Receptor binding characteristics of nimodipine and other 1,4-dihydropyridine Ca++ antagonists in relation to their pharmacokinetics in senescent brain

Characteristics of L-type calcium (Ca++) antagonist receptors in brains of senescence-accelerated prone mice (SAMP8:) showing age-related deterioratio n of learning and memory were examined using (+)-[H-3]PN 200-110 as a radio ligand. There was a significant decrease in maximal number of binding sites (Bmax) for (+)-[H-3]PN 200-110 in brains of SAMP8 compared to the control mice (SAMR1) both in vitro and in vivo. Following intravenous injection of (+)-[H-3]PN 200-110, the area under the curve for brain concentration of th e radioligand (AUC(brain)) in SAMP8 was significantly smaller than that in SAMR1. These data suggest a decrease in the density of Ca++ antagonist rece ptors in brain of SAMP8. Chronic oral administration of nimodipine and nica rdipine to SAMP8 caused a significant increase in Bmax values of (+)-[H-3]P N 200-110 binding in the cerebral cortex and hippocampus. This may reflect up-regulation of brain Ca++ antagonist receptors as a result of the prolong ed blockade by nimodipine and nicardipine. On the other hand, similar admin istration of amlodipine failed to produce enhancement of Bmax values of (+) -[H-3]PN 200-110 binding. The brain concentration of [H-3]nimodipine after intravenous injection of the radioligand in mice and its ratio to plasma co ncentration were significantly higher than those of (-)-[3H]amlodipine. Als o, a significant amount of specific binding in brain of these mice was dete cted in vivo with [H-3]nimodipine but not with (-)-[H-3]amlodipine. Thus. t he present study provides pharmacokinetic and pharmacodynamic evidence for the utility of nimodipine against neurological disorders associated with th e aging brain.