Cardioprotective effects of a novel calpain inhibitor SNJ-1945 for reperfusion injury after cardioplegic cardiac arrest.
We have previously indicated that calpain inhibitor-1 prevents the heart from ischemia- reperfusion injury associated with the impairment of total Ca(2+) handling by inhibiting the proteolysis of alpha-fodrin. However, this inhibitor is insoluble with water and inappropriate for clinical application. The aim of the present study was to investigate the protective effect of a newly developed calpain inhibitor, SNJ-1945 (SNJ), with good aqueous solubility on left ventricular (LV) mechanical work and energetics in the cross-circulated rat hearts. SNJ (150 microM) was added to KCl (30 meq) cardioplegia (CP). Mean end-systolic pressure at midrange LV volume (ESP(mLVV)) and systolic pressure-volume area (PVA) at mLVV (PVA(mLVV); a total mechanical energy per beat) were hardly changed after CP plus SNJ arrest-reperfusion (post-CP + SNJ), whereas ESP(mLVV) and PVA(mLVV) in post-CP group were significantly (P < 0.01) decreased. Mean myocardial oxygen consumption for the total Ca(2+) handling in excitation-contraction coupling did not significantly decrease in post-CP + SNJ group, whereas it was significantly (P < 0.01) decreased in post-CP group. The mean amounts of 145- and 150-kDa fragments of alpha-fodrin in the post-CP group were significantly larger than those in normal and post-CP + SNJ groups. In contrast, the mean amounts of L-type Ca(2+) channel and sarcoplasmic reticulum Ca(2+)-ATPase were not significantly different among normal, post-CP, and post-CP + SNJ groups. Our results indicate that soluble SNJ attenuates cardiac dysfunction due to CP arrest-reperfusion injury associated with the impairment of the total Ca(2+) handling in excitation-contraction coupling by inhibiting the proteolysis of alpha-fodrin.
Yoshikawa
Yoshiro
Y
Department of Physiology II, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
Zhang
Guo-Xing
GX
Obata
Koji
K
Ohga
Yoshimi
Y
Matsuyoshi
Hiroko
H
Taniguchi
Shigeki
S
Takaki
Miyako
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors*; D002219:Carbamates / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D006324:Heart Arrest, Induced / Q000009:adverse effects*; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D010101:Oxygen Consumption / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology; D013049:Spectrin
D002118:Calcium; D020746:Calcium Channels, L-Type; D002154:Calpain; D002219:Carbamates; D002316:Cardiotonic Agents; D002352:Carrier Proteins; D008840:Microfilament Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013049:Spectrin; C515164:((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester