(Circulation. 2000;101:2849.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Long-Term Endothelin Receptor Antagonist Administration Improves Alterations in Expression of Various Cardiac Genes in Failing Myocardium of Rats With Heart Failure
From the Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Correspondence to Takashi Miyauchi, MD, PhD, Cardiovascular Division, Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan. E-mail t-miyauc{at}md.tsukuba.ac.jp
Background—We reported that long-term (3-month) treatment with the endothelin (ET) type A (ETA) receptor antagonist BQ-123 markedly improved survival in rats with chronic heart failure (CHF). However, it is not known whether long-term treatment with an ET receptor antagonist improves alterations in the expression of cardiac genes in failing hearts.
Methods and Results—CHF rats and control sham-operated rats were treated with BQ-123, SB209670 (ETA/B dual receptor antagonist), or saline (vehicle) for 3 months. The survival of CHF rats was markedly higher in the BQ-123 or SB209670 treatment group than in the saline treatment group. The changes in the gene expression of classic molecular markers for failing hearts (mRNA levels of atrial natriuretic peptide and ß-myosin heavy chain) were greatly inhibited by BQ-123 or SB209670 treatment in CHF rats. Long-term BQ-123 treatment also normalized the alterations in the expression of functional molecular markers in failing hearts (eg, mRNA levels of ryanodine receptor, sarcoplasmic reticulum Ca2+-ATPase, angiotensin-converting enzyme, angiotensin II type 1 receptor, and prepro-ET-1).
Conclusions—We demonstrated for the first time that long-term (3-month) treatment with an ET receptor antagonist improves the alterations in the expression of various cardiac genes of classic molecular markers (eg, mRNA in atrial natriuretic peptide and ß-myosin heavy chain) and of functional molecular markers (eg, mRNA levels of ryanodine receptor, sarcoplasmic reticulum Ca2+-ATPase, angiotensin-converting enzyme, angiotensin II type 1 receptor, and prepro-ET-1) in the failing hearts of CHF rats, suggesting that the great improvement of survival in CHF rats by an ET blocker is partly attributed to the prevention of molecular changes in failing hearts.
Key Words: endothelin • heart failure • genes
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