Smoking is a major risk factor for the development of atherosclerosis. Because endothelial dysfunction may be a marker for future atherosclerosis, we investigated the effects of smoking on endothelium-dependent control of vascular tone.Methods and ResultsThe effects of brachial arterial infusions ofNG-monomethyl-L- arginine (L-NMMA), a nitric oxide synthesis inhibitor; sodium nitroprusside; endothelin-1; and norepinephrine on forearm blood flow (strain-gauge plethysmography) were compared in 29 long- term smokers and 16 nonsmokers. The acute effects of smoking on systemic hemodynamics, plasma catecholamines, and forearm vascular responses to these compounds were investigated in smokers only. Smokers did not differ from nonsmokers (n= 16) regarding the vascular effects of sodium nitroprusside (n= 13) or vasoconstriction due to norepinephrine and endothelin-1 (n= 16). Low- dose endothelin-1-induced vasodilation, believed to reflect endothelial prostacyclin or nitric oxide release, was absent in smokers (n= 16), and their increase of forearm vascular resistance (FVR) after L-NMMA (n=13) was impaired impaired (35.6±27.9% versus 118.8±43.2%,P< .001). Shortterm smoking (n=11) increased blood pressure, heart rate, and plasma epinephrine concentrations (P< .05 or less); enhanced endothelin-1-induced vasoconstriction (ΔFVR, 457±192% versus 254±143%,P< 01); and decreased norepinephrine- induced vasoconstriction (P< .05), but had no effect on the other interventions.ConclusionsLong-term smoking is associated with a diminished nitric oxide-dependent component of basal vascular tone and an impaired endothelium-dependent vasodilator response to low-dose endothelin-1 and short-term smoking enhances endothelin-1-induced vasoconstriction. Impaired endothelial control of vascular tone might reflect impairment of normal antiatherosclerotic endothelial functions in smokers, but the relevance of smoking-induced enhancement of endothelin-1 vasoconstriction remains to be determined.