Effects ' of ' nonsetective endothelin - l receptor antagonism on cardiac

dssue from sham-operated (Sham), untreated-fistula (Fist), and bosentan (100 mg'kg-1'day-r)-treated animals Gist + Bos) was analyzed for mast cell density, MMP activity, and myocardial collagen volume ' : ' H;h;; ai''i and 5 days after the qeation of an aortocaval fistula. r When compared with untreated flstulas, bosentan treafrnent prevented the marked increase in LV mast cell density at I day postfistula (3.1 -r , 0.3 vs. 1.3 I 0.3 LV mast cells/mm2, Fist vs. Fist * Bos, P < 0.01). .aOOitionally, the substantial increase in MMP-2 activation in the untreated fistula at I day was prevented following bosentan treatuent : (1.6 + 0.3 vs. 0.9 -f 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 + O.IVo myocardial tissue, Sham vs. Fist, P < 0.01) was significantly attenuated following bosentan treatment at both the land 5-day time points. Lastly, a 2-wk preventative treatrnent'nith bosentan resulted in significant attenuation of the increase in LV end-systolic and -diastolic volumes conpared with those in untreated fistula hearts. In summary, nonselective ET-l antagonism prevents the acute increases in cardiac mast cell density and MMP activation induced secondary to chronic volume overload. By preventing these events, ET-l antagonism was efficacious in aftenuating ventricular dilatation and limiting the development of structural and functional deficits in the first 2 wk of chronic volume overload. Accordingly, these results are the first to demonstrate that cardiac mast cells are responsive to the endogenous endothelin systen in vivo. Another nouil findine from this studv is that Clronic nonspecific endothelin antagonism iay inadvertently potentiate ETI -mediated signaling.