MPC-1304, ANOTHER TYPE OF DIHYDROPYRIDINE, POSSESSING HIGHLY POTENT VASODILATING ACTION

We investigated the vasodilating action of MPC-1304, one of the most p otent dihydropyridines causing hypotension, in anesthetized dogs and c ompared this with its binding properties. After intraarterial injectio n, MPC-1304 was 3 times less potent than other dihydropyridines (nitre ndipine, nifedipine, nicardipine and nisoldipine) in increasing femora l blood flow. After infusion of these drugs, however, MPC-1304 was the most potent in increasing femoral blood flow. The onset and recovery of the effect of MPC-1304 on femoral blood flow were slower than for n ifedipine. Higher doses of Bay K 8644 were needed to antagonize the st imulating activity of MPC-1304 than for nifedipine. In a competition a ssay of [H-3]nitrendipine binding, MPC-1304 and its metabolites bound to the dihydropyridine receptor with lower affinity than the other dih ydropyridines. The binding affinity of [H-3]MPC-1304 was lower than th at of [H-3]nitrendipine, consistent with the potency of this drug to i ncrease femoral blood flow by bolus injection. The association and dis sociation of [H-3]MPC-1304 was slower than those of [H-3]nitrendipine, which is consistent with the slow onset and long-lasting vasodilating effects of MPC-1304 on femoral blood flow. Moreover, diltiazem reduce d a part of [H-3]MPC-1304 binding in a competitive manner. In ex vivo binding assays with serum and aorta obtained after oral administration of the drug in spontaneously hypertensive rats, MPC-1304 inhibited [3 H]nitrendipine binding to membrane preparations less potently than ni fedipine. From these results, we conclude that MPC-1304 is a different type of dihydropyridine possessing the most potent vasodilating actio n of the representative dihydropyridines tested. Its activity cannot b e explained solely by a slow interaction with voltage-dependent Ca2+ c hannels.