The effect of helodermin on vascular physiology was studied in anesthetized dogs using a synthetic replicate of helodermin and helodermin related peptides. Intraarterial infusion of helodermin caused a dose-dependent increase in femoral blood flow. Helodermin was 16 times less potent than VIP and 5 times more potent than PHM (human PHI). The helodermin effect lasted significantly longer; the half-life of the helodermin effect was 6.5 times longer than VIP. Synthetic helodermin (Hd) N-terminal fragment Hd(1-27)NH2 retained substantial activity similar to the full helodermin molecule but the prolonged effect was lost. Hd(7-35) and Hd(22-35) were inactive in this system. Intravenous injection of synthetic helodermin produced prolonged systemic hypotension and tachycardia; and, similar to VIP, it increased the common carotid arterial blood flow while those of the superior mesenteric and femoral arteries were decreased. The results demonstrate the VIP-like vasodilating activity and cardiovascular effects of helodermin in anesthetized dogs.