Possible involvement of calpain activation in pathogenesis of chronic heart failure after acute myocardial infarction.
Changes in proteolytic activity of the myocardium during the development of heart failure after left coronary artery ligation (CAL) of rats were examined. Hemodynamics of the rats at the eighth week (8w-CAL rat), but not at the second week (2w-CAL rat), after CAL showed the symptoms of chronic heart failure. Contents of mu-calpin and m-calpain, but not an intrinsic calpain inhibitor calpastatin, in the viable left ventricular muscle (viable LV) and the right ventricular muscle (RV) of the 2w-CAL and 8w-CAL rats were increased, which was associated with an elevation of intrinsic activities of leupeptin-sensitive, Ca(2+)-activated proteolysis in the cytosolic fractions of the viable LV and RV. Oral administration of 3 mg/kg/d trandolapril or 1 mg/kg/d candesartan from the second to eighth week after CAL improved the hemodynamics of 8w-CAL rats. The drug treatment attenuated the increases in mu-calpain and m-calpain contents and the elevation of the proteolytic activity of the viable LV and RV in the 8w-CAL rat. The drug treatment increased calpastatin content of the RV in the 8w-CAL rat. These results suggest that sustained activation of calpain is involved in the development of chronic heart failure and that trandolapril and candesartan prevent the activation of calpains after CAL.
Takahashi
Masaya
M
Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.
Tanonaka
Kouichi
K
Yoshida
Hiroyuki
H
Koshimizu
Miki
M
Daicho
Takuya
T
Oikawa
Ryo
R
Takeo
Satoshi
S
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure; D002135:Calcium-Binding Proteins / Q000032:analysis; D002154:Calpain / Q000032:analysis / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology*; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D051381:Rats; D017208:Rats, Wistar
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D002135:Calcium-Binding Proteins; C033668:calpastatin; D002154:Calpain