BLOCK OF ENDOTHELIN-1-INDUCED RELEASE OF THROMBOXANE A(2) FROM THE GUINEA-PIG LUNG AND NITRIC-OXIDE FROM THE RABBIT KIDNEY BY A SELECTIVE ET(B) RECEPTOR ANTAGONIST, BQ-788

1 The present study characterizes the receptors responsible for endothelin-1-induced release of thromboxane A(2) from the guinea pig lung and of endothelium-derived nitric oxide from the rabbit perfused kidney, by the use of the selective ET(A) receptor antagonist, BQ-123, and a novel selective ET(B) receptor antagonist, BQ-788. 2 In the guinea pig perfused lung, endothelin-1 (ET-1) (5 nM) induced a marked increase of thromboxane A(2) which was reduced by 17 +/- 5.0, 70 +/- 1.0 and 93 +/- 1.2% by BQ-788 infused at concentrations of 1, 5 and 10 nM respectively. In contrast, BQ-123 (0.1 and 1.0 mu M) had little or no effect on the ET-1-induced release of thromboxane A(2). 3 In the same perfused model, the selective ET(B) agonist, IRL 1620 (50 nM), stimulated the release of thromboxane A(2), but not prostacyclin. The eicosanoid-releasing properties of IRL 1620 were abolished by BQ-788 at 10 nM, yet were unaffected by BQ-123 (1 mu M). 4 In the rabbit perfused kidney, BQ-788 (10 nM) potentiated the increase of perfusion pressure induced by endothelin-1 (1, 5 and 10 nM) by approximately 90%, but not that induced by angiotensin II (1 mu M). Furthermore, the selective ET(B) receptor antagonist did not reduce the release of prostacyclin triggered by either peptide. 5 In another series of experiments, pretreatment of the perfused kidney with a nitric oxide synthase inhibitor, L-NAME (100 mu M), potentiated the presser responses to both endothelin-1 and angiotensin II. Under L-NAME treatment, BQ-788 did not further potentiate the presser response to endothelin-1. 6 Our results illustrate the predominant role of ET(B) receptor activation in the release of thromboxane A(2) and nitric oxide triggered by endothelin-1 in the guinea pig perfused lung and rabbit kidney respectively.