CARDIOVASCULAR PROFILE OF RO-40-5967, A NEW NONDIHYDROPYRIDINE CALCIUM-ANTAGONIST, DELINEATED IN ISOLATED, BLOOD-PERFUSED DOG HEARTS

Coronary and cardiac effects of Ro 40-5967 were compared in isolated, blood-perfused dog heart preparations. Intraarterial Ro 40-5967 increased blood flow in all preparations. In sinoatrial preparations, Ro 40-5967 decreased sinus rate and produced atrial stand-still when administered at high doses. In paced atrioventricular (AV) node preparations, Ro 40-5967 injected into the posterior septal artery (which perfuses the AV node) increased AV conduction time and at high doses produced second- or third-degree AV block. In the same preparations, Ro 40-5967 had little effect on AV conduction time, even at higher doses, when injected into the anterior septal artery (which perfuses the His-Purkinje ventricular system). In paced papillary muscle preparations, Ro 40-5967 reduced the force of contraction only at high doses. In spontaneously beating papillary muscle preparations, Ro 40-5967 decreased the force of contraction only at high doses and had no effect on the rate of automaticity even at higher doses. The dose that doubled blood flow was about one-fifth of the dose that produced a 15% decrease in sinus rate and also one-fifth of the dose that produced a 15% increase in AV conduction time. The dose that reduced the force of contraction by half was >10 times the dose that doubled blood flow. The results indicate that the cardiovascular profile of Ro 40-5967 differs from those of verapamil and diltiazem but instead resembles that of dihydropyridine derivatives, which are classified as vasoselective calcium antagonists.