Pharmacologic characterization of endothelin receptor responses in the isolated perfused rat lung.
Endothelin receptor subtypes were characterized in isolated perfused rat lungs using the peptide ETA-receptor antagonists BQ 610 and BQ 123, the nonpeptide mixed ETA-/ETB-receptor antagonist bosentan, and the ETB-receptor agonist IRL 1620. Intra-arterial injection of 1 nmol IRL 1620 caused an enhanced reduction in pulmonary conductance compared with 1 nmol endothelin (ET-1) or 0.33 nmol IRL 1620. Pretreatment of lungs with BQ 610, BQ 123, or bosentan aggravated the bronchoconstriction induced by 1 nmol ET-1 so that it was comparable to that induced by 1 nmol IRL 1620. Although perfusion with 1 nmol IRL 1620 had only minor effects on vascular conductance, 1 nmol ET-1 caused a marked decrease in this parameter. This vasonconstriction was prevented by BQ 610, BQ 123, or bosentan. High concentrations of the stable prostacyclin metabolite, 6-keto-PGF1 alpha, were found in the perfusate of lungs treated with 1 nmol IRL 1620 or 1 nmol ET-1. The ET-1-induced release of 6-keto-PGF1 alpha was blocked by bosentan, but not by BQ 610. ET-1, but not IRL 1620, provoked the release of thromboxane B2. The main effect of ETA-receptor stimulation is vasoconstriction, whereas ETB-receptor stimulation causes bronchoconstriction. Both actions, however, are attenuated by the other receptor, i.e., the ETA-induced vasoconstriction is attenuated by ETB-receptor-induced release of vasodilators such as prostacyclin, whereas the ETB-receptor-induced bronchoconstriction is attenuated by an unknown ETA-receptor-dependent bronchodilatory mechanism.
Uhlig
S
S
Biochemical Pharmacology, University of Konstanz, Germany.
von Bethmann
A N
AN
Featherstone
R L
RL
Wendel
A
A
D000704:Analysis of Variance; D000818:Animals; D000077300:Bosentan; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D011464:Epoprostenol / Q000032:analysis; D005260:Female; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000819:agonists / Q000187:drug effects*; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013931:Thromboxanes / Q000032:analysis; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D009842:Oligopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D013449:Sulfonamides; D013931:Thromboxanes; C074308:sovateltide; C087220:BQ 610; D011464:Epoprostenol; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)