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 pressor 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 (i.c.v.) 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 micrograms i.c.v.), antagonized systemic and regional circulatory effects of ET-1. Centrally administered clonidine (1 microgram i.c.v.) produced hypotension and bradycardia, known to be mediated through the sympathetic nervous system. Pretreatment with an ETA receptor antagonist, BMS-182874 (50 micrograms/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.
Gulati
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Department of Pharmaceutics and Pharmacodynamics, University of Illinois at Chicago 60612-7231, USA.
Rebello
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S
Kumar
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D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D007276:Injections, Intraventricular; D008297:Male; D009928:Organ Specificity; D011168:Portal System / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects
D019332:Endothelin-1