Subpressor dose asymmetric dimethylarginine modulates renal function in humans through nitric oxide synthase inhibition.
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.
Kielstein
J T
JT
Department of Internal Medicine, Medical School Hannover, Germany. Kielstein@yahoo.com
Simmel
S
S
Bode-Böger
S M
SM
Roth
H J
HJ
Schmidt-Gayk
H
H
Haller
H
H
Fliser
D
D
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
C487735:dimethylarginine; D009569:Nitric Oxide; D001120:Arginine; D012964:Sodium; D019001:Nitric Oxide Synthase; D012083:Renin; D006152:Cyclic GMP; D009638:Norepinephrine; D010130:p-Aminohippuric Acid