Use of A-192621 and IRL-2500 to unmask the mesenteric and renal vasodilator role of endothelin ET(B) receptors.
Endothelin-1 (ET-1) is known to cause a transient (<1 min) depressor followed by a sustained (>1 h) pressor response. The former through the activation of ET(B) receptors, and the latter through the activation of ET(A) and ET(B) receptors. This study examines if ET(B) receptors mediate sustained mesenteric and renal dilation in anesthetized rats. Intravenous bolus ET-1 (0.8, 1.4, and 2 nmol/kg) and IRL-1620 (ET(B) agonist, 2, 5, and 10 nmol/kg) caused transient decrease followed by sustained increases in mean arterial pressure (MAP) that were accompanied by increases in total peripheral resistance (TPR), reductions in cardiac output (CO), and mesenteric and renal vasoconstriction. Pretreatment with FR-139317 (ET(A) antagonist, 1 mg/kg) attenuated the pressor and constrictor effects of ET-1 but did not alter responses to IRL-1620. IRL-2500 (ET(B) antagonist, 5 mg/kg) slightly inhibited the renal constrictor effect of IRL-1620, whereas A-192621 (ET(B) antagonist, 5 mg/kg) abolished all hemodynamic responses to IRL-1620. Both IRL-2500 and A-192621 markedly enhanced MAP, TPR, and mesenteric, and the renal constrictor effects of ET-1. Therefore, A-192621 was more effective than IRL-2500 in blocking IRL-1620-induced vasoconstriction, but both augmented constrictor responses to ET-1. The potentiation of ET-1-induced vasoconstriction by ET(B) receptor antagonists revealed a sustained vasodilator role of ET(B) receptors.
Leung
Susan Wai Sum
SW
Department of Pharmacology & Therapeutics, Faculty of Medicine, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.
Lim
Su Lin
SL
Pang
Catherine Cheuk Ying
CC
Man
Ricky Ying Keung
RY
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
C120508:A 192621; D001381:Azepines; D001713:Biphenyl Compounds; D004151:Dipeptides; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; C098287:IRL 2500; D007211:Indoles; D010446:Peptide Fragments; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C074308:sovateltide; C079574:FR 139317