The site and mechanism of action of the antihypertensive agent cicletanine have been studied. In the pithed rat model, intravenous (i.v.) cicletanine was able to reduce the elevated blood pressure induced by continuous infusion of the alpha 1-adrenergic agonist, methoxamine, in a dose-related manner. In strip preparation of the aorta from deoxycorticosterone (DOCA)-salt-treated rats, cicletanine was found to prevent the contraction induced by 1 microM noradrenaline. When subeffective doses of phentolamine (0.25 mg/kg p.o.) plus cicletanine (3 mg/kg p.o.) were given together, a clear-cut antihypertensive effect was observed in DOCA-salt rats. Moreover, subchronic administration of cicletanine (30 mg/kg p.o.), during the one month period of DOCA-salt administration to produce high blood pressure readings, was able to prevent cardiac noradrenaline depletion. These data suggest that the antihypertensive effect of cicletanine, which is clinically well tolerated, may be due to a multifactorial mechanism of its action, through which it might alter a number of physiological mediators while exercising a slight potency on each of them.