The role of alpha 2-adrenergic receptor stimulation in the regulation of systemic vascular capacity and venous return, a major determinant of cardiac output, is not well understood. With the influence of the central nervous system isolated from the systemic circulation, the direct peripheral vascular effects of two specific, chemically distinct alpha 2-adrenergic receptor agonists, UK 14,304 and B-HT 920, were investigated in 19 dogs on total cardiopulmonary bypass with constant arterial perfusion and central venous pressure. Five-minute intra-arterial infusions of UK 14,304 (200 micrograms/min) resulted in increased arterial resistance (mean arterial pressure increased 18 +/- 4 [SEM] mm Hg; p less than 0.01) and a decrease in systemic vascular capacity (81 +/- 20 ml; p less than 0.01). This decrease in systemic vascular capacity appears to result from vasoconstriction, since there was no decrease in transhepatic resistance to portal flow and no significant change in hepatic vein flow to suggest redistribution of arterial blood flow. Yohimbine abolished both the arterial and systemic capacity effects, whereas prazosin did not. Intra-arterial administration of B-HT 920 (200 theta grams/min) in five dogs produced similar changes in arterial resistance and systemic capacity. These findings provide direct evidence for beta 2-adrenergic control, not only of arterial resistance but also of systemic vascular capacity, which in the intact animal would increase venous return to the heart.