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

1. N-G-monomethyl-L-arginine (L-NMMA) constricts human forearm resistance v asculature and selectively attenuates vasodilator responses to endothelium- dependent vasodilators. Incomplete inhibition of such responses could be du e to an inadequate dose of L-NMMA or to NO-independent vasodilator mechanis ms. 2 This study sought to determine doses Of L-NMMA that are maximally effecti ve 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)). 3 The effect of L-NMMA on basal flow approached maximum (53 +/- 2% reductio n) at a dose of 16 mu mol min(-1). L-NMMA (16 mu mol min(-1)) did not signi ficantly influence responses to nitroprusside, but antagonized acetylcholin e and albuterol (each P < 0.001, by repeated measures analysis of variance) . 4 Inhibition of acetylcholine by L-NMMA (16 mu mol min(-1)) was strongly in fluenced 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. 5 A higher dose of L-NMMA (64 mu mol min(-1)) did not significantly inhibit the response to acetylcholine (330 nmol min(-1)). Responses to this dose o f acetylcholine were unaffected by a cyclooxygenase (COX) inhibitor (indome tacin) alone but combined COX and NO inhibition attenuated acetylcholine re sponses by 42 +/- 19%, implying that there is a compensatory increase in th e contribution of prostaglandins or NO to acetylcholine-induced dilatation when one or other pathway is inhibited.