L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship.
OBJECTIVE
Administration of L-arginine by intravenous infusion or via oral absorption has been shown to induce peripheral vasodilation in humans, and to improve endothelium-dependent vasodilation. We investigated the pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of L-arginine after a single intravenous infusion of 30 g or 6 g, or after a single oral application of 6 g, as compared with the respective placebo, in eight healthy male human subjects.


METHODS
L-arginine levels were determined by h.p.l.c. The vasodilator effects of L-arginine were assessed non-invasively by blood pressure monitoring and impedance cardiography. Urinary nitrate and cyclic GMP excretion rates were measured as non-invasive indicators of endogenous NO production.


RESULTS
Plasma L-arginine levels increased to (mean +/- s.e.mean) 6223+/-407 (range, 5100-7680) and 822+/-59 (527-955) micromol l(-1) after intravenous infusion of 30 g and 6 g L-arginine, respectively, and to 310+/-152 (118-1219) micromol l(-1) after oral ingestion of 6 g L-arginine. Oral bioavailability of L-arginine was 68+/-9 (51-87)%. Clearance was 544+/-24 (440-620), 894+/-164 (470-1190), and 1018+/-230 (710-2130) ml min(-1), and elimination half-life was calculated as 41.6+/-2.3 (34-55), 59.6+/-9.1 (24-98), and 79.5+/-9.3 (50-121) min, respectively, for 30 g i.v., 6 g i.v., and 6 g p.o. of L-arginine. Blood pressure and total peripheral resistance were significantly decreased after intravenous infusion of 30 g L-arginine by 4.4+/-1.4% and 10.4+/-3.6%, respectively, but were not significantly changed after oral or intravenous administration of 6 g L-arginine. L-arginine (30 g) also significantly increased urinary nitrate and cyclic GMP excretion rates by 97+/-28 and 66+/-20%, respectively. After infusion of 6 g L-arginine, urinary nitrate excretion also significantly increased, (nitrate by 47+/-12% [P<0.05], cyclic GMP by 67+/-47% [P= ns]), although to a lesser and more variable extent than after 30 g of L-arginine. The onset and the duration of the vasodilator effect of L-arginine and its effects on endogenous NO production closely corresponded to the plasma concentration half-life of L-arginine, as indicated by an equilibration half-life of 6+/-2 (3.7-8.4) min between plasma concentration and effect in pharmacokinetic-pharmacodynamic analysis, and the lack of hysteresis in the plasma concentration-versus-effect plot.


CONCLUSIONS
The vascular effects of L-arginine are closely correlated with its plasma concentrations. These data may provide a basis for the utilization of L-arginine in cardiovascular diseases.
Bode-Böger
S M
SM
Institute of Clinical Pharmacology, Medical School, Hannover, Germany.
Böger
R H
RH
Galland
A
A
Tsikas
D
D
Frölich
J C
JC
D000284:Administration, Oral; D000328:Adult; D001120:Arginine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D009566:Nitrates; D009569:Nitric Oxide; D001120:Arginine; D006152:Cyclic GMP