Cardiovascular effects of losulazine hydrochloride, a peripheral norepinephrine-depleting agent, in nonhuman primates

THE CARDIOVAscular actions of losulazine hydrochloride, a peripheral norepinephrine-depleting agent in rodents, have been determined in conscious cynomolgus monkeys. Acute oral administration of losulazine at 0.1, 1, 10 and 30 mg/kg evoked dose-related hypotensive responses in the absence of significant alterations of heart rate. Although variable, the acute hypotensive effects of losulazine were associated with both reductions of peripheral vascular resistance and reductions in cardiac output. Acute oral administration of doses of losulazine ranging from 0.1 to 30 mg/kg did not cause orthostatic hypotension. Blockade of prostaglandin synthesis and of cholinergic, beta adrenergic and histaminergic receptors did not abolish the hypotensive effect of losulazine at 1 mg/kg i.v. Ganglionic blockade abolished the hypotensive effect of losulazine (1 mg/kg i.v. and 10 mg/kg p.o.), indicating that the hypotensive activity of losulazine was dependent on the presence of sympathetic neuronal activity. Additive combination studies of losulazine and nitroprusside, phentolamine, reserpine or guanethidine implied that losulazine, reserpine and guanethidine had the same site of action, i.e., inhibition of adrenergic neuron function. A comparison of the profiles of effect of losulazine, guanethidine, guanadrel and reserpine on blood pressure, heart rate, blood pressure responses to norepinephrine and tyramine and blood pressure after desipramine pretreatment indicated that losulazine and reserpine had similar mechanisms of action. The data presented in this report are consistent with the conclusion that losulazine reduced arterial blood pressure in nonhuman primates via depletion of norepinephrine from postganglionic adrenergic neurons.