In rats nitric oxide modulates renal autoregulation in steady state experiments and the myogenic mechanism in dynamic studies. Interactive modulation of autoregulation by nitric oxide and endothelin, predominantly involving endothelin B receptors, has been reported though it remains unclear whether the interaction affects the myogenic component of autoregulation. Non-selective inhibition of nitric oxide synthase (L-nitro-arginine methyl-ester, L-NAME) with endothelin A and B selective receptor antagonists, BQ-123 and BQ-788, all infused into the renal artery, plus time series analysis were used to test the interactive actions of nitric oxide and endothelin on renal vascular conductance and on autoregulation. Non-selective endothelin receptor antagonism blunted the constrictor response to subsequent L-NAME, but had no effect on previously established L-NAME-induced vasoconstriction. BQ-123 did not affect conductance and caused only minor reduction in myogenic autoregulatory efficiency. Responses to BQ-123 and L-NAME were additive and not interactive. BQ-788 and L-NAME each caused strong vasoconstriction alone and in the presence of the other, indicating that coupling between nitric oxide and endothelin B mediated events is not obligatory. L-NAME augmented myogenic autoregulation, and subsequent BQ-788 did not alter this response. However, BQ-788 infused alone also enhanced myogenic autoregulation, but resulted in significant impairment of myogenic autoregulation by subsequent L-NAME. Thus the interaction between nitric oxide and endothelin is clearly non-additive and, because it is asymmetrical, can not be explained simply by convergence on a common signal pathway. Instead one must postulate some degree of hierarchical organization and that nitric oxide acts downstream to ET-B activation.