Cardiovascular effects of the 1-(2″ pyrimidyl)-4 piperonyl piperazine (ET 495)

Abstract

ET 495 is a new piperazine derivative inducing complex cardiovascular changes. In dogs infusion of low doses (20 μg/kg/min i.v.) or intraduodenal administration (2 mg/kg) induced a long lasting increase in femoral blood flow and decrease in splanchnic blood flow without changing blood pressure, heart rate, cardiac output and cerebral, coronary, or renal blood flow. By intravenous route (0.2 mg/kg), the peripheral vasodilatation followed a short hypertensive phase and polypnea. This hypertension appeared to be due to selective stimulation of cardioaortic chemoreceptors and was abolished by hexamethonium or by destruction of the chemoreceptors with acetic acid. This hypertension was accompanied by an increased discharge of sympathetic nerves; the discharge was more marked in the splanchnic nerve than in the lumbar sympathetic chain or in the cardiac nerve. Femoral vasodilatation was reversed by denervation of the lind limb, by ganglion blocking drugs and by depletion of catecholamines with reserpine or guanethidine. Moreover, the vasodilator phase was accompanied by a reduction of sympathetic discharges. This decreased sympathetic tome was more marked in the lumbar sympathetic chain than in the splanchnic nerve and less obvious in the cardiac nerve. The site of the reduced sympathetic tone was ascertained by localized injections. Injection of low doses of ET 495 into the main pulmonary artery induced hypotension, bradycardia and femoral vasodilatation. Injection of low doses into the femoral artery increased blood flow but after denervation of the hind limb, the same injection reduced the blood flow. Thus it appeared that ET 495 stimulated receptors located in the main pulmonary artery and femoral bed leading to reflex vasodilatation. In cat and rats ET 495, induced hypotension, bradycardia, reduction of respiration and decreased splanchnic discharges. These effects were reduced by bilateral vagotomy. It is concluded that ET 495 induces a selective increase in femoral blood flow in dogs by a shift from the splanchnic circulation.