The purpose of this study was to characterize the mode of action of nematocyst venom from the Portuguese man-of-war (Physalia physalis) on isolated rabbit arterial ring segments, and to see if these in vitro effects were similar to those observed in the intact skeletal muscle vasculature of the dog (see Loredo et al., J. Pharmacol. Exp. Ther. 232: 301-304, 1985). The venom (0.021-4.28 micrograms/ml) produced dose-dependent relaxations of norepinephrine precontracted arterial segments from various vascular beds. Venom-induced relaxations were blocked by sodium meclofenamate (10-20 micrograms/ml), but not by atropine (6 micrograms/ml), propranolol (4-12 micrograms/ml) or quinacrine (2-4 X 10(-5) M). These results were similar to those observed in the intact skeletal muscle vascular bed of the dog and further implicate the stimulation of endogenous prostaglandin synthesis as the mechanism by which P. physalis venom dilates vasculature.