title: Influence of long-term treatment of imidapril on mortality, cardiac function, and gene expression in congestive heart failure due to myocardial infarction.
abstract: Although it is generally accepted that the efficacy of imidapril, an angiotensin-converting enzyme inhibitor, in congestive heart failure (CHF) is due to improvement of hemodynamic parameters, the significance of its effect on gene expression for sarcolemma (SL) and sarcoplasmic reticulum (SR) proteins has not been fully understood. In this study, we examined the effects of long-term treatment of imidapril on mortality, cardiac function, and gene expression for SL Na+/K+ ATPase and Na+ -Ca2+ exchanger as well as SR Ca2+ pump ATPase, Ca2+ release channel (ryanodine receptor), phospholamban, and calsequestrin in CHF due to myocardial infarction. Heart failure subsequent to myocardial infarction was induced by occluding the left coronary artery in rats, and treatment with imidapril (1 mg.kg(-1).day(-1)) was started orally at the end of 3 weeks after surgery and continued for 37 weeks. The animals were assessed hemodynamically and the heart and lung were examined morphologically. Some hearts were immediately frozen at -70 degrees C for the isolation of RNA as well as SL and SR membranes. The mortality of imidapril-treated animals due to heart failure was 31% whereas that of the untreated heart failure group was 64%. Imidapril treatment improved cardiac performance, attenuated cardiac remodeling, and reduced morphological changes in the heart and lung. The depressed SL Na+/K+ ATPase and increased SL Na+-Ca2+ exchange activities as well as reduced SR Ca2+ pump and SR Ca2+ release activities in the failing hearts were partially prevented by imidapril. Although changes in gene expression for SL Na+/K+ ATPase isoforms as well as Na+-Ca2+ exchanger and SR phospholamban were attenuated by treatments with imidapril, no alterations in mRNA levels for SR Ca2+ pump proteins and Ca2+ release channels were seen in the untreated or treated rats with heart failure. These results suggest that the beneficial effects of imidapril in CHF may be due to improvements in cardiac performance and changes in SL gene expression.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Department of Physiology, Faculty of Medicine, University of Manitoba, 351 Tache Avenue, Winnipeg, Manitoba R2H 2A6, Canada.
authors.forename: Bin
authors.initials: B
authors.lastname: Ren
authors.forename: Qiming
authors.initials: Q
authors.lastname: Shao
authors.forename: Pallab K
authors.initials: PK
authors.lastname: Ganguly
authors.forename: Paramjit S
authors.initials: PS
authors.lastname: Tappia
authors.forename: Nobuakira
authors.initials: N
authors.lastname: Takeda
authors.forename: Naranjan S
authors.initials: NS
authors.lastname: Dhalla
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002155:Calsequestrin / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D048289:Imidazolidines / Q000494:pharmacology*; D008168:Lung / Q000473:pathology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D012313:RNA / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012508:Sarcolemma / Q000473:pathology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D002155:Calsequestrin; D048289:Imidazolidines; D012313:RNA; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban; C065166:imidapril