The role of adrenomedullin (ADM) in volume and pressure homeostasis remains undefined. Accordingly, we compared the biological responses to infusions of ADM and nitroprusside (NP; matched for reduction of arterial pressure) and assessed their effects on responses to ANG II and norepinephrine in eight conscious sheep. During matched falls in arterial pressure (8-10 mmHg, both P < 0.001) ADM and NP induced similar increases in heart rate. ADM increased cardiac output (P < 0.001), and the fall in calculated peripheral resistance was greater with ADM than NP (P = 0.013). ADM infusions raised plasma ADM levels (P < 0.001), plasma renin activity (P = 0.001), and ANG II (P < 0.001) but tended to blunt any concurrent rise in aldosterone compared with NP (P = 0.056). ADM maintained both urine flow (P < 0.001) and sodium excretion (P = 0.01) compared with falls observed with NP. ADM attenuated the vasopressor actions of exogenous ANG II (P = 0.006) but not norepinephrine. In addition, ADM antagonized the ANG II-induced rise in plasma aldosterone (P < 0.001). In conclusion, ADM induces a different spectrum of hemodynamic, renal, and endocrine actions to NP. These results clarify mechanisms by which ADM might contribute to volume and pressure homeostasis.