Effect of centrally administered endothelin agonists on systemic and regional blood circulation in the rat: role of sympathetic nervous system.

The aims of the present study were to determine (1) the hypotensive and regional circulatory effects of centrally administered endothelin (ET) ETA and ETB agonists, and (2) the role of the sympathetic nervous system in the mediation of hypotensive effects due to centrally administered ET-1. The systemic haemodynamics and regional blood circulation in urethane anaesthetized rats following intracerebroventricular (i.c.v.) administration of ET-1, ET-2, SRT6b, ET-3 and SRT6c (10, 30 and 90 ng) were determined by a radioactive microsphere technique. The effect of centrally administered ET-1 on sympathetic nerve activity was also analysed. Systemic haemodynamics and regional blood circulation were determined before (baseline) and 30 min after administration of ET agonists. Cumulative administration of three doses of saline (5 microliters, i.c.v. at 30 min intervals) did not produce any significant cardiovascular effects. ET-1, ET-2 and SRT6b produced a decrease in blood pressure (51%, 47% and 41%, respectively) along with a decrease in cardiac output (58%, 60% and 45%, respectively) and stroke volume. Heart rate and total peripheral resistance were not affected. ET-1, ET-2 and SRT6b also produced a significant reduction in blood flow to the brain, kidneys, heart, portal, mesentery and pancreas, gastrointestinal tract (GIT) and musculoskeletal system. The effect of ET-2 on the cardiovascular system was less intense in comparison with ET-1 and SRT6b. Centrally administered specific ETB receptor agonists ET-3 and SRT6c did not produce any change in systemic haemodynamics and regional blood flow. Centrally administered ET-1 (90 ng) produced a significant decrease (61%) in sympathetic nerve activity 30 min after drug administration, along with a fall in blood pressure. It is concluded that centrally administered ETA agonists produce significant cardiovascular effects mediating through the sympathetic nervous system.