The objective of this study was to investigate the effect a non selective endothelin-1 receptor antagonist (Bosentan) had on the acute myocardial remodeling process including left ventricular (LV) mast cells and matrix metalloproteinase (MMP) activity secondary to volume overload. Additionally, we investigated the overall functional outcome of preventative endothelin receptor antagonism during 14 days of chronic volume overload. LV tissue from sham-operated (sham), untreated fistula (Fist), and bosentan (100mg/kg) treated animals (Fist+Bos) (n=6-8 per group) was analyzed for mast cell density, MMP activity, and myocardial collagen volume fraction 1 and 5days after the creation of an aorto-caval fistula. Compared to untreated fistulas, Bosentan treatment prevented the marked increase in LV mast cell density at 1 day post fistula (3.1 ± 0.3 vs. 1.3 ± 0.3 LV mast cells/mm², Fist vs. Fist+Bos, p≤ 0.01). Additionally, the substantial increase in MMP-2 activation in the untreated fistula at 1 day was prevented following bosentan treatment (1.6 ± 0.2 vs. 0.8 ± 0.1 arbitrary activity units, Fist vs. Fist+Bos, p≤ 0.01). The marked decrease in collagen volume fraction seen in the Fist group (1.4 ± 0.1 vs. 0.8 ± 0.1 % myocardial tissue, sham vs. Fist, p≤ 0.01) was significantly attenuated following bosentan treatment at both the 1 and 5 day time points. Lastly, a two week preventative treatment with bosentan resulted in significantly attenuated changes in left ventricular end systolic and diastolic volumes compared to untreated fistula hearts. In summary, non-selective ET-1 antagonism prevents the acute increases in cardiac mast cell density and MMP activation induced secondary to chronic volume overload. By preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits in the first two weeks of chronic volume overload. Accordingly, these results are the first to demonstrate that cardiac mast cells are responsive to the endogenous endothelin system in vivo. Another novel finding from this study is that chronic non-specific endothelin antagonism may inadvertently potentiate ET-1 mediated signaling.