Endothelin modulates the cardiovascular effects of clonidine in the rat.
Clonidine decreases mean arterial pressure (MAP) by acting as an α(2)-adrenergic receptor (AR) agonist in the central nervous system; it also acts on peripheral α-ARs to produce vasoconstriction. Endothelin (ET) has been shown to modulate the action of ARs. The present study was conducted to determine the involvement of ET in cardiovascular effects of clonidine. Intravenous administration of clonidine (10, 30 and 90μgkg(-1)) produced a dose-dependent decrease in MAP and heart rate (HR). Treatment with ET-1 (100, 300 and 900ngkg(-1)) significantly attenuated clonidine (10μgkg(-1)) induced fall in MAP and HR. Rats treated with ET-1 (900ngkg(-1)) showed an increase in MAP and HR after clonidine administration compared to untreated rats, while ET(A/B) antagonist, TAK-044 (1mgkg(-1)) and ET(A) antagonist, BMS-182874 (9mgkg(-1)) potentiated the hypotensive effect of clonidine. ET(B) receptor agonist, IRL-1620 (5μgkg(-1)) produced significant attenuation of clonidine induced fall in MAP and HR, while ET(B) receptor antagonist, BQ-788 (0.3mgkg(-1)), potentiated the hypotensive effect of clonidine. Prazosin (0.1mgkg(-1)) completely blocked ET-1 induced changes in cardiovascular effects of clonidine. Clonidine-induced contraction of rat abdominal aortic ring was potentiated by ET-1, which was completely blocked by prazosin. Clonidine produced an increase in ET(A) receptor expression in the brain and abdominal aorta while ET(B) receptors were not affected. It is concluded that ET enhances the responsiveness of vascular ARs to the constrictor effect of clonidine and ET antagonists potentiate the hypotensive effect of clonidine suggesting that a combination of ET antagonist with clonidine may be a useful option to treat hypertension.
Lavhale
Manish S
MS
Department of Pharmaceutical Sciences, Midwestern University Chicago College of Pharmacy, 555 31st St., Downers Grove, IL 60515, USA.
Briyal
Seema
S
Parikh
Niket
N
Gulati
Anil
A
D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology*; D016232:Endothelins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
D058647:Adrenergic alpha-2 Receptor Agonists; D000959:Antihypertensive Agents; D016232:Endothelins; D009842:Oligopeptides; D010446:Peptide Fragments; D010880:Piperidines; D017466:Receptors, Endothelin; C074308:sovateltide; C086539:BQ 788; D003000:Clonidine; D011224:Prazosin