L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship

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Abstract

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 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) μmol 1−1 after intravenous infusion of 30 g and 6 g L-arginine, respectively, and to 310±152 (118-1219) μmol 1−1 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.

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