Although cigarette smoking is an established risk factor for atherosclerosis, the true mediator of vessel diseases associated with smoking is not known. Because endothelin-1 (ET-1) exhibits potent vasoconstrictor activity, it may act as a mediator in this condition. We determined venous ET-1 and nicotine levels in 12 smokers (age 21-24 years, 2-52 pack-years) before and 10 min, 4 h, and 8 h after the beginning of smoking. To distinguish an isolated effect of nicotine, 11 nonsmokers (age 24-50 years) were investigated while they were wearing a transdermal nicotine delivery system (TNDS). ET-1 was measured by RIA and nicotine by HPLC. Baseline ET-1 plasma levels before the exposure to either smoking or nicotine administration were comparable in smokers (1.07 +/- 0.3 pg/ml) and in nonsmokers (1.04 +/- 0.3 pg/ml). Smokers had borderline significantly higher ET-1 plasma levels within 10 min after the onset of smoking (1.3 +/- 0.3 pg/ml vs. 1.08 +/- 0.3 pg/ml; p = 0.055) but not after 4 and 8 h. Nonsmokers exposed to TNDS did not exhibit any significant plasma ET-1 changes. We conclude that the increase in plasma ET-1 after cigarette smoking is of borderline significance and is a transitory phenomenon restricted to the first 10 min after the onset of smoking. Although nicotine itself seems to be an unlikely mediator, other smoke components, such as CO or tar, may be responsible for the increase in plasma ET-1 in smokers. The absence of an ET-1 increase after transcutaneous nicotine application underscores the safety of TNDS in smoking withdrawal therapy.