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

Abstract

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 < or = 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 < or = 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 < or = 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 < or = 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.

• Authors: David B Murray, Ronald McMillan, Gregory L Brower, Joseph S Janicki
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 297 Issue 1 Pg. H109-16 (Jul 2009) ISSN: 1522-1539 [Electronic] United States
• PMID: 19429817 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Endothelin A Receptor Antagonists
• Isoxazoles
• Matrix Metalloproteinase Inhibitors
• Sulfonamides
• TBC 3214
• Tumor Necrosis Factor-alpha
• Collagen
• Matrix Metalloproteinases

Topics

• Animals
• Blood Volume (physiology)
• Blotting, Western
• Collagen (metabolism)
• Cytokines (metabolism)
• Endothelin A Receptor Antagonists
• Enzyme-Linked Immunosorbent Assay
• Extracellular Matrix (drug effects)
• In Vitro Techniques
• Isoxazoles (pharmacology)
• Male
• Mast Cells (physiology)
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinases (metabolism)
• Rats
• Rats, Sprague-Dawley
• Sulfonamides (pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)
• Ventricular Function, Left (drug effects)
• Ventricular Remodeling (drug effects)