Gender influences volume regulation via several mechanisms; whether these include microvascular exchange, especially in the heart, is not known. In response to adenosine (Ado), permeability (P(s)) to protein of coronary arterioles of female pigs decreases acutely. Whether Ado induces similar P(s) changes in arterioles from males or whether equivalent responses occur in coronary venules of either sex has not been determined. Hypotheses that 1) basal P(s) properties and 2) P(s) responses to vasoactive stimuli are sex independent were evaluated from measures of P(s) to two hydrophilic proteins, alpha-lactalbumin and porcine serum albumin (PSA), in arterioles and venules isolated from hearts of adult male and female pigs. Consistent with hypothesis 1, basal P(s) values of both microvessel types were independent of sex. Contrary to hypothesis 2, P(s) responses to Ado varied with sex, protein, and vessel type. Confirming earlier studies, Ado induced a approximately 20% decrease in P(s) to both proteins in coronary arterioles from females. In arterioles from males, Ado did not change P(s) for alpha-lactalbumin (P(s)(alpha-lactalb), 3 +/- 13%), whereas P(s) for PSA (P(s)(PSA)) decreased by 27 +/- 8% (P < 0.005). In venules from females, Ado elevated P(s)(PSA) by 44 +/- 20% (P < 0.05), whereas in those from males, Ado reduced P(s)(PSA) by 24 +/- 5% (P < 0.05). The variety of outcomes is consistent with transvascular protein and protein-carried solute flux being regulated by multiple sex-dependent mechanisms in the heart and provides evidence of differences in exchange homeostasis of males and females in health and, likely, disease.