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.