In hypertensive humans, the development of end-stage renal disease is often associated with an endothelial dysfunction attributed to a decrease in the bioavailability of nitric oxide (NO). An early endothelial dysfunction is also reported in most animal models of hypertension and profound alterations in renal function are observed in aged hypertensive animals. As kidneys play an important role in blood pressure regulation, the purpose of the present study was to determine whether a chronic treatment with a NO synthase inhibitor, L-NAME (Nω- nitro-L-arginine methyl ester) accelerates the renal dysfunction in younger adult spontaneously hypertensive rats (SHR). Indeed, in this model, the alterations in cardiac function mimic those observed in aging SHR. Male SHR were subjected to chronic L-NAME-treatment (6 mg/ kg/day) for two weeks. At 19 weeks, the kidneys were isolated, perfused with oxygenated physiological salt solution and changes in renal perfusion pressure continuously recorded. During a sustained constriction caused by methoxamine, bolus injections of acetylcholine and of the NO donor sodium nitroprusside caused dose-dependent dilatations in both groups of SHR. The responses to acetylcholine were not affected by the L-NAME treatment while those to sodium nitroprusside were significantly augmented. In the two groups, indomethacin, a cyclooxygenase inhibitor, did not affect the vasodilatation caused by acetylcholine. However, an acute treatment with another NO synthase inhibitor, L-nitroarginine, produced a major inhibition of the acetylcholine response in the SHR while it did not affect it in the kidney of SHR chronically treated with L-NAME. In the presence of indomethacin plus L-nitro-arginine, TRAM-34, an inhibitor of Ca2+-activated K+ channels of intermediate conductance, IK(Ca), blocked the responses to acetylcholine in both groups of SHR. These data show that in SHR, the acetylcholine-induced vasodilatation involves both NO release and an endothelium-derived hyperpolarizing factor (EDHF)-mediated component while in the L-NAME-treated SHR, the NO-component is abolished and the EDHF-mediated component becomes the major contributor to this vasodilatation. In the kidney of L-NAME-treated SHR, EDHF-mediated responses are a compensatory mechanism that sustain endothelium-dependent dilatations when NO activity is impaired. The responses involve IK(Ca), activation and must be further characterized.