Vol. 281, Issue 1, 337-346, 1997

-Adrenergic Activity and Cardiovascular Effects of Besipirdine HCl (HP 749) and Metabolite P7480 in Vitro and in the Conscious Rat and Dog

John W. Hubbard, Scott T. Nordstrom, Craig P. Smith, Karen M. Brooks, Lynn Laws-Ricker, Lily Zhou and Hugo M. Vargas

Section of Clinical Pharmacology, Clinical Research Department (J.W.H.), Neuroscience (C.P.S., S.T.N.) and Investigative Pharmacology (K.M.B., L.L.R., L.Z., H.M.V.), Hoechst Marion Roussel, Inc., Bridgewater, New Jersey

Besipirdine displays potent adrenergic activity in a variety of pharmacological and behavioral tests. Based on this property, we evaluated the effects of besipirdine and its N-despropyl metabolite N-despropyl-besipirdine (P7480) on cardiovascular function in rats and dogs. Besipirdine and P7480 bind alpha-2 adrenoceptors (K_I: 380 and 10 nM, respectively) and facilitate the stimulated release of [³H]norepinephrine from rat cortical slices due to presynaptic autoreceptor blockade. In rat aorta rings and the pithed rat, P7480, but not besipirdine, also behaved as a postsynaptic alpha-1 adrenoceptor agonist. In conscious rats, besipirdine (2-10 mg/kg, p.o.) and P7480 (3-10 mg/kg, p.o.) produced dose-related increases in mean arterial pressure. Inhibition of hepatic cytochrome P-450 enzyme activity blocked the pressor effect of besipirdine, but not of P7480; therefore, P7480 mediated besipirdine's pressor effect. The bradycardia after either agent was unaffected. In conscious dogs, besipirdine (0.1-2 mg/kg, p.o.) also produced dose-related hypertension and bradycardia. The hypertension, but not the bradycardia, were sensitive to prazosin (3 mg/kg, p.o.), but not hexamethonium (10 mg/kg, p.o.). Muscarinic and beta-adrenergic receptor blockade studies in anesthetized dogs demonstrated the bradycardia to be due to withdrawal of cardiac sympathetic tone. These findings suggest that besipirdine's peripheral hypertensive effect is primarily mediated by the pressor metabolite P7480, although facilitated norepinephrine release may contribute. Besipirdine's bradycardic action appears to be centrally mediated, because both compounds lacked direct negative chronotropic activity on spontaneously beating guinea pig atria in vitro.