Cardioprotective effects of a novel calpain inhibitor SNJ-1945 for reperfusion injury after cardioplegic cardiac arrest

Departments of 1 Physiology II and 2 Thoracic-Cardiovascular Surgery, Nara Medical University School of Medicine, Kashihara, Nara, Japan Submitted September 8, 2009 ; accepted in final form November 25, 2009 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 -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 µM) 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 -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 -fodrin. cardiac function; systolic pressure-volume area; oxygen consumption; -fodrin Address for reprint requests and other correspondence: M. Takaki, Dept. of Physiology II, Nara Medical Univ. School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan (e-mail: mtakaki{at}naramed-u.ac.jp ).