title: Evidence in vivo showing increase of baseline nitric oxide generation and impairment of endothelium-dependent vasodilation in normotensive patients on chronic hemodialysis.
abstract: Cardiovascular mortality is excessive in hemodialyzed patients. Observations in atherosclerosis suggest that endothelial dysfunction and impaired nitric oxide (NO) may be involved. However, the relation of endothelial NO to its vascular effects has not been studied conclusively in uremia. Therefore, to study these questions an invasive technique was used in normotensive patients who were on hemodialysis (HD; n = 11) and in matched control subjects (n = 11). Pharmacologic agents were infused into the brachial artery to test the chain of events from NO generation to smooth muscle cell relaxation, measuring forearm blood flow by venous occlusion plethysmography. Glyceroltrinitrate (GTN 1:2.2 nmol/min; GTN 2:4.4; GTN 3:8.8), infused to establish 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, and 338 +/- 29%; HD patients: 161 +/- 7, 206 +/- 12, and 262 +/- 24%; baseline = 100% for each group, P: = 0.032 by ANOVA). All subsequent data were corrected 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 patients: 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 micromol/min; LMA 2:2; LMA 3:4), given to block baseline NO generation, showed an enhanced response in HD patients (control 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 norepinephrine (60, 120, and 240 pmol/min) was comparable in both groups, which indicated similar endothelium-independent vasoconstriction. In summary, in normotensive 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 was increased. It is concluded that in HD patients, the NO system has a reduced capacity to regulate vascular tone and this impairment is most significant under conditions of NOS stimulation.
authors.affiliation: Nephrology, Department of Medicine, University Hospital Dresden, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Passauer
authors.affiliation: Nephrology, Department of Medicine, University Hospital Dresden, Germany.
authors.forename: Eckhart
authors.initials: E
authors.lastname: Büssemaker
authors.affiliation: Institute of Medical Informatics and Biometry, University Hospital Dresden, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Range
authors.affiliation: Nephrology, Department of Medicine, University Hospital Dresden, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Plug
authors.affiliation: Nephrology, Department of Medicine, University Hospital Dresden, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gross
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D001794:Blood Pressure; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D005996:Nitroglycerin / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects; D006435:Renal Dialysis / Q000009:adverse effects*; D013997:Time Factors; D014664:Vasodilation; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D005996:Nitroglycerin; D000109:Acetylcholine; D009638:Norepinephrine