The effect of histamine on coronary vascular permeability was assessed under conditions of elevated venous pressure in the spontaneously beating, isolated canine heart perfused with autologous blood. The apparent volume of fluid filtered from the vasculature to the interstitium (VF) was calculated from the increase in plasma protein concentration and also from the increase in hematocrit. The ratio of the protein-filtered volume to the hematocrit-filtered volume (VF,Pr/VF,Hct) was used to evaluate changes in permeability. In the absence of histamine, the VF,Pr/VF,Hct was near unity (1.05 +/- 0.11), which indicated that the blood proteins and the red blood cells had concentrated equally. Thus the transudate was essentially protein free. On exposure to histamine (3.8 +/- 0.3 microgram base/ml blood), VF,Pr/VF,Hct decreased to 0.37 +/- 0.06 (P less than 0.001), which indicated that coronary vascular permeability had increased. This value remained constant throughout the 60 min of histamine exposure. Aortic perfusion pressure decreased significantly (P less than 0.05) from 111 +/- 11 to 84 +/- 5 mmHg during the 1st min of histamine exposure and rose slowly thereafter. In four of the seven hearts, concomitant increases in left ventricular isovolumic pressure development (13-31 mmHg) and heart rate (4-29 beats/min) were observed. In the remaining hearts, neither variable was affected by histamine. We conclude that histamine causes an increase in the permeability of the canine coronary microvasculature but fails to increase heart rate or left ventricular performance consistently.