The mechanism of centrally mediated cardiovascular actions of the three structurally different calcium antagonists, verapamil, diltiazem and nicardipine, in rats

Abstract

Centrally mediated cardiovascular effects of the three structurally different calcium antagonists (Ca-antagonists), i.e., verapamil, diltiazem and nicardipine, were studied in rats. In conscious rats, when administered intracerebroventricularly (i.c.v.) in doses of 0.3, 1 and 3 micrograms/kg/min for 30 min, all the three Ca-antagonists induced dose-dependent increases in mean arterial pressure (MAP) and pulse rate (PR), whereas nicardipine administered intravenously (i.v.) caused a decrease in MAP and an increase in PR. In anesthetized rats all the three Ca-antagonists in a dose of 3 micrograms/kg/min for 60 min i.c.v. significantly potentiated the hypotensive and bradycardic effects of i.c.v. clonidine. Nicardipine, in a dose of 0.3 microgram/kg/min for 60 min i.c.v., attenuated the hypotensive and bradycardic effects of i.c.v. clonidine or B-HT 920, an alpha 2-adrenoceptor agonist, in anesthetized rats, whereas it did not modify the cardiovascular effect of i.c.v. angiotensin II or gamma-aminobutylic acid in conscious rats. Nicardipine, in a dose of 0.3 microgram/kg/min for 60 min i.v., did not modulate the hypotensive and bradycardic effects of i.c.v. clonidine. 3-Isobutyl-l-methylxanthine (IBMX), a cyclic AMP phosphodiesterase inhibitor, in a dose of 3 micrograms/kg/min for 60 min i.c.v., also attenuated the hypotensive and bradycardic effects of i.c.v. clonidine. Potentiation by the three i.c.v. Ca-antagonists of the hypotensive and bradycardic effects of clonidine would be explainable if their inhibitory effect on Ca-influx is exerted at presynaptic nerve terminals but not at postsynaptic. The mechanisms of the cardiovascular effect of i.c.v. Ca-antagonists still remain to be elucidated but may be independent of a central alpha 2-adrenoceptor mechanism. Dihydropyridine Ca-antagonists like nicardipine are also potent inhibitor of cyclic AMP phosphodiesterase. Since IBMX mimicked the effect of nicardipine, the effect of a low dose of i.c.v. nicardipine in attenuating the hypotensive and bradycardic effects of i.c.v. clonidine may be mediated by inhibition of cyclic AMP phosphodiesterase in the central nervous system.