We studied the effects of cigarette smoking, sham smoking and smoking during adrenergic blockade in 10 subjects to determine whether smoking released the sympathetic neurotransmitter norepinephrine, as well as the adrenomedullary hormone epinephrine, and whether smoking-associated hemodynamic and metabolic changes were mediated through adrenergic mechanisms. Smoking-associated increments in mean (+/- S.E.M.) plasma norepinephrine (227 +/- 23 to 324 +/- 39 pg per milliliter, P less than 0.01) and epinephrine (44 +/- to 113 +/- 27 pg per milliliter, P less than 0.05) were demonstrated. Smoking-associated increments in pulse rate, blood pressure, blood glycerol and blood lactate/pyruvate ratio were prevented by adrenergic blockade; increments in plasma growth hormone and cortisol were not. Since significant smoking-associated increments, in pulse rate, blood pressure and blood lactate/pyruvate ratio, preceded measurable increments in plasma catecholamine concentrations, but were adrenergically mediated, these changes should be attributed to norepinephrine released locally from adrenergic axon terminals within the tissues rather than to increments in circulating catecholamines.