L-ARGININE-INDUCED VASODILATION IN HEALTHY HUMANS - PHARMACOKINETIC-PHARMACODYNAMIC RELATIONSHIP

Aims 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 th e pharmacokinetics and pharmacokinetic-pharmacodynamic relationship of L-arginine after a single intravenous infusion of 30 g or 6 g, or aft er a single oral application of 6 g, as compared with the respective p lacebo, in eight healthy male human subjects. Methods L-arginine level s were determined by h.p.l.c. The vasodilator effects of L-arginine we re assessed non-invasively by blood pressure monitoring and impedance cardiography. Urinary nitrate and cyclic GMP excretion rates were meas ured as non-invasive indicators of endogenous NO production. Results P lasma L-arginine levels increased to (mean+/-s.e.mean) 6223+/-407 (ran ge, 5100-7680) and 822+/-59 (527-955) mu mol l(-1) after intravenous i nfusion of 30 g and 6 g L-arginine, respectively, and to 310+/-152 (11 8-1219) mu mol l(-1) after oral ingestion of 6 g L-arginine. Oral bioa vailability 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 peri pheral resistance were significantly decreased after intravenous infus ion of 30 g L-arginine by 4.4+/-1.4% and 10.4+/-3.6%, respectively, bu t were not significantly changed after oral or intravenous administrat ion 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 excr etion also significantly increased, (nitrate by 47+/-12% [P<0.05], cyc lic GMP by 67+/-47% [P=ns]), although to a lesser and more variable ex tent 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 prod uction closely corresponded to the plasma concentration half-life of L -arginine, as indicated by ai; equilibration half-life of 6+/-2 (3.7-8 .4) min between plasma concentration and effect in pharmacokinetic-pha rmacodynamic analysis, and the lack of hysteresis in the plasma concen tration-versus-effect plot. Conclusions The vascular effects of L-argi nine are closely correlated with its plasma concentrations. These data may provide a basis for the utilization of L-arginine in cardiovascul ar diseases.