Downregulation of nitric oxide synthase in chronic renal insufficiency: role of excess PTH

The available data on the effect of chronic renal failure (CRF) on nitric oxide (NO) metabolism are Limited and contradictory. We studied rats with CRF 6 wk after a five-sixths nephrectomy and compared the results with those in the sham-operated controls, felodipine-treated CRF, and parathyroidectomized (CRF-PTX) animals. CRF was produced by surgical resection of the upper and lower thirds of the left kidney, followed by contralateral nephrectomy. We chose this model, as opposed to that produced by renal artery branch ligation, because the latter causes exuberant hypertension (HTN), which independently affects NO metabolism. The CRF group exhibited a mild HTN coupled with elevated basal platelet cytosolic Ca(2+) concentration ([Ca(2+)](i)), blunted hypotensive response to L-arginine, decreased hypertensive response to NO synthase (NOS) inhibitor, N(G)-monomethyl-L-arginine, and normal hypotensive response to NO donor, sodium nitroprusside. This was associated with a significant reduction in urinary excretion of stable NO metabolites (NOX) and depressed NOS activity, as well as endothelial and inducible NO synthase (eNOS and NOS, respectively) protein contents of thoracic aorta and the remnant kidney in the CRF animals. Calcium channel blockade and PTX lowered blood pressure, increased urinary NOX, and enhanced vascular NOS activity, as well as eNOS and iNOS protein expressions in the tested tissues. Thus CRF animals exhibited significant reductions in vascular NOS activity and eNOS and iNOS expressions. These abnormalities were reversed by calcium channel blockade and PTX, suggesting the possible causal role of CRF-induced dysregulation of [Ca(2+)](i).