Role of sympathetic nervous system in cardiovascular effects of centrally administered endothelin-1 in rats

Centrally administered endothelin-1 (ET-1) produces a biphasic response, an initial increase followed by a decrease in blood pressure (BP). The presser effect is due to stimulation of the sympathetic nervous system and/or release of vasopressin. The mechanism responsible for the depressor effect after central administration of ET-1 is still not known. Systemic and regional circulatory effects of intracerebroventricular (icy) administration of ET-1 (100 ng) were determined in anesthetized rats, using a radioactive microsphere technique. BP, cardiac output, and stroke volume were significantly decreased 30, 60, and 120 min after central administration of ET-1. Heart rate and total peripheral resistance were not altered. ET-1 produced a reduction in blood flow to the brain (83%), heart (62%), kidneys (53%), gastrointestinal tract (43%), portal system (46%), and musculoskeletal system (55%). To determine the role of the central nervous system in cardiovascular effects of centrally administered ET-1, experiments were performed in cervical-sectioned rats. The changes in systemic and regional blood circulation induced by centrally administered ET-1 in normal rats were not observed in cervical-sectioned rats. Pretreatment with a specific antagonist of ETA receptors, BQ-123 (10 mu g icy), antagonized systemic and regional circulatory effects of ET-1. Centrally administered clonidine (1 mu g icy) produced hypotension and bradycardia, known to be mediated through the sympathetic nervous system. Pretreatment with an ETA receptor antagonist, BMS-182874 (50 mu g/kg iv), blocked clonidine-induced hypotension and bradycardia. We conclude that centrally administered ET-1 stimulates ETA receptors to produce systemic and regional circulatory changes mediated by the sympathetic nervous system.