title: Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats.
abstract: The objective of this study was to investigate the effect a nonselective endothelin-1 (ET-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 (100 mg.kg(-1).day(-1))-treated animals (Fist + Bos) was analyzed for mast cell density, MMP activity, and myocardial collagen volume fraction at 1 and 5 days after the creation of an aortocaval fistula. When compared with untreated fistulas, bosentan treatment prevented the marked increase in LV mast cell density at 1 day postfistula (3.1 +/- 0.3 vs. 1.3 +/- 0.3 LV mast cells/mm2, Fist vs. Fist + Bos, P <or= 0.01). Additionally, the substantial increase in MMP-2 activation in the untreated fistula at 1 day was prevented following bosentan treatment (1.6 +/- 0.3 vs. 0.9 +/- 0.1 arbitrary activity units, Fist vs. Fist + Bos, P <or= 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 <or= 0.01) was significantly attenuated following bosentan treatment at both the 1- and 5-day time points. Lastly, a 2-wk preventative treatment with bosentan resulted in significant attenuation of the increase in LV end-systolic and -diastolic volumes compared with those in untreated fistula hearts. In summary, nonselective 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 2 wk 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 nonspecific endothelin antagonism may inadvertently potentiate ET-1-mediated signaling.
authors.affiliation: University of South Carolina, School of Medicine, Department of Cell and Developmental Biology and Anatomy, Columbia, SC 29208, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Murray
authors.forename: Jason D
authors.initials: JD
authors.lastname: Gardner
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Brower
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Janicki
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077300:Bosentan; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D008297:Male; D008407:Mast Cells / Q000187:drug effects*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology*; D009210:Myofibrils / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D000959:Antihypertensive Agents; D016207:Cytokines; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D020782:Matrix Metalloproteinases; D000077300:Bosentan