Abstract

Intravenous infusion of LY141865 (20 micrograms/kg) lowered systemic vascular resistance in anesthetized dogs resulting in a fall in mean arterial blood pressure. These effects require an intact nervous system and involve dopamine receptors as they were abolished by hexamethonium or sulpiride pretreatment. LY141865 does not appear to interact with adrenergic receptors because it did not increase diastolic blood pressure or cardiac rate of normal or hexamethonium-treated dogs, and yohimbine pretreatment did not antagonize its systemic vasodilator and hypotensive actions. Hemodynamic analysis demonstrated that infusion of LY141865 (20 and 100 micrograms/kg i.v.) resulted in persistent arterial hypotension due solely to reduced systemic vascular resistance; aortic blood flow index was maintained. LY141865 produced slight bradycardia and sustained increments in stroke volume index at the highest tested dose. Left ventricular filling pressure was unchanged by LY141865. Regional blood flows to heart, stomach, colon, small intestine, kidneys and marrow-laden bone were not changed during hemodynamic alterations produced by LY141865, although evidence of arteriovenous shunting of blood was observed in skin and skeletal muscle. Comparable systemic vasodilation and arterial hypotension induced by infusion of nitroglycerin reduced gastric and colonic blood flows, but did not produce detectable shunting. The composite data are interpreted to be a reflection of the ability of LY141865 to interact with DA2 dopamine receptors and thereby inhibit neurogenic release of norepinephrine. The present results and known oral efficacy of LY141865 lend further support for the development and use of dopamine receptor agonists for the treatment of cardiovascular disease.