Separation of the Coronary Vasodilator from the Cardiac Effects of PN 200–110, a New Dihydropyridine Calcium Antagonist, in the Dog Heart

Abstract

Coronary vasodilator and cardiac effects of PN 200-110 [isopropyl-4-(2,1,3-benzoadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate] 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 .apprx. 3 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, 2nd- or 3rd-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 .apprx. 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 .apprx. 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 > SA nodal automaticity > AV nodal conduction > 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.