The effect of vasopressin released by cigarette smoking on blood pressure (BP), heart rate (HR), and skin blood flow (SBF) was investigated in 12 normotensive habitual smokers. At a 1-wk interval, each subject smoked within 10 min two cigarettes before and after intravenous injection of either the specific vascular vasopressin antagonist d(CH2)5Tyr(Me)AVP (5 micrograms/kg) or its vehicle administered in double-blind fashion. SBF was assessed with a laser Doppler flowmeter. Smoking increased plasma vasopressin (P less than 0.01). In six subjects subsequently treated with the antagonist, plasma vasopressin rose to greater than 10 pg/ml and SBF fell by 18.2 +/- 4.8%. This SBF reduction was prevented by the vasopressin antagonist. In contrast, the vehicle had no effect. In the 24 studies taken together, there was a significant correlation (r = -0.60, P less than 0.01) between the SBF decrease during the first smoking period and the plasma vasopressin levels measured afterwards. The BP and HR rise caused by smoking was not modified by the antagonist. Thus it appears that the decrease in SBF induced by smoking is due to enhanced vasopressin secretion.