The objective of this study was to investigate the ability of selective ET_A (TBC 3214) endothelin-1 receptor antagonism to prevent the acute myocardial remodeling process secondary to volume overload. Left ventricular tissue from sham-operated (Sham) and untreated (Fist), and TBC 3214 (Fist + TBC, 25 mg/kg/d) treated fistula animals was analyzed for mast cell density, matrix metalloproteinase (MMP) activity, and extracellular collagen volume fraction 1 and 5 days following the initiation of volume overload. Compared to Fist, TBC 3214 treatment prevented the increase in LV mast cell density at 1 day and 5 days. Additionally, at 1 day post fistula a substantial decrease in MMP-2 activity below Sham levels was observed following endothelin receptor antagonism (p 0.05). This same effect was also seen at 5 days post fistula (p 0.05) The marked decrease in myocardial collagen volume fraction seen in Fist hearts (0.7 ± 0.1 vs. 1.6 ± 0.1% myocardial area, Fist vs. Sham, p 0.05) was prevented by TBC 3214 (1.7 ± 0.1% Fist + TBC, p< 0.05 vs. Fist). This preservation of the collagen matrix was also present on day 5 in the TBC treated group versus the Fist group (1.0 ± 0.1 vs. 1.4 ± 0.1%, Fist vs. Fist + TBC, p 0.01). Lastly, an eight week preventative treatment with TBC 3214 resulted in a significantly attenuated increase in left ventricular end systolic and diastolic volumes compared to untreated fistula hearts. In conclusion, the novel findings of this study indicate that the activation of cardiac mast cells and subsequent matrix metalloproteinase activation/collagen degradation during the acute stages of volume overload is prevented by blockade of the ET_A receptor subtype. Furthermore, by preventing these events ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits.