title: A new calpain inhibitor protects left ventricular dysfunction induced by mild ischemia-reperfusion in in situ rat hearts.
abstract: 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.
authors.affiliation: Department of Physiology II, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Takeshita
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: S
authors.initials: S
authors.lastname: Mitsuyama
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: G-X
authors.initials: GX
authors.lastname: Zhang
authors.forename: K
authors.initials: K
authors.lastname: Obata
authors.forename: H
authors.initials: H
authors.lastname: Ito
authors.forename: S
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Miyako
authors.initials: M
authors.lastname: Takaki
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects; D013049:Spectrin
chemical_list: D002118:Calcium; D002154:Calpain; D002219:Carbamates; D002316:Cardiotonic Agents; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D008840:Microfilament Proteins; 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