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 cardi ac and peripheral vascular response. The purpose of this study was to inves tigate the pharmacokinetic-pharmacodynamic profile of L-NMMA and pharmacoki netic interactions with L-arginine in healthy subjects. Methods Plasma pharmacokinetics were analysed from two different studies: I n 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 30 5 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 mu g 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 mu g ml(-1) (mean +/- s.d.) with elimination half-life of 63.5 +/- 14.5 min and clearance of 12.2 +/- 3.5 mi mm(-1) kg(-1) and caused a small hypertensive response, decreased CO by 13%, FPA by 26%, exhNO by 4 6% 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 mu g ml (-1), drug effects over time were in good agreement with an E-max model (r( 2) > 0.98 each), which also suggested that concentrations producing half-ma ximum effects were higher for FPA than for CO and exhNO. The coinfusion wit h L-arginine caused a nearly two-fold increase in plasma L-NMMA levels, ind icating a pharmacokinetic interaction. Conclusions In the absence of a systemic hypertensive response, L-NMMA sign ificantly decreased CO, exhNO, and FPA. The concentration calculated to pro duce a half maximal effect was equivalent for exhNO and CO, but markedly hi gher for FPA. Furthermore, measurement of FPA is susceptible to changes in L-NMMA levels at small plasma concentrations.