We evaluated the effect of systemically administered histamine on coronary vascular permeability (CVP) of pentobarbital-anesthetized, open-chest dogs with and without beta-receptor blockade. We determined changes in CVP by comparing prenodal cardiac lymph flow and lymph-to-plasma protein concentration ratio before and after 30 min of histamine infusion. Histamine was infused into the left ventricle at 150 micrograms/min to produce pathological blood histamine concentrations of approximately 0.5 micrograms/ml. Histamine increased CVP in only one of seven dogs without beta-receptor blockade but increased CVP in four of seven beta-blocked animals. In a second series of experiments, the effect of histamine on CVP was assessed in an in situ isolated heart-lung preparation. In this preparation, similar blood histamine concentrations increased CVP in the same fraction of experiments (4 of 7) as was observed for beta-blocked dogs. Therefore, isolating the heart from the effects of all systemically derived histamine antagonistic substances did not appear to make the coronary vessels any more vulnerable to histamine than only blocking the actions of catecholamines. We conclude that 1) catecholamines provide protection for the coronary microvasculature against histamine-induced increases in the CVP; and 2) the probability that vascular permeability will increase in the heart when histamine exposure occurs through the general circulation is remote. Thus, if histamine-induced increases in CVP occur, then they probably result from the release of histamine from myocardial storage sites.