IMPAIRED ENDOTHELIAL FUNCTION IN PATIENTS WITH NEPHROTIC RANGE PROTEINURIA

Proteinuria is associated with increased cardiovascular morbidity and mortality. Release of nitric oxide by the endothelium has been advance d as an important defense mechanism against vessel-wall damage. In the present study we therefore tested the hypothesis that proteinuria is associated with a defect in nitric oxide-dependent vasodilation, by us ing venous occlusion plethysmography of the forearm in nine patients w ith nephrotic range proteinuria (>3.5 g/24 hr) and normal renal functi on (creatinine 83.1 +/- 8.7 mu mol/liter), eight patients with active glomerulonephritis but normal renal function (creatinine 81.2 +/- 5.4 mu mol/liter) and low range proteinuria (<1.0 g/24 hr), and ten health y volunteers. We infused L-NMMA (2 mg/min) to inhibit basal nitric oxi de production, serotonin (0.1, 0.3 and 1.0 ng/kg/min) as an endotheliu m-dependent vasodilator, and nitroprusside (1, 10, 30 and 100 ng/kg/mi n) as an endothelium-independent vasodilator into the brachial artery. Administration of L-NMMA decreased basal forearm vascular resistance (FVR) by 30 +/- 4% in the nephrotic subjects, 38 +/- 4% in the non-nep hrotic patients and by 37 +/- 2% in the healthy controls (P = 0.15). U pon the highest dose of serotonin FVR decreased in nephrotic subjects by 40 +/- 5%, which was less than in non-nephrotic patients (56 +/- 3% ; P < 0.05) or in healthy controls (55 +/- 3%; P < 0.05). The maximal decrease in FVR upon nitroprusside infusion was not different between the groups (respectively 84 +/- 2, 84 +/- 3 and 84 +/- 2%). The impair ed serotonin-induced vasodilation could be attributed to a defect in n itric oxide production, since L-NMMA almost completely prevented serot onergic vasodilation. The defect in agonist-induced nitric oxide relea se or activity could not be explained by decreased substrate availabil ity, as infusion of excess L-arginine (0.2 mg/kg/min) did not improve vasodilation. The nephrotic subjects also had an increased lysophospha tidylcholine content in the low-density-lipoprotein fraction, which ha s been shown to interfere with Gi-protein-dependent signal transductio n pathways, including serotonin-induced vasodilation. In conclusion, n ephrotic-range proteinuria is accompanied by impaired endothelium-depe ndent vasomotion.