title: 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.
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects*; D004110:Diltiazem / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D009529:Nicardipine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014700:Verapamil / Q000494:pharmacology*
chemical_list: D014700:Verapamil; D009529:Nicardipine; D004110:Diltiazem