A sustained occupancy in vivo of cardiovascular calcium antagonist receptors by mepirodipine and its relation to pharmacodynamic effect in spontaneously hypertensive rats
Yamada, S.; Matsuoka, Y.; Kato, Y.; Kimura, R.; Inagaki, O.
Journal of Pharmacology and Experimental Therapeutics 262(2): 589-594
1992
ISSN/ISBN: 0022-3565 PMID: 1323654 Document Number: 402305
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 (B-max) compared to control values. At 12 hr later, the B-max value returned to the control value. On the other hand, the mepirodipine administration had little effect on the dissociation constant (K-d) 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 B-max values for (+)-(3H)PN 200-110 binding only at 0.5 hr after mepirodipine administration. In contrast, nifedipine administration had a significant increase in K-d values for cardiac (+)-(3H)PN 200-110 binding without a change in B-max 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 mu-Ci) to SHR, there was specific binding of the ligand in particulate fractions of heart, aorta, ileum and cerebral cortex, but not liver and kidney. The in vivo specific binding of (+)-(3H)PN 200-110 in cardiac, aortic and ileal tissues of SHR was significantly (34-90%) decreased at 0.5 and 6 hr after an oral administration of mepirodipine (3 mg/kg). The present study indicates that mepirodipine may produce a selective and sustained occupancy in vivo of cardiovascular Ca++ antagonist receptors in SHR. Thus, the in vivo measurement of receptor occupancy in SHR by Ca++ antagonists may become a useful method to evaluate their pharmacokinetics and pharmacodynamics.