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Beneficial effects of angiotensin-converting enzyme inhibition on sarcoplasmic reticulum function in the failing heart of the Dahl rat.

Abstract
Inhibition of angiotensin-converting enzyme (ACE) retards the process of myocardial remodeling and contractile dysfunction that leads to heart failure. However, the intracellular mechanisms by which ACE inhibition preserves myocardial contractility are largely unclear. Using a model of heart failure induced by hypertension in Dahl salt-sensitive (DS) rats, the mechanisms by which ACE inhibitors (ACEI) exert a beneficial effect on myocardial contractility were studied. Dahl salt-resistant (DR) rats, DS rats not given temocapril (DS/T-), and DS rats treated with temocapril (10 mg/kg per day from 10 to 17 weeks of age, DS/T+) were fed an 8% NaCl diet from 8 to 17 weeks of age (n=8, each group). Echocardiography, hemodynamic measurement, histology, contraction of isolated skinned papillary muscle, and Western blot analysis were carried out. At an elevated final blood pressure similar to that of the DS/T- rats, DS/T+ rats exhibited (1) a decrease in left ventricular (LV) mass associated with decreases in both cardiomyocyte size and interstitial fibrosis; (2) improvement of both systolic and diastolic LV function; and (3) an increase in caffeine contraction after constant Ca(2+)-loading with 8-bromo-cAMP into the sarcoplasmic reticulum (SR) associated with an increase in Ser16-phosphorylated phospholamban, as compared with the DS/T- rats. In addition to inhibition of myocardial remodeling, a restoration of the Ca(2+)-handling ability of the SR by normalized phosphorylated phospholamban may contribute to the improved LV contractile function achieved by chronic treatment with an ACEI.
AuthorsShinji Satoh, Yasuko Ueda, Nobuhiro Suematsu, Jun-Ichi Oyama, Toshiaki Kadokami, Masahiro Sugano, Yasuji Yoshikawa, Naoki Makino
JournalCirculation journal : official journal of the Japanese Circulation Society (Circ J) Vol. 67 Issue 8 Pg. 705-11 (Aug 2003) ISSN: 1346-9843 [Print] Japan
PMID12890915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Angiotensin-Converting Enzyme Inhibitors
  • Calcium-Binding Proteins
  • Thiazepines
  • phospholamban
  • temocapril hydrochloride
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium-Transporting ATPases
Topics
  • Angiotensin-Converting Enzyme Inhibitors (pharmacology)
  • Animals
  • Calcium-Binding Proteins (metabolism)
  • Calcium-Transporting ATPases (metabolism)
  • Cardiac Output, Low (diagnostic imaging, etiology, pathology, physiopathology)
  • Echocardiography
  • Hemodynamics
  • Hypertension (complications)
  • Myocardial Contraction (drug effects)
  • Myocardium (pathology)
  • Phosphorylation
  • Rats
  • Rats, Inbred Dahl
  • Sarcoplasmic Reticulum (drug effects)
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Thiazepines (pharmacology)

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