Cardiac versus coronary vasodilator actions of isobutylmethylxanthine in dogs: comparison with theophylline

Cardiac and coronary vasodilator effects of isobutylmethylxanthine (IBMX) and theophylline were compared in isolated, blood-perfused papillary muscle, sino-atrial (SA) node and atrioventricular (AV) node preparations of dogs. IBMX (1 nmol-1 mumol) and theophylline (30 nmol-10 mumol) were injected intra-arterially. In paced papillary muscle preparations, both agents increased the force of contraction. In spontaneously beating papillary muscle preparations, both agents increased the rate of ventricular automaticity. In SA node preparations, both agents increased sinus rate. In AV node preparations, both agents decreased AV conduction time only when they were injected into the artery supplying the AV node. In all preparations, both agents increased coronary blood flow. However, both agents were not homogeneously effective on these cardiovascular variables, but showed selectivity in the following order: Ventricular muscle contraction not equal to coronary blood flow greater than SA nodal automaticity not equal to AV nodal conduction greater than ventricular automaticity. These results indicate that IBMX and theophylline have almost an identical profile in their cardiac and coronary vasodilator effects. The two agents were different in that IBMX was 40-50 times as potent as theophylline in producing these effects. Thus, both agents appeared to express their cardiovascular profiles mainly through inhibition of cyclic AMP phosphodiesterase, although theophylline has been claimed to have additional actions.     

Cardiovascular actions of the dihydropyridine calcium antagonist nimodipine in the dog

When injected i.v. into anaesthetized, open-chest dogs, isopropyl (2-methoxyethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinedicarboxylate (nimodipine, Bay e 9736) (0.3-10 micrograms/kg) produced an increase in coronary sinus outflow and decreases in mean arterial blood pressure, coronary resistance, arterio-venous oxygen difference and heart rate in a dose-dependent manner, but virtually no change in myocardial oxygen consumption. At 3 micrograms/kg i.v. of the drug coronary resistance fell nearly to half the pre-drug value, coronary sinus outflow nearly doubled and heart rate decreased by about 10 beats/min. Myocardial oxygen consumption was slightly reduced at 30 micrograms/kg i.v. and atrioventricular (AV) conduction time was slightly increased at 10 and 30 micrograms/kg i.v. of the drugs. When the coronary vascular and cardiac effects of nimodipine were assessed in isolated, blood-perfused dog heart preparations, i.e., sinoatrial node, AV node and papillary muscle preparations, by intra-arterial administration, the following was revealed. In nearly twice the dose doubling coronary arterial blood flow, nimodipine produced a 15% decrease in sinus rate and a 15% increase in AV conduction time. However, in reducing the force of contraction of the papillary muscle by half the pre-drug value was needed nearly 17 times the dose of nimodipine doubling coronary arterial blood flow. Suppression of AV conduction by large doses of nimodipine was evident only when it was injected into the artery supplying the AV node but not into the artery supplying the His-Purkinje-ventricular system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Is the cardiovascular profile of BRL 34915 characteristic of potassium channel activators?

To see whether the cardiovascular profile of BRL 34915, a potent vasodilator, is characteristic of potassium channel activators, we investigated its cardiac effects by use of isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. BRL 34915 was injected intraarterially. It produced an increase in (coronary) blood flow in all preparations. In paced papillary muscle preparations, BRL 34915, although in large doses, produced a decrease in the force of contraction, leading nearly to abolition. The negative inotropic effect of BRL 34915 was accompanied by a marked acceleration of the repolarization of field cardiac action potentials. In some preparations, fibrillation occurred after profound negative inotropy and subsided spontaneously. In unpaced papillary muscles, BRL 34915 in large doses decreased rate of ventricular automaticity. In SA node preparations, BRL 34915 in large doses reduced sinus rate down to approximately 64% of the basal rate and produced atrial standstill in some. In AV node preparations, BRL 34915 in large doses slightly prolonged AV conduction time only when injected into the AV node artery. Nevertheless, it produced third-degree AV block in some. These cardiac effects of BRL 34915 are very similar to those of nicorandil and pinacidil, whose cardiac effects result exclusively from an increase in membrane K conductance in cardiac muscle cells. Like nicorandil and pinacidil, BRL 34915 was highly vasoselective.     

