The present study was undertaken to investigate the effects of human adrenomedullin, a newly discovered peptide present in normal human plasma, as well as a fragment of adrenomedullin, on systemic hemodynamics in the anesthetized rat. Intravenous (i.v.) bolus injections of rat adrenomedullin, rat adrenomedullin-(11-50), human adrenomedullin-(13-52) decreased mean systemic arterial pressure in a dose-dependent manner. Since rat adrenomedullin and human adrenomedullin did not decrease cardiac output, the decreases in systemic arterial pressure reflect dose-dependent reductions in systemic vascular resistance. The systemic vasodepressor responses to similar doses of the adrenomedullin fragments studied and to their respective parent adrenomedullin peptides were similar. The present data demonstrate that the entire adrenomedullin molecule is not required for full systemic vasodilator activity in vivo suggesting that rat adrenomedullin-(11-50) or a structurally similar peptide, if formed endogenously, could mediate the hemodynamic properties of adrenomedullin in vivo. Since rat adrenomedullin had significantly greater systemic vasodilator activity than human adrenomedullin at similar doses in the rat, the present data suggest that adrenomedullin has greater systemic vasodilator activity in its native species and that limited changes in the peptide's sequence confer markedly different vascular activity in vivo.