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

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Abstract
Aims It has been demonstrated that inhibition of endothelium derived nitric oxide with NG‐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−1, drug effects over time were in good agreement with an Emax 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.