title: Calpain inhibitor-1 protects the rat heart from ischemia-reperfusion injury: analysis by mechanical work and energetics.
abstract: We hypothesized that calpain inhibitor-1 protected left ventricular (LV) function from ischemia-reperfusion injury by inhibiting the proteolysis of alpha-fodrin. To test this hypothesis, we investigated the effect of calpain inhibitor-1 on LV mechanical work and energetics in the cross-circulated rat hearts that underwent 15-min global ischemia and 60-min reperfusion (n = 9). After ischemia-reperfusion with calpain inhibitor-1, mean end-systolic pressure at midrange LV volume and systolic pressure-volume area (PVA) at midrange LV volume (total mechanical energy per beat) were hardly changed, although they were significantly (P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. Mean myocardial oxygen consumption per beat (Vo(2)) intercepts (PVA-independent Vo(2); Vo(2) for the total Ca(2+) handling in excitation-contraction coupling and basal metabolism) of Vo(2)-PVA linear relations were also unchanged after ischemia-reperfusion with calpain inhibitor-1, although they were significantly (P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. There were no significant differences in O(2) costs of LV PVA and contractility among the hearts in control (or normal) postischemia-reperfusion and postischemia-reperfusion with calpain inhibitor-1. Western blot analysis of alpha-fodrin and the immunostaining of 150-kDa products of alpha-fodrin confirmed that calpain inhibitor-1 almost completely protected the proteolysis of alpha-fodrin. Our results indicate that calpain inhibitor-1 prevents the heart from ischemia