Experimental evidence indicates that arginine vasopressin (AVP) contributes to the release of ACTH under certain conditions. The present study investigates the role of vasopressin as a secretagogue of ACTH during cigarette smoking or nicotine infusion with additional injection of corticotropin releasing hormone (CRH) and using the specific AVP antagonist d(CH2)sTyr(Me)-AVP. We first tested the effect of the AVP antagonist (10 gg/kg body weight i.v.) on ACTH and cortisol release following cigarette smoking in 15 healthy young male smokers. Smoking led to marked increments in plasma nicotine and to a small rise in plasma ACTH and cortisol. Mean plasma ACTH and cortisol levels were at no time significantly altered by the antagonist. This might be due to a slight agonistic effect of the AVP antagonist, to high interindividual variability of the ACTH and cortisol responses after smoking or to a neglegible role of AVP in smoking-induced ACTH release. In a second study we performed the following tests in six healthy male non-smokers : (1) nicotine infusion (1.0 gg/kg body weight per min); (2) CRH i.v. (100 gg); (3) AVP antagonist i.v. (5 gg/ kg); (4) nicotine infusion plus CRH i.v. ; (5) nicotine infusion plus AVP antagonist i.v. ; (6) nicotine infusion plus CRH and AVP antagonist i.v. ; and (7) sham infusion. Nicotine infusion led to greater increments of AVP, ACTH and cortisol than smoking without causing nausea. Peak nicotine levels after nicotine infusion were lower than after smoking. The AVP antagonist in the reduced dosage given alone had no effect on hormone levels. However, it slightly attenuated the effect of nico-Abbreviations: ACTH=adrenocorticotropic hormone; ANO-VA = analysis of variance; AVP = arginin vasopressin; CRH = corticotropin releasing hormone; K + = potassium; d (CH2)s Tyr (Me)-AVP = vasopressin (V1)-antagonist * Supported by a grant from Forschungsrat Rauchen und Gesundheit tine on ACTH and cortisol (P<0.05, ANOVA). Nicotine and CRH given together stimulated ACTH and cortisol in a less than additive manner. The combined effect of nicotine and CRH was not inhibited by the antagonist. Our results indicate that the effect of nicotine on ACTH and cortisol may be partly mediated by hypothalamic AVP. Nicotine may also enhance CRH release by stimulating acetylcholine receptors of hypothalamic CRH neurons.