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

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) 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.

Figures

Figure 1

Urinary nitrate excretion rates of nitrate (a) and cyclic GMP (b) in healthy human subjects before and after the infusion of 30 g (•) or 6 g (▪) l-arginine or placebo (□), or oral ingestion of 6 g l-arginine (▴) or placebo (▵). Values represent mean±s.e.mean of n = 8 subjects. *P < 0.05 vs baseline.

Figure 2

Effects of intravenous l-arginine (30 mg (•), 6 mg (▪)) and placebo (□) on systolic and diastolic blood pressure in healthy human subjects. Values represent mean±s.e.mean of n = 8 subjects. The shaded area represents the duration of the infusion. *P < 0.05 vs baseline.

Figure 3

Effects of intravenous infusion of 30 g (•) or 6 g (▪) of l-arginine, or placebo (□) on cardiac output (a) and total peripheral resistance (b) in healthy human subjects. Values represent mean±s.e.mean of n = 8 subjects. *P < 0.05 vs baseline.

Figure 4

Time course of plasma l-arginine concentrations after intravenous or oral administration of l-arginine in healthy human subjects.

Figure 5

(a) Comparison of the time course of plasma l-arginine concentrations, total peripheral resistance, and urinary nitrate excretion rates in healthy human subjects after intravenous infusion of 30 g of l-arginine. (b) Plot of plasma l-arginine concentrations against effect (change in total peripheral resistance).