The local intra-arterial infusion of histamine, in doses which produce maximal increases in protein efflux, failed to increase lymph total protein concentration in canine forelimbs perfused at constant inflow with autologous blood from dogs subjected to severe hemorrhagic hypotension. Norepinephrine and isoproterenol in low concentrations were less effective in antagonizing protein efflux produced by high doses of histamine than by low doses of this agent. This suggests that other vasoactive substances released in response to a hemorrhagic stimulus may also be physiological antagonists of the direct actions of histamine on the microvascular membrane. The simultaneous infusion of vasopressin or serotonin, or pretreatment with high doses of glucocorticoids, antagonizes the protein efflux produced by local intra-arterial infusions of histamine into forelimbs perfused at constant inflow. Angiotensin II, acetylcholine, low doses of glucocorticoids, and papaverine all failed to alter measurably the protein efflux produced by histamine under similar conditions. We conclude that a variety of hormones and other vasoactive agents may function as antagonists of the direct action of histamine on the microvascular membrane, and that the antagonism of histamine-induced protein efflux is independent of changes in histamine receptor blockade, blood flow, microvascular pressure, and perfused surface area. Moreover, in experiments employing adrenergic blocking agents, the antagonism of histamine-induced protein efflux by catecholamines was due to stimulation of β-adrenergic receptors.Circ Res 46: 264-275, 1980