There are fundamental differences between males and females with regard to susceptibility to heart disease. Although numerous animal models of heart failure have demonstrated that premenopausal females are afforded cardioprotection and therefore fare better in the face of cardiac disease than their male counterparts, many questions as to how this occurs still exist. Recently, we have shown: 1) that increased mast cell density is associated with adverse ventricular remodeling; and 2) chemically induced mast cell degranulation using compound 48/80 resulted in remarkable changes in matrix metalloproteinase (MMP) activity, cardiac collagen structure, and cardiac diastolic function in normal male rats. With the known gender differences in cardiac disease in mind, we sought to examine the effects of chemically induced cardiac mast cell degranulation in isolated, blood-perfused hearts of intact females, ovariectomized females, and ovariectomized females treated with 17-estradiol. In response to mast cell degranulation, no significant differences in cardiac function, MMP-2 activity, or collagen volume fraction (CVF) were observed between intact females or ovariectomized females treated with estrogen. Whereas, in the ovariectomized female group, a significant rightward shift in the left ventricular pressure-volume relationship was noted post 48/80, accompanied by a marked 133% increase in active MMP-2 values over that seen in intact female hearts post 48/80 (p 0.05) and a significant reduction in CVF below control (0.46 ± 0.23 vs. 0.73 ± 0.13, respectively; p 0.05). These findings indicate that estrogen's cardioprotective role can be partially mediated by its effects on cardiac mast cells, MMPs, and the extracellular matrix.