In anesthetized rats we tested the hypothesis that cigarette smoke potentiates acid-induced duodenal mucosal injury by inducing mesenteric vasoconstriction. Rats inhaled room air or 6 or 12 ml/min cigarette smoke. Study 1: 0.1 N HCl-induced duodenal mucosal injury and H+ loss were assessed by histologic evaluation and titration, respectively. Study 2: Superior mesenteric artery blood flow was assessed by pulsed Doppler flowmetry before and during inhalation of cigarette smoke or room air. Twelve milliliter per minute of cigarette smoke aggravated 0.1 N HCl-induced duodenal mucosal injury by significantly increasing the number of villi with deep villous damage. The increased damage was associated with significantly greater loss of H+ from the duodenal lumen. Cigarette smoke produced a dose-related reduction in mesenteric blood flow. We conclude that the vasoconstrictive effect of cigarette smoke on mesenteric blood flow may be involved in the potentiation of acid-induced duodenal mucosal injury.