The effects of N-acetylcysteine, a sulfhydryl group donor, on nitroglycerin-induced headache and dilation of temporal and radial arteries were investigated in 11 healthy volunteers. Nitroglycerin, 0.06 microgram/kg/min, was infused for 20 minutes immediately after and 120 minutes after pretreatment with N-acetylcysteine (100 mg/kg) or placebo. Arterial diameters were measured with high frequency ultrasound, and pain was scored by use of a previously evaluated 10-point scale. Plasma levels of free (n = 2) and total (n = 11) N-acetylcysteine were determined. N-Acetylcysteine potentiated the headache response (median headache score, 3 versus 1), and the headache retained its vascular characteristics. Temporal artery dilation was also potentiated by N-acetylcysteine, 139% +/- 3% versus 127% +/- 3% of baseline, whereas the radial artery was unaffected. The potentiation was most pronounced after the first nitroglycerin infusion (12% versus 4.5% compared with placebo). A prolonged dilation of the temporal artery was observed only after the first nitroglycerin infusion, when high levels of N-acetylcysteine were present.