ETB RECEPTOR AND NITRIC-OXIDE SYNTHASE BLOCKADE INDUCE BQ-123-SENSITIVE PRESSOR EFFECTS IN THE RABBIT

Endothelin-l (0.25 nmol/kg, injected into the left cardiac ventricle) induces a protracted increase of mean arterial pressure that is signif icantly reduced by the selective ETA receptor antagonist BQ-123 (1 and 10 mg/kg) in the anesthetized rabbit. The sole administration of the selective ETB antagonist BQ-788 (0.25 mg/kg) induces a pressor respons e abolished by BQ-123 (1 mg;kg). Concomitant to the increase in mean a rterial pressure, BQ-788 induces a significant increase in plasma leve ls of endothelin-l and its precursor big endothelin-l. The nitric oxid e synthase inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg) also increases arterial blood pressure, and the response is re duced dose-dependently by BQ-123 (1 and 10 mg/kg). In addition, the ad ministration of BQ-788 in thr presence of L-NAME induced a further inc rease in arterial blood pressure. The duration of the presser response to L-NAME IE is also significantly reduced by an endothelin-convertin g enzyme inhibitor, phosphoramidon (10 mg/kg). Finally, L-NAME induces an increase in plasma levels of big endothelin-l but not endothelin-l . Our results illustrate that blockade of either nitric oxide synthase or ETB receptors triggers a raise in plasma levels of endothelin-l or its precursor. These later moieties are suggested to be significantly involved, through the activation of ETA receptors, in the presser eff ects of L-NAME and BQ-788 in the anesthetized rabbit.