Evidence in vivo showing increase of baseline nitric oxide generation and impairment of endothelium-dependent vasodilation in normotensive patients on chronic hemodialysis

Cardiovascular mortality is excessive in hemodialyzed patients. Observation s in atherosclerosis suggest that endothelial dysfunction and impaired nitr ic oxide (NO) may be involved. However, the relation of endothelial NO to i ts vascular effects has not been studied conclusively in uremia. Therefore, to study these questions an invasive technique was used in normotensive pa tients who were on hemodialysis (HD; n = 11) and in matched control subject s (n = 11). Pharmacologic agents were infused into the brachial artery to t est the chain of events from NO generation to smooth muscle cell relaxation , measuring forearm blood flow by venous occlusion plethysmography. Glycero ltrinitrate (GTN 1:2.2 nmol/min; GTN 2:4.4; GTN 3:8.8), infused to establis h the reaction of the vessel wall to defined doses of NO, caused a reduced response in HD patients (control subjects: 183 +/- 20 [SEM], 246 +/- 26, an d 338 +/- 29%; HD patients: 161 +/- 7, 206 +/- 12, and 262 +/- 24%; baselin e = 100% for each group, P = 0.032 by ANOVA). All subsequent data were corr ected for this decreased response to defined doses of NO in HD patients. L- arginine (10 mg/min), given to exclude substrate deficiency of NO synthase (NOS), caused no significant changes (control subjects: 108 +/- 4%; HD pati ents: 103 +/- 4%; P = NS). Acetylcholine (ACH 1:55 nmol/min; ACH 2:110; ACH 3:220), infused to stimulate endothelial NOS, had a significantly reduced effect in HD patients (control subjects: 246 +/- 32, 340 +/- 40, and 465 +/ - 52%; HD patients: 251 +/- 55, 244 +/- 36, and 318 +/- 50%; P = 0.002). N- monomethyl-L-arginine (LMA 1:1 mu mol/min; LMA 2:2; LMA 3:4), given to bloc k baseline NO generation, showed an enhanced response in HD patients (contr ol subjects: 90 +/- 2, 83 +/- 2, and 74 +/- 4%; HD patients: 84 +/- 3, 73 /- 3, and 64 +/- 4%; P = 0.037). Vascular response to three doses of norepi nephrine (60, 120, and 240 pmol/min) was comparable in both groups, which i ndicated similar endothelium-independent vasoconstriction. In summary, in n ormotensive HD patients, (1) vasodilation to defined doses of exogenous NO was reduced, (2) there was no evidence of substrate deficiency of NOS, and (3) stimulation of NOS was impaired; however, (4) baseline NO generation wa s increased. It is concluded that in HD patients, the NO system has a reduc ed capacity to regulate vascular tone and this impairment is most significa nt under conditions of NOS stimulation.