The effect of prostaglandin E2 and histamine and their interaction on microvascular permeability in the rat mesentery was examined using fluorescent in vivo microscopy. Leak of a fluorescein-albumin conjugate from microvessels was determined 3 min after the topical application of prostaglandin E2 and/or histamine. The size of the leak (micron 2) was quantitated using a grid over the face of the videomonitor. To determine the role of endogenous prostaglandin, some rats were pretreated with 10 mg kg-1 indomethacin intravenously. All studies were performed coded. Dose-response studies performed with either prostaglandin E2 or histamine alone revealed that each agent increased microvascular permeability in a dose-related fashion. On a molar basis, prostaglandin E2 was more potent than histamine in this regard. When a low dose of prostaglandin E2 was administered together with a low or intermediate dose of histamine, the size of the resulting leak was significantly greater than the sum of the size of leak produced by each agent given separately. When rats were pretreated with 10 mg kg-1 indomethacin intravenously to inhibit prostaglandin synthesis, the histamine dose response was shifted to the right. From these experiments, we conclude that: In the rat mesentery, both topical prostaglandin E2 and histamine increase microvascular permeability to macromolecules in a dose-related fashion. Prostaglandin E2 is significantly more potent than histamine in this regard. Both exogenous and endogenous prostaglandin potentiate histamine's effect on microvascular permeability.