ALPHA-ADRENERGIC ACTIVITY AND CARDIOVASCULAR EFFECTS OF BESIPIRDINE HCL (HP-749) AND METABOLITE P7480 IN-VITRO AND IN THE CONSCIOUS RAT ANDDOG

Besipirdine displays potent adrenergic activity in a variety of pharma cological and behavioral tests. Based on this property, we evaluated t he effects of besipirdine and its N-despropyl metabolite N-despropyl-b esipirdine (P7480) on cardiovascular function in rats and dogs. Besipi rdine and P7480 bind alpha-2 adrenoceptors (K-i: 380 and 10 nM, respec tively) and facilitate the stimulated release of [H-3]norepinephrine f rom rat cortical slices due to presynaptic autoreceptor blockade. In r at aorta rings and the pithed rat, P7480, but not besipirdine, also be haved as a postsynaptic alpha-1 adrenoceptor agonist. In conscious rat s, besipirdine (2-10 mg/kg, p.o.) and P7480 (3-10 mg/kg, p.o.) produce d dose-related increases in mean arterial pressure. Inhibition of hepa tic cytochrome P-450 enzyme activity blocked the pressor effect of bes ipirdine, but not of P7480; therefore, P7480 mediated besipirdine's pr essor effect. The bradycardia after either agent was unaffected. In co nscious dogs, besipirdine (0.1-2 mg/kg, p.o.) also produced dose-relat ed hypertension and bradycardia. The hypertension, but not the bradyca rdia, were sensitive to prazosin (3 mg/kg, p.o.), but not hexamethoniu m (10 mg/kg, p.o.). Muscarinic and beta-adrenergic receptor blockade s tudies in anesthetized dogs demonstrated the bradycardia to be due to withdrawal of cardiac sympathetic tone. These findings suggest that be sipirdine's peripheral hypertensive effect is primarily mediated by th e pressor metabolite P7480, although facilitated norepinephrine releas e may contribute. Besipirdine's bradycardic action appears to be centr ally mediated, because both compounds lacked direct negative chronotro pic activity on spontaneously beating guinea pig atria in vitro.