Characterization of endothelin receptors and endothelin-converting enzyme activity in the rabbit lung.
We had earlier shown that endothelin-1 (ET-1)-induced vasoconstriction and prostacyclin (PGI2) release in the rabbit kidney are exclusively linked to ETA receptor activation. In contrast, another study showed that ET-1 inhibited platelet aggregation ex vivo through the release of PGI2 solely via the activation of ETB receptors. In an attempt to identify the organs involved in the ET-1-induced release of PGI2 in vivo, we characterized the receptors responsible for the release of this eicosanoid and also monitored the activity of the endothelin-converting enzyme (ECE) in rabbit pulmonary lobe. In this perfused organ, a 5-min infusion of ET-1 (50 nM) triggered a marked release of PGI2 and an increase in perfusion pressure, both of which were mimicked by the selective ETB agonist IRL 1620 (0.5 microM). Furthermore, a selective ETB antagonist, BQ-788 (10 nM), markedly blunted the release of PGI2 induced by ET-1 (50 nM). On the other hand, ET-2 was also able to trigger the release of PGI2 and to increase the perfusion pressure in this organ. The immediate precursor of ET-1, big ET-1 (0.5 microM), also induced a protracted increase in perfusion pressure. In contrast, big ET-2 (0.5 microM) was significantly weaker than big ET-1 in increasing perfusion pressure. Our results suggest that the receptors responsible for the release of PGI2 in the lung are (in contrast to the kidney) predominantly of the ETB type. Furthermore, the ECE localized in the rabbit pulmonary vasculature is relatively selective for big ET-1. On the basis of these results, we suggest that ETB-mediated inhibition of platelet aggregation ex vivo is due to a marked release of PGI2 generated from the pulmonary vasculature in the rabbit.
Gratton
J P
JP
Department of Pharmacology, Medical School, Université de Sherbrooke, Québec, Canada.
Maurice
M C
MC
D'Orléans-Juste
P
P
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000494:pharmacology*; D011464:Epoprostenol / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008666:Metalloendopeptidases; D011817:Rabbits; D017466:Receptors, Endothelin / Q000502:physiology*
D016232:Endothelins; D017466:Receptors, Endothelin; D011464:Epoprostenol; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes