ETA selective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina Submitted 5 September 2008 ; accepted in final form 8 May 2009 The objective of this study was to investigate the ability of selective endothelin receptor subtype A (ET A ) endothelin receptor antagonism (ETA) 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 + ETA, 25 mg·kg –1 ·day –1 )-treated fistula animals was analyzed for mast cell density, matrix metalloproteinase (MMP) activity, and extracellular collagen volume fraction (CVF) 1 and 5 days following the initiation of volume overload. Compared with Fist, ETA treatment prevented the increase in left ventricular mast cell density at 1 day and 5 days. Additionally, at 1 day postfistula, a substantial decrease in MMP-2 activity below Sham levels was observed following endothelin receptor antagonism (1.7 ± 0.7 vs. 0.3 ± 0.3 vs. 0.9 ± 0.2 arbitrary activity units, Fist vs. Fist + ETA vs. Sham, P 0.05). This same effect was also seen at 5 days postfistula (1.9 ± 0.3 vs. 0.5 ± 0.1 arbitrary activity units, Fist vs. Fist + ETA, P 0.05). The marked decrease in myocardial CVF seen in Fist hearts (0.7 ± 0.1 vs. 1.6 ± 0.1% myocardial area, Fist vs. Sham, P 0.05) was prevented by ETA (1.7 ± 0.1% Fist + ETA, P < 0.05 vs. Fist). This preservation of the collagen matrix was also present on day 5 in the TBC-treated group vs. the Fist group (1.0 ± 0.1 vs. 1.4 ± 0.1%, Fist vs. Fist + ETA, P 0.01). Furthermore, an 8-wk preventative treatment with ETA significantly attenuated the increase in left ventricular end systolic and diastolic volumes compared with untreated fistula hearts. In conclusion, the novel findings of this study indicate that the activation of cardiac mast cells and subsequent MMP activation/collagen degradation during the acute stages of volume overload are 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. endothelin-1; mast cell; matrix metalloproteinase; TBC-3214 Address for reprint requests and other correspondence: D. B. Murray, Univ. of Mississippi, School of Pharmacy, Dept. of Pharmacology, 219A Faser, Univ., MS 38677 (e-mail: dmurray{at}olemiss.edu )