Endothelin antagonizes the hypotension and potentiates the hypertension induced by clonidine.
Modification of clonidine-induced cardiovascular effects by endothelin-1 (ET-1) was studied in male Sprague-Dawley rats. A dose-dependent decrease in blood pressure and heart rate was produced by clonidine (100, 250 and 500 micrograms/kg i.v.). Lower doses produced only a fall in blood pressure (through central alpha-adrenoceptors) while higher doses of clonidine produced an initial hypertensive response (through peripheral alpha-adrenoceptors) and subsequent longer lasting hypotension and bradycardia. The hypotension and bradycardia induced by 100 and 250 micrograms/kg i.v. dose of clonidine were completely blocked by ET-1 (100 ng/kg i.v.) pretreatment. Conversely, the hypertensive response induced by high dose of clonidine (500 micrograms/kg i.v.) was significantly potentiated by ET-1 pretreatment. In cervical sectioned rats, i.v. administered clonidine failed to produce any hypotensive effect, indicating lack of central effect of clonidine. ET-1 significantly (P < 0.0005) potentiated the hypertensive response of a low dose (50 micrograms/kg i.v.) of clonidine in cervical-sectioned rats. I.c.v. administration of clonidine (1, 2, 4 and 6 micrograms) produced a dose-dependent decrease in blood pressure and heart rate. ET-1 pretreatment (25 ng i.c.v.) transiently blocked the clonidine-induced decrease in blood pressure and heart rate for about 10 min but the hypotension and bradycardia was observed subsequently. Since the major site of action of clonidine is the ventral surface of medulla, clonidine was applied directly to the ventral surface of medulla and produced a decrease in blood pressure and heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)
Gulati
A
A
Department of Pharmacodynamics, University of Illinois, Chicago 60612.
Srimal
R C
RC
D000287:Administration, Topical; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016232:Endothelins / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D008526:Medulla Oblongata; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000502:physiology
D016232:Endothelins; D003000:Clonidine