[Tic(4)]EM1 and [Tic(4)]EM2, new endomorphins (EMs) analogues, caused relaxation of rat aorta rings precontracted with phenylphrine in a concentration-dependent manner and were 240- to 370-fold more potent than EMs. This effect was inhibited by endothelium removal or by incubation with NO synthase inhibitor L-NNA or opioid receptor antagonist naloxone. The results demonstrate that [Tic(4)]EMs have NO- and endothelium-dependent vasorelaxant effects which are mediated by the opioid receptor.