The purpose of this study was to examine pressor responsiveness in a rabbit model with adrenal perturbation. Adrenals in rabbits were stabbed with a needle, and the rabbits were given water (adrenal-water group) or 0.9% NaCl (adrenal-salt) to drink; additional rabbits were sham-operated and given water (sham-water group) or 0.9% NaCl (sham-salt group) to drink. Acute experiments were performed two weeks later on conscious rabbits. All four groups of rabbits had the same body weights, mean arterial pressures, heart rates, and plasma concentrations of Na+ and K+. Intravenous norepinephrine infusions at several doses produced greater pressor responses in the adrenal-water and adrenal-salt groups than in the sham-water or sham-salt groups. Administration 1-sarcosine-8-isoleucine angiotensin II ([Sar1, Ile8]Ang II) did not alter the pressor responses to norepinephrine in either the sham-water or the adrenal-salt groups. Cross-circulation of blood between adrenal-salt donor rabbits and normal recipient rabbits at 10 ml/min for 5 min resulted in enhanced pressor responses to norepinephrine in the recipients at 5 min after the cross-circulation. Similar cross-circulation experiments between sham-water donors and normal recipients did not alter the pressor responses to norepinephrine in the recipients. These studies demonstrated that rabbits with adrenal perturbations have pressor hyper-responsiveness to norepinephrine, which does not involve angiotensin II mechanisms, but is mediated by a fast-acting blood-borne factor.