Pharmacokinetic-pharmacodynamic profile of systemic nitric oxide-synthase inhibition with L-NMMA in humans

Aims. It has been demonstrated that inhibition of endothelium derived nitric oxide with N(G)-monomethyl-L-arginine (L-NMMA) results in a different cardiac and peripheral vascular response. The purpose of this study was to investigate the pharmacokinetic-pharmacodynamic profile of L-NMMA and pharmacokinetic interactions with L-arginine in healthy subjects. Methods. Plasma pharmacokinetics were analysed from two different studies: In study 1, 3 mg kg^-1 L-NMMA was administered i.v. over 5 min and systemic haemodynamics, cardiac output (CO), fundus pulsation amplitude (FPA), and NO-exhalation (exhNO) were measured at baseline and 15, 65, 95, 155, and 305 min after start of drug administration (n = 7). In study 2, 17 mg kg^-1 min^-1 of the physiologic substrate for nitric oxide synthase, L-arginine, was coinfused i.v. over 30 min with a primed constant infusion of 50 μg kg^-1 min^-1 L-NMMA (n = 8). Results. Bolus infusion of L-NMMA resulted in a maximum plasma concentration of 12.9 ± 3.4 μg ml^-1 (mean ± s.d.) with elimination half-life of 63.5 ± 14.5 min and clearance of 12.2 ± 3.5 ml min^-1 kg^-1 and caused a small hypertensive response, decreased CO by 13%, FPA by 26%, exhNO by 46% and increased systemic vascular resistance by 16% (P < 0.05 each) 15 min after start of drug administration. Although only limited data points were available in the L-NMMA plasma concentration range between 0 and 4 μg ml^-1, drug effects over time were in good agreement with an E(max) model (r² > 0.98 each), which also suggested that concentrations producing half-maximum effects were higher for FPA than for CO and exhNO. The coinfusion with L-arginine caused a nearly two-fold increase in plasma L-NMMA levels, indicating a pharmacokinetic interaction. Conclusions. In the absence of a systemic hypertensive response, L-NMMA significantly decreased CO, exhNO, and FPA. The concentration calculated. to produce a half maximal effect was equivalent for exhNO and CO, but markedly higher for FPA. Furthermore, measurement of FPA is susceptible to changes in L-NMMA levels at small plasma concentrations.