A sustained occupancy in vivo of cardiovascular calcium antagonist receptors by mepirodipine and its relation to pharmacodynamic effect in spontaneously hypertensive rats

S Yamada, Y Matsuoka, Y Kato, R Kimura and O Inagaki

Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan.

The occupancy in vivo of cardiovascular and cortical Ca++ antagonist receptors by mepirodipine in spontaneously hypertensive rats (SHR) was investigated. At 0.5, 3 and 6 hr after an oral administration of mepirodipine (3 mg/kg) in SHR, there was a significant (69, 51 and 41%, respectively) decrease in the number of cardiac (+)-[3H]PN 200-110 binding sites (Bmax) compared to control values. At 12 hr later, the Bmax value returned to the control value. On the other hand, the mepirodipine administration had little effect on the dissociation constant (Kd) for cardiac (+)-[3H]PN 200-110 binding except at 0.5 hr, when there was a significant increase in the value, suggesting a change in the density rather than affinity of Ca++ antagonist receptors. In the cerebral cortex of these rats, there was a significant (34%) decrease in Bmax values for (+)-[3H]PN 200-110 binding only at 0.5 hr after mepirodipine administration. In contrast, nifedipine administration had a significant increase in Kd values for cardiac (+)- [3H]PN 200-110 binding without a change in Bmax values. The occupancy of cardiac Ca++ antagonist receptors by mepirodipine correlated significantly with its hypotensive effect in SHR. There was approximately a 39 mm Hg reduction of blood pressure by occupying 50% of these receptors. After an i.v. injection of (+)-[3H]PN 200-110 (15 microCi) to SHR, there was specific binding of the ligand in particulate fractions of heart, aorta, ileum and cerebral cortex, but not liver and kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 262, Issue 2, pp. 589-594, 08/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics