Potassium channel-mediated vasorelaxation is impaired in experimental renal failure

Chronic renal failure is associated with increased cardiovascular morbidity and abnormal arterial tone, but the underlying pathophysiological mechanis ms are poorly understood. Therefore, we studied the responses of isolated m esenteric arterial rings from Wistar-Kyoto rats in standard organ chambers 6 wk after subtotal (5/6) nephrectomy or sham operation. Subtotal nephrecto my resulted in a 1.7-fold elevation of plasma urea nitrogen, whereas blood pressure was not significantly affected. Endothelium-mediated relaxations o f norepinephrine-precontracted rings to ACh were impaired in renal failure rats. The nitric oxide (NO) synthase inhibitor N-G-nitro-L-arginine methyl ester inhibited relaxations to ACh more effectively in the renal failure gr oup, whereas the cyclooxygenase inhibitor diclofenac did not significantly affect the response in either group. Inhibition of Ca2+-activated K+ channe ls by charybdotoxin and apamin attenuated NO synthase- and cyclooxygenase-r esistant relaxations to ACh in control but not renal failure rats and aboli shed the difference between these groups. Endothelium-independent relaxatio ns to isoproterenol and cromakalim, vasodilators acting via beta-adrenocept ors and ATP-sensitive K+ channels, respectively, were impaired in the renal failure group, whereas relaxations to the Na donor nitroprusside were simi lar in both groups. In conclusion, endothelium-mediated relaxation in renal failure rats was impaired in the absence and presence of NO synthase and c yclooxygenase inhibition but not with prevented smooth muscle hyperpolariza tion. Endothelium-independent relaxations to isoproterenol and cromakalim w ere also attenuated after 5/6 nephrectomy. These results suggest that impai red vasodilatation in experimental renal failure could be attributed to red uced relaxation via arterial K+ channels.