Quantitative aspects of the inhibition by NG‐monomethyl‐L‐arginine of responses to endothelium‐dependent vasodilators in human forearm vasculature

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Abstract
NG‐monomethyl‐L‐arginine (L‐NMMA) constricts human forearm resistance vasculature and selectively attenuates vasodilator responses to endothelium‐dependent vasodilators. Incomplete inhibition of such responses could be due to an inadequate dose of L‐NMMA or to NO‐independent vasodilator mechanisms. This study sought to determine doses of L‐NMMA that are maximally effective in reducing basal and stimulated forearm blood flow. Drugs were infused via the brachial artery in 32 healthy men. Acetylcholine (11 – 330 nmol min−1) was compared with albuterol (0.33 – 10 nmol min−1), and nitroprusside (1.7 – 20 nmol min−1). The effect of L‐NMMA on basal flow approached maximum (53±2% reduction) at a dose of 16 μmol min−1. L‐NMMA (16 μmol min−1) did not significantly influence responses to nitroprusside, but antagonized acetylcholine and albuterol (each P−1) was strongly influenced by acetylcholine dose (73±7% inhibition at 11 nmol min−1, P−1, P=NS, Student's paired t‐test). Significant inhibition of albuterol was observed at all doses. A higher dose of L‐NMMA (64 μmol min−1) did not significantly inhibit the response to acetylcholine (330 nmol min−1). Responses to this dose of acetylcholine were unaffected by a cyclo‐oxygenase (COX) inhibitor (indometacin) alone but combined COX and NO inhibition attenuated acetylcholine responses by 42±19%, implying that there is a compensatory increase in the contribution of prostaglandins or NO to acetylcholine‐induced dilatation when one or other pathway is inhibited. British Journal of Pharmacology (2001) 134, 939–944; doi:10.1038/sj.bjp.0704338