MPC-1304, another type of dihydropyridine, possessing highly potent vasodilating action.
We investigated the vasodilating action of MPC-1304, one of the most potent dihydropyridines causing hypotension, in anesthetized dogs and compared this with its binding properties. After intraarterial injection, MPC-1304 was 3 times less potent than other dihydropyridines (nitrendipine, nifedipine, nicardipine and nisoldipine) in increasing femoral 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 nifedipine. Higher doses of Bay K 8644 were needed to antagonize the stimulating activity of MPC-1304 than for nifedipine. In a competition assay of [3H]nitrendipine binding, MPC-1304 and its metabolites bound to the dihydropyridine receptor with lower affinity than the other dihydropyridines. The binding affinity of [3H]MPC-1304 was lower than that of [3H]nitrendipine, consistent with the potency of this drug to increase femoral blood flow by bolus injection. The association and dissociation of [3H]MPC-1304 was slower than those of [3H]nitrendipine, which is consistent with the slow onset and long-lasting vasodilating effects of MPC-1304 on femoral blood flow. Moreover, diltiazem reduced a part of [3H]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 [3H]nitrendipine binding to membrane preparations less potently than nifedipine. From these results, we conclude that MPC-1304 is a different type of dihydropyridine possessing the most potent vasodilating action of the representative dihydropyridines tested. Its activity cannot be explained solely by a slow interaction with voltage-dependent Ca2+ channels.
Miyoshi
K
K
Pharmacology Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Kanda
A
A
Miyake
H
H
Ichihara
K
K
Kamei
H
H
Nagasaka
M
M
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D009124:Muscle Proteins; D014665:Vasodilator Agents; C059427:aranidipine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester