Endothelin-B receptor-dependent modulation of the pressor and prostacyclin-releasing properties of dynamically converted big endothelin-1 in the anesthetized rabbit.

Abstract

Big endothelin-1 (ET-1) injected systemically in vivo induces a long-lasting pressor response, in contrast to its active metabolite ET-1, which alters in a biphasic fashion the mean arterial pressure (MAP) of the anesthetized rabbit. In this study we investigated the effect of selective ETA or ETB receptor blockade on the pressor response and increase in plasma prostacyclin (PGI2) levels (determined by RIA) induced by big ET-1 in the anesthetized rabbit. Pretreatment (5 min) of the rabbit with the ETB receptor antagonist BQ-788 (0.25 mg/kg) potentiated the ET-1 (1 nmol/kg) and, interestingly, big ET-1 (0.5 nmol/kg) induced pressor responses. The selective ETA receptor antagonist BQ-123 (1 mg/kg) significantly reduced the big ET-1 (0.5 and 3 nmol/kg) pressor responses. Big ET-1 (3 nmol/kg) injected i.v. induced an increase in plasma PGI2 levels in contrast to intra-arterial (i.a.) administration. This increase was prevented by BQ-123 (1 mg/kg) but not by BQ-788 (0.25 nmol/kg). Furthermore, in the presence of BQ-788, i.a. administration of big ET-1 (3 nmol/kg) induced a significant release of PGI2. These results show that vasodilator ETB receptors may be activated after conversion of big ET-1 to its active metabolite. Furthermore, after pulmonary conversion of big ET-1, ETA receptors may be responsible for the release of vasodilator and anti-aggregatory prostacyclin, which modulates the big ET-1-induced responses in the rabbit.