1. Subthreshold concentrations of endothelin (ET)-1 enhance the contractile responses to noradrenaline (NA). We investigated possible mechanisms underlying the ET-1-induced enhancement of vasoconstrictor responses to NA in rat perfused mesenteric arteries. 2. Perfusion of arteries with subpressor dose of ET-1 (3 x 10-10 mol/L) significantly potentiated the pressor responses to NA (10-6, 3 x 10-6 and 10-5 mol/L) and this action of ET-1 was endothelium independent. 3. The protein kinase C (PKC) inhibitors staurosporine (10-8 mol/L) and calphostin C (10-7 mol/L) markedly attenuated the ET-1-induced enhancement of NA responses. Vasoconstrictor responses to NA were potentiated when vessels were perfused with phorbol 12-myristate 13-acetate (10-8 mol/L). 4. The potentiating effect of ET-1 was efficiently suppressed by Y-27632 (10-6 mol/L), a selective Rho-kinase inhibitor. In the presence of both staurosporine and Y-27632, contractile responses to NA alone were decreased markedly and ET-1-induced potentiation was abolished. 5. Both staurosporine and Y-27632 decreased contractile responses to NA in arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats to levels observed in normotensive control animals. 6. These findings suggest that ET-1-mediated potentiation of responses to NA occurs through activation of either PKC or Rho-kinase. This mechanism seems to contribute to the enhanced vasoconstrictor responces to NA observed in DOCA-salt hypertensive rats, in which the responses to NA are enhanced tonically by endogenous vascular ET-1.