Graded caval occlusion in conscious rabbits caused a biphasic cardiovascular response. Phase I was characterized by a fall in systemic vascular conductance so that arterial pressure was maintained. When cardiac output had fallen to 64 +/- 3% of its baseline level, phase II supervened. During phase II, conductance rose abruptly and arterial pressure fell to a life-threatening level (< 40 mm Hg). Intravenous (i.v.) or central (fourth ventricular) administration of the adrenocorticotrophin (ACTH) fragment ACTH-(1-24) prevented the occurrence of phase II. The central dose of ACTH-(1-24) needed to block the occurrence of phase II was approximately 39 times less than the i.v. dose. Central administration of the delta 1-opioid receptor agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) reversed this effect of both central and i.v. ACTH-(1-24). I.v. ACTH-(1-24) also lowered arterial pressure while raising cardiac output and vascular conductance. These effects were insensitive to propranolol and hyoscine methyl bromide, and were not mimicked by cortisol or adrenaline. It is concluded that ACTH-(1-24) has an acute, adrenal-independent, peripheral vasodilator effect as well as a central, anti-shock, effect.