SYSTEMIC HEMODYNAMIC AND REGIONAL CIRCULATORY EFFECTS OF CENTRALLY ADMINISTERED ENDOTHELIN-1 ARE MEDIATED THROUGH ET(A) RECEPTORS

Central endothelin (ET) has been implicated in the regulation of the cardiovascular system. The effect of intracerebroventricular (i.c.v.) administration of ET-1 or IRL 1620 (5, 15 and 45 ng) on the systemic hemodynamics and regional circulation was studied in anesthetized rats using a radioactive microsphere technique. Systemic hemodynamics and regional blood circulation were determined before (baseline) and at 30 min after the injection of each dose of ET-1 or IRL 1620. Administration of saline (5 mu l, i.c.v.) did not produce any significant cardiovascular effects. The lower doses of ET-1 (5 and 15 ng) did not produce any significant effect on blood pressure (BP), heart rate (HR), cardiac output (GO), stroke volume (SV), total peripheral resistance (TPR) and regional blood circulation. However, the higher dose (45 ng) produced a transient rise (26%) followed by a sustained fall (48%) in BP. The decrease in BP was accompanied by significant decreases in CO (44%) and SV (39%), while HR and TPR were not affected. ET-1 (45 ng, i.c.v.) also produced a significant reduction in blood flow to the brain (75%), heart (49%), kidneys (66%), GIT (40%), portal system (52%) and musculo-skeletal system (38%), while blood flow to the skin was not affected. To determine pharmacological specificity of the central effects of ET-1, studies were performed in rats pretreated with BQ-123, a specific ET(A) receptor antagonist. Pretreatment with BQ-123 (10 mu g, i.c.v.), 15 min prior to the administration of ET-1, completely antagonized the systemic hemodynamic as well as the regional circulatory effects of ET-1 (45 ng, i.c.v.). In order to determine whether stimulation of central ET(B) receptors produces any cardiovascular effects, studies were performed using IRL 1620, a specific ET(B) receptor agonist. Administration of IRL 1620 (5, 15 and 45 ng, i.c.v) did not produce any effect on systemic hemodynamics and regional blood circulation in rats. It is concluded that ET(A) but not ET(B) receptors are involved in the central cardiovascular actions of ET.