Regional vascular effects of MPC-1304, a novel dihydropyridine derivative, in conscious normotensive and spontaneously hypertensive rats

K Miyoshi, A Kanda, Y Nozawa, M Nakano and H Miyake

Pharmacology Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.

The purpose of this study was to compare the regional vascular effect of a novel dihydropyridine derivative, MPC-1304 [(+/-)- methyl-2- oxopropyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3, 5- pyridinedicarboxylate], with that of nifedipine and manidipine in conscious spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The radioactive microsphere technique was used to measure systemic and regional hemodynamic parameters before and 1 hr after p.o. administration of drugs. In SHR, MPC-1304 at a dose of 1 mg/kg reduced the mean blood pressure and systemic vascular resistance and increased cardiac output, as did nifedipine (10 mg/kg) and manidipine (3 mg/kg). MPC-1304, as well as nifedipine, significantly increased the blood flow in pulmonary, gastric, small intestinal and skeletal muscular beds and reduced their vascular resistance. Manidipine increased regional blood flow only in small intestinal and skeletal muscular beds. Only MPC-1304 increased the renal blood flow. In WKY, MPC-1304 and nifedipine reduced the mean blood pressure and systemic vascular resistance to lesser degrees than in SHR. Both drugs significantly increased coronary and skeletal muscular blood flow. MPC-1304 significantly reduced the renal blood flow without altering renal vascular resistance, in striking contrast to its renal effect in SHR. These findings suggest that MPC- 1304 possesses a genetic hypertension-dependent renal vasodilating action, unlike nifedipine and manidipine. One possible mechanism for this difference in the effect on renal circulation between SHR and WKY may involve the potent antagonizing effects of MPC-1304 on alpha-2 adrenoceptor-mediated vasoconstriction.

Volume 277, Issue 3, pp. 1328-1336, 06/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics