The role of aradrenergic 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 α2-adrenergk receptor agonists, UK 14,304 and BHT 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 μ/min) resulted in increased arterial resistance (mean arterial pressure increased 18 ± 4 [SEM] mm Hg;p< 0.01) and a decrease hi systemic vascular capacity (81 ± 20 ml;p< 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 &thetas;g/min) in five dogs produced similar changes in arterial resistance and systemic capacity. These findings provide direct evidence for β2-adrenergic control, not only of arterial resistance but also of systemic vascular capacity, which in the intact nnlmnl would increase venous return to the heart.