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

N G ‐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 <0.001, by repeated measures analysis of variance). Inhibition of acetylcholine by L ‐NMMA (16 μmol min −1 ) was strongly influenced by acetylcholine dose (73±7% inhibition at 11 nmol min −1 , P <0.01; 4±11% inhibition at 330 nmol min −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