snj-1945 and Ventricular-Dysfunction--Left

We have previously indicated that a new soluble calpain inhibitor, SNJ-1945 (SNJ), attenuates cardiac dysfunction after cardioplegia arrest-reperfusion by inhibiting the proteolysis of α-fodrin in in vitro study. Nevertheless, the in vivo study design is indispensable to explore realistic therapeutic approaches for clinical use. The aim of the present in situ study was to investigate whether SNJ attenuated left ventricular (LV) dysfunction (stunning) after mild ischemic-reperfusion (mI-R) in rat hearts. SNJ (60 μmol/l, 5 ml i.p.) was injected 30 min before gradual and partial coronary occlusion at proximal left anterior descending artery. To investigate LV function, we obtained curvilinear end-systolic pressure-volume relationship by increasing afterload 60 min after reperfusion. In the mI-R group, specific LV functional indices at midrange LV volume (mLVV), end-systolic pressure (ESP(mLVV)), and pressure-volume area (PVA(mLVV): a total mechanical energy per beat, linearly related to oxygen consumption) significantly decreased, but SNJ reversed these decreases to time control level. Furthermore, SNJ prevented the α-fodrin degradation and attenuated degradation of Ca(2+) handling proteins after mI-R. Our results indicate that improvements in LV function following mI-R injury are associated with inhibition of the proteolysis of α-fodrin in in situ rat hearts. In conclusion, SNJ should be a promising tool to protect the heart from the stunning.

Topics: Animals; Biomechanical Phenomena; Blotting, Western; Calcium; Calpain; Carbamates; Cardiotonic Agents; Carrier Proteins; Cysteine Proteinase Inhibitors; Disease Models, Animal; Male; Microfilament Proteins; Myocardial Reperfusion Injury; Myocardium; Oxygen Consumption; Rats; Rats, Wistar; Stroke Volume; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Pressure

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.

Topics: Animals; Calcium; Calcium Channels, L-Type; Calpain; Carbamates; Cardiotonic Agents; Carrier Proteins; Disease Models, Animal; Heart Arrest, Induced; Male; Microfilament Proteins; Myocardial Reperfusion Injury; Oxygen Consumption; Rats; Rats, Wistar; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Ventricular Dysfunction, Left