The effects of histamine alone and in the presence of AVP or DDAVP on microvascular permeability to macromolecules was evaluated in the superfused hamster cheek pouch. FITC-Dextran (MW 70,000) was employed as a macromolecular tracer to quantitate the increase in macromolecular permeability produced by the topical application of histamine. Intra-vital light microscopy was utilized to quantitate and localize FITC-D extravasation sites along the vascular tree, and fluorimetric measurement of the FITC-D concentration in the suffusate (S) and plasma (P) was used to calculate the FITC-D S/P ratio to quantitate the increase in macromolecular permeability. The infusion of histamine for 5 minutes at a rate which produced a suffusate histamine concentration of 1 X 10(-5) M produced a marked increase in the number of venular FITC-D leakage sites, the [FITC-D]s, and the FITC-D S/P ratio. These effects of histamine were prevented by treatment with either AVP or DDAVP which was infused at a rate sufficient to produce a suffusate concentration of 1 X 10(-8) M. AVP produced profound vasoconstriction whereas DDAVP prevented the histamine-induced increase in the formation of venular FITC-D leakage sites, the [FITC-D]s, and FITC-D S/P ratio without producing vasoconstriction. These data suggest that the antagonism of the histamine-induced increase in macromolecular permeability by AVP and DDAVP is not dependent on vasoconstriction per se, but rather is attributable to the stimulation of a vasopressin receptor on the venular endothelial cell which is identical to or similar to the vasopressin receptor mediating the anti-diuretic effects of these agents.