title: Subpressor dose asymmetric dimethylarginine modulates renal function in humans through nitric oxide synthase inhibition.
abstract: Increased blood concentrations of the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) have been linked to high blood pressure and to cardiovascular mortality. We evaluated the effects of a subpressor ADMA dose on NO production, renal hemodynamics, sodium handling and active renin and noradrenalin plasma concentrations in 12 healthy subjects (age 26 +/- 1 year) using a double-blind placebo-controlled study design. Infusion of ADMA caused a significant decrease in plasma cyclic guanosine monophosphate (cGMP) levels, i.e. the second messenger of NO (from 6.1 +/- 0.4 to 4.3 +/- 0.3 pmol/l; p < 0.05). In parallel, effective renal plasma flow (ERPF) decreased while renovascular resistance (RVR) increased significantly (ERPF from 667 +/- 9 to 603 +/- 10 ml/min/1.73 m2; RVR from 79 +/- 2 to 91 +/- 2 ml/min/mm Hg; both p < 0.05 vs. baseline). Infusion of placebo did not cause significant changes in plasma cGMP levels, ERPF and RVR (cGMP from 5.7 +/- 0.5 to 5.9 +/- 0.6 pmol/l; ERPF from 665 +/- 12 to 662 +/- 11 ml/min/1.73 m2; RVR from 79 +/- 2 to 78 +/- 2 ml/min/mm Hg; all non-significant). Moreover, urinary sodium excretion was significantly lower with infusion of ADMA as compared with placebo infusion (128 +/- 8 vs. 152 +/- 7 micromol/min; p < 0.05). In contrast, blood pressure, active renin and noradrenalin plasma concentrations did not change significantly with either infusion protocol. Acute infusion of a subpressor ADMA dose modulates several aspects of renal function in humans without affecting the activity of the renin-angiotensin and sympathetic system. Whether chronic (intrarenal) NO synthase inhibition in individuals with increased ADMA blood levels may cause persistent renal vasoconstriction and sodium retention must be evaluated.
authors.affiliation: Department of Internal Medicine, Medical School Hannover, Germany. Kielstein@yahoo.com
authors.forename: J T
authors.initials: JT
authors.lastname: Kielstein
authors.forename: S
authors.initials: S
authors.lastname: Simmel
authors.forename: S M
authors.initials: SM
authors.lastname: Bode-Böger
authors.forename: H J
authors.initials: HJ
authors.lastname: Roth
authors.forename: H
authors.initials: H
authors.lastname: Schmidt-Gayk
authors.forename: H
authors.initials: H
authors.lastname: Haller
authors.forename: D
authors.initials: D
authors.lastname: Fliser
mesh_terms: D000328:Adult; D001120:Arginine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000097:blood; D012964:Sodium / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000493:pharmacokinetics
chemical_list: C487735:dimethylarginine; D009569:Nitric Oxide; D001120:Arginine; D012964:Sodium; D019001:Nitric Oxide Synthase; D012083:Renin; D006152:Cyclic GMP; D009638:Norepinephrine; D010130:p-Aminohippuric Acid