Maxadilan is a potent vasodilator isolated from salivary gland extracts of the sand fly. Although cutaneous vasodilatation is probably the most important physiologic effect of maxadilan (i.e., assisting the sand fly in obtaining a blood meal), it also has effects on other vascular beds. In rabbit isolated aorta, recombinant maxadilan exhibited endothelium-independent relaxations with an IC50 of 24 nM for norepinephrine-induced (1 microM) contractions. Synthetic maxadilan had one-third the potency, with a corresponding IC50 of 74 nM for norepinephrine-induced (1 microM) contractions. Pretreatment with a number of receptor and channel blockers, including tetraethylammonium (1 mM), glyburide (1 microM), barium (0.5 mM), indomethacin (10 microM), propranolol (10 microM), cimetidine (10 microM) and nifedipine (10 microM) did not affect maxadilan-induced relaxations. After treatment with maxadilan, contractions recurred very slowly over approximately 40 min. At a concentration of 1 microM, maxadilan induced a 2- to 3-fold increase in cellular cyclic AMP levels. Maxadilan's activity was selective according to vessel type, with maximal activity in rabbit aorta and mesenteric artery and no activity in porcine and bovine coronary arteries. These studies suggest that maxadilan acts by raising the intracellular levels of cyclic AMP in the smooth muscle of selected blood vessels.