Effects of separate and combined ETA and ETB blockade on ET-1-induced constriction in perfused rat lungs.
To evaluate the role of endothelin (ET) receptors in ET-1-induced pulmonary vasoreactivity, we studied the effects of ET-receptor agonists and antagonists in isolated perfused rat lungs. ET-1 (1-10 nM) caused concentration-dependent pulmonary vasoconstriction and gross pulmonary edema at a concentration of 10 nM. The combination of the selective ETA antagonist BQ-123 and the selective ETB antagonist BQ-788 inhibited ET-1-induced pulmonary vasoconstriction more effectively than BQ-123 alone, whereas BQ-788 alone enhanced the constriction. ET-1-induced hydrostatic pulmonary edema was prevented by the combination of BQ-123 and BQ-788 but not by either BQ-123 or BQ-788 alone. After the addition of 125 ng of exogenous ET-1, the perfusate levels of ET-1 were significantly higher in BQ-788-treated lungs than in either the vehicle control or BQ-123-treated lungs. The selective ETB agonist IRL-1620 also caused pulmonary vasoconstriction and edema, both of which were completely inhibited by BQ-788. ET-1-induced transient vasodilation was abolished by BQ-788 but was unaffected by BQ-123. These results suggest that in the isolated perfused rat lung, ET-1-induced vasoconstriction is mediated by both ETA and ETB receptors, whereas ET-1-induced transient vasodilation is mediated exclusively by the ETB receptor. Blockade of ETB receptors may result in enhanced ET-1 activity (via the ETA receptor) through inhibition of the ETB-mediated clearance of ET-1. Thus combined ETA and ETB blockade is required for the complete inhibition of ET-1-induced vasoconstriction in the rat pulmonary circulation.
D000818:Animals; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D009842:Oligopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D010880:Piperidines; C074308:sovateltide; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)