PHARMACOLOGICAL PROFILE OF A NEW CORONARY VASODILATOR DRUG, 2-NICOTINAMIDOETHYL NITRATE (SG-75)

1. In anaesthetized, open-chest dogs, 2-nicotinamidoethyl nitrate (SG-75) administered intravenously (0.3–1 mg/kg) or intraduodenally (3 mg/kg) produced decreases in systemic blood pressure, coronary resistance, heart rate and an increase in coronary sinus outflow, but virtually no change in myocardial oxygen consumption and atrioventricular conduction. The effects of SG-75 administered intraduodenally emerged within a few minutes after dosing and lasted over about 1 h. 2. In isolated, blood-perfused sino-atrial node preparations of the dog SG-75 administered into the sinus node artery decreased slightly sinus rate at the dose which doubled blood flow through the artery. 3. In isolated, blood-perfused atrioventricular node preparations of the dog SG-75 administered into the atrioventricular node artery did not impair atrioventricular conduction even in doses which increased blood flow through the artery to more than twice the basal level. 4. In isolated, blood-perfused papillary muscle preparations of the dog SG-75 administered into the anterior septal artery scarcely affected force of contraction of the papillary muscle at the dose which doubled blood flow through the artery, although in further large doses it produced a transient decrease in the force of contraction. In extremely large doses it produced ventricular fibrillation. 5. In anaesthetized, open-chest dogs in which cardiac input was kept constant SG-75 (0.01–1 mg/kg) administered into the ascending aorta increased venous return without changing systemic output. 6. 2-Nicotinamidoethyl alcohol, a denitrated compound of SG-75, had no vasodilator action in doses comparable to those of the parent compound. 7. These results indicate SG-75 to be a potential antianginal drug having no cardiodepressant actions but having properties uncharacteristic of the nitrates.     

Profile of cardiovascular effects of NKH477, a novel forskolin derivative, assessed in isolated, blood-perfused dog heart preparations: comparison with isoproterenol.

Cardiac and coronary vasodilator effects of NKH477, a novel water-soluble forskolin derivative, and isoproterenol, a nonselective beta-adrenoceptor full agonist, were compared in isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. Both agents were injected intraarterially. The two agents increased the force of contraction of the paced papillary muscle and of the unpaced muscle, and the rate of automaticity of the latter. They increased sinus rate and accelerated AV nodal conduction. In producing these cardiac effects, both agents were similar, although NKH477 was 120-350 times less potent than isoproterenol; however, NKH477 differed distinctly from isoproterenol in that the former increased coronary blood flow more greatly than the latter. Thus, NKH477 is more coronary vasodilatory than positive inotropic, and more positive inotropic than positive chronotropic. Such a cardiovascular profile of NKH477 was similar to that of forskolin, except for the duration of actions; NKH477 was longer-acting than forskolin.     

The effects of indecainide, a new antidysrhythmic drug, on nodal tissues in the isolated rabbit heart

The effects of indecainide, previously shown to be a class 1c antiarrhythmic drug restricting fast inward current, have been studied on rabbit sinoatrial (SA) node and atrioventricular (AV) node. Indecainide at concentrations up to 2.9 mumol/L in 5 preparations did not produce a sinus bradycardia, nor reduce the maximum rate of rise of the intracellular action potential of sinus node cells, but it did antagonize the tachycardia induced by increasing the extracellular calcium concentration. Indecainide slightly prolonged AV conduction time [from 49.07 +/- 4.43 ms to 57.37 +/- 0.90 ms at 2.9 mumol/L (means +/- SEM in four preparations)], but this small delay could be attributed to slowing of conduction in atrial fibres leading to the node, rather than to an effect on the AV nodal cells themselves. It is concluded that indecainide does not block channels carrying inward calcium current in nodal tissues.     

