Role of ET(B) receptors in local clearance of endothelin-1 in rat heart: studies with the antagonists PD 155080 and BQ-788.
The effects of two endothelin (ET) receptor antagonists, PD 155080 (ET(A) selective) and BQ-788 (ET(B) selective), on cardiac function and ET-1 release were studied in isolated rat hearts. In normoxic hearts, infusion of PD 155080 (50 nM-5 microM) reduced coronary resistance, but had no effect on ET-1 release. Low concentrations of BQ-788 (2 and 20 nM) had no effect on coronary resistance; high concentrations (0.2 and 2 microM) increased it approximately 2-fold; all concentrations increased ET-1 release (up to 24-fold). Similar results were obtained in reperfused hearts. Although concentrations of ET-1 were higher in interstitial fluid than coronary effluent, levels never exceeded the low pg/ml range. These results indicate that (1) ET(A) receptors mediate coronary constriction, whereas ET(B) receptors bind and sequester ET-1, and (2) ET-1 displaced by ET(B) antagonist accesses ET(A) receptors resulting in coronary constriction.
Brunner
F
F
Institut für Pharmakologie und Toxikologie, Karl-Franzens-UniversitätGraz, Austria. friedrich.brunner@kfunigraz.ac.at
Doherty
A M
AM
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; C093322:PD 155080; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C076213:PD 142893; C086539:BQ 788