Selective blockade of endothelin receptor subtypes on systemic and renal vascular responses to endothelin-1 and IRL1620, a selective endothelin ETB-receptor agonist, in anesthetized rats.
By using BQ-788 as a selective endothelin ETB-receptor antagonist and FR139317 as a selective endothelin ETA-receptor antagonist, we have characterized the receptor subtypes mediating the systemic and renal vascular effects of endothelin-1 and IRL1620, a selective endothelin ETB-receptor agonist (succinyl-[Glu9,Ala11,5]-endothelin-1(8-21)), in anesthetized rats. Bolus intravenous injection of endothelin-1 (0.5 nmol/kg) and IRL1620 (1.65 nmol/kg) produced a transient fall in systemic blood pressure followed by a sustained increase. The initial fall in blood pressure observed after endothelin-1 and IRL1620 administration was completely blocked by BQ-788 (0.5 mumol/kg, i.v.), whereas the pressor response was blocked by FR139317 (0.8 mumol/kg, i.v.). Renal blood flow was decreased and calculated renal vascular resistance was dramatically increased by endothelin-1 and IRL1620. The reduction of renal blood flow by endothelin-1 was significantly suppressed by FR139317 but potentiated by BQ-788. Both BQ-788 and FR139317 partially blocked the renal vasoconstriction by IRL1620. Pretreatment by BQ-788 itself decreased renal blood flow by 14.1%. These results indicate that the systemic depressor responses induced by endothelin-1 and IRL1620 are mediated through the endothelin ETB-receptor, and the pressor responses are mediated through the endothelin ETA-receptor. In the renal vasculature of anesthetized rats, it is suggested that vasoconstriction is mediated through both endothelin ETA- and ETB-receptors and that endothelin ETB-receptors may be also involved in vasodilating responses to endothelin peptides.
Matsuura
T
T
Department of Pharmacology, Osaka City University Medical School, Japan.
Yukimura
T
T
Kim
S
S
Miura
K
K
Iwao
H
H
D000758:Anesthesia; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010880:Piperidines / 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*
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D007211:Indoles; D009842:Oligopeptides; D010446:Peptide Fragments; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C074308:sovateltide; C079574:FR 139317; C086539:BQ 788