MECHANISMS UNDERLYING THE CARDIOVASCULAR ACTION OF A NEW DIHYDROPYRIDINE VASODILATOR, YC-93

1.The mechanisms underlying the cardiovascular action of YC-93, a new dihydropyridine vasodilator with cyclic AMP phosphodiesterase inhibitory activity, was investigated by comparing its effects wth those of papaverine in various isolated, blood-perfused heart preparations of the dog. 2. In all preparations YC-93 injected into the nutrient arteries produced a dose-dependent increase in blood flow, and in this respect YC-93 was about twenty times more potent than papaverine on a weight basis. 3. In sinoatrial node preparations YC-93 injected into the sinus node artery decreased sinus rate in a dose-dependent manner, and in large doses produced atrial standstill. 4. In atrioventricular (a.v.) node preparations YC-93 injected into the a.v. node artery increased a.v. conduction time in a dose-dependent manner, and in large doses produced a second or third degree block of a.v. conduction. However YC-93 injected into the anterior septal artery scarcely affected a.v. conduction. 5. In spontaneously contracting papillary muscle preparations YC-93 injected into the anterior septal artery failed to affect ventricular automaticity in doses which markedly decreased developed tension of papillary muscles. 6. In papillary muscle preparations driven at a fixed rate YC-93 injected into the anterior septal artery produced a dose-dependent decrease in developed tension of papillary muscles. 7. Unlike YC-93, papaverine decreased a.v. conduction time in a.v. node preparations and increased developed tension of papillary muscle preparations. 8. The cardiac effects of YC-93 elucidated in the present experiments are characteristic of calcium-antagonistic vasodilators. The action of YC-93 as an inhibitor of cyclic AMP phosphodiesterase does not appear to play a role in its cardiac action.     

Comparative effects of a new calcium channel antagonist, mepirodipine, on rabbit spontaneously beating sino-atrial node cells.

The effects of mepirodipine, a new 1,4-dihydropyridine calcium antagonist, on the membrane potentials were examined on spontaneously beating rabbit sino-atrial (SA) node cells and on the membrane currents under voltage-clamped conditions. Mepirodipine 3 x 10(-9) M significantly decreased the action potential amplitude and the maximum rate of depolarization. The action potential duration and the cycle length were prolonged. Sinus arrest occurred at 10(-8) M in all of five preparations. In voltage-clamped SA node cells, mepirodipine in concentrations higher than 3 x 10(-9) M decreased the slow inward current. It did not affect the steady state outward current and the hyperpolarization-activated inward current. Verapamil, diltiazem and nifedipine produced similar changes in the action potential parameters, but at a concentration of 10(-6) M. At concentrations higher than 10(-5) M, they elicited sinus arrest. These results suggest that mepirodipine is a more potent inhibitor of spontaneous calcium-dependent SA node impulse generation than the three other calcium antagonists tested.     

Effect of DHP-218, a novel dihydropyridine phosphonate, on atrioventricular nodal conductivity compared with its vascular effect in dogs

The effect of DHP-218, a dihydropyridine phosphonate Ca2+ channel blocker, on atrioventricular (AV) nodal conductivity was compared with its vascular effect in dogs. In isolated, blood-perfused AV node preparations, a long-lasting increase in AV conduction time which culminated in second- or third-degree AV block at large doses occurred when DHP-218 was injected into the AV node artery, but not when injected into the artery that supplies the His-Purkinje-ventricular system. However, with DHP-218, a far longer-lasting increase in blood flow through both arteries occurred, and at smaller doses it occurred with little effect on AV conduction. In anesthetized, open-chest dogs of which heart rate was controlled at 150 beats/min, intravenous DHP-218 produced an initially rather quick and later very slowly developing and long-lasting fall in blood pressure. AV conduction time was prolonged only after the largest dose. The functional refractory period of the AV conduction system was rather shortened in all doses examined except for the largest dose. A marked increase in AV conduction time which culminated in third-degree AV block was seen in one of six dogs, only under conditions in which the heart was deprived of central neural control. These results indicate appreciable selectivity of DHP-218 for vasculature versus the AV node.     

Effect of MCI-176, a new calcium antagonist, on the calcium induced contraction of isolated porcine coronary arteries

Calcium antagonistic activity of MCI-176, a new calcium antagonist, was compared with those of diltiazem and nifedipine in isolated depolarized porcine coronary arteries. MCI-176, diltiazem and nifedipine competitively inhibited calcium contraction of the large coronary arteries, and their pA2 values were 7.49, 6.89 and 9.55, respectively. Similar competitive inhibition by MCI-176, diltiazem and nifedipine of calcium contraction was also observed in the small coronary arteries, and their pA2 values were 7.38, 6.83 and 9.91, respectively. Although calcium antagonistic activity of nifedipine was several hundreds times more potent than MCI-176 and diltiazem, the action of nifedipine, unlike MCI-176 and diltiazem, favored the small coronary arteries rather than the large coronary arteries.