N-ACETYLCYSTEINE DOES NOT INFLUENCE THE ACTIVITY OF ENDOTHELIUM-DERIVED RELAXING FACTOR IN-VIVO

Nitric oxide forms complexes with an array of biomolecular carriers th at retain biological activity. This reactivity of nitric oxide in phys iological systems has led to some dispute as to whether endothelium-de rived relaxing factor is nitric oxide or a closely related adduct ther eof, such as a nitrosothiol. In vitro bioassays used to address this q uestion are limited by the exclusion of biological thiols that are req uisite for nitrosothiol formation. Thus, the purpose of this study was to obtain insight into the identity of endothelium-derived relaxing f actor in vivo. We reasoned that if endothelium-derived relaxing factor is nitric oxide, infusion of physiological concentrations of thiol wo uld potentiate its bioactivity by analogy with effects seen in vitro, whereas nitrosothiol would be resistant to such modulation. We used ve nous-occlusion plethysmography to study forearm blood how in normal su bjects. Methacholine (0.3 to 10 mu g/min) and nitroglycerin (1 to 30 m u g/min) were infused via the brachial artery to elicit endothelium-de pendent and endothelium-independent vasodilation, respectively. Dose-r esponse determinations were made for each drug before and after an int ra-arterial infusion of the reduced thiol, N-acetylcysteine, at rates estimated to achieve a physiological concentration of 1 mmol/L. Methac holine increased forearm blood flow in a dose-dependent manner. Infusi on of N-acetylcysteine did not change the sensitivity (ED(50), 1.7 ver sus 1.7 mu g/min, P=NS) or maximal response to methacholine. In contra st, thiol increased the sensitivity to nitroglycerin (ED(50), 4.7 vers us 2.8 mu g/min, P<.01). Thus, conflicting with reports in vitro, thio l does not modulate endothelium-derived relaxing factor responses in v ivo. These data indicate that sulfhydryl groups are not a limiting fac tor for endothelium-derived relaxing factor responses in forearm resis tance vessels in normal humans and are in keeping with reports that ni trosothiol contributes to endothelium-derived relaxing factor bioactiv ity in plasma and vascular smooth muscle. Potentiation of the effects of nitroglycerin by N-acetylcysteine can be attributed to its enhanced biotransformation to an endothelium-derived relaxing factor equivalen t, such as nitrosothiol. These observations support the notion of an e quilibrium between nitric oxide and nitrosothiol in biological systems that may be influenced by redox state.