Endothelin-1 (0.25 nmol/kg, injected into the left cardiac ventricle) induces a protracted increase of mean arterial pressure that is significantly reduced by the selective ET(A) receptor antagonist BQ-123 (1 and 10 mg/kg) in the anesthetized rabbit. The sole administration of the selective ET(B) antagonist BQ-788 (0.25 mg/kg) induces a pressor response abolished by BQ-123 (1 mg/kg). Concomitant to the increase in mean arterial pressure, BQ-788 induces a significant increase in plasma levels of endothelin-1 and its precursor big endothelin-1. The nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg) also increases arterial blood pressure, and the response is reduced dose-dependently by BQ-123 (1 and 10 mg/kg). In addition, the administration of BQ-788 in the presence of L-NAME induced a further increase in arterial blood pressure. The duration of the pressor response to L-NAME is also significantly reduced by an endothelin-converting enzyme inhibitor, phosphoramidon (10 mg/kg). Finally, L-NAME induces an increase in plasma levels of big endothelin-1 but not endothelin-1. Our results illustrate that blockade of either nitric oxide synthase or ET(B) receptors triggers a raise in plasma levels of endothelin-1 or its precursor. These later moieties are suggested to be significantly involved, through the activation of ET(A) receptors, in the pressor effects of L-NAME and BQ-788 in the anesthetized rabbit.
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.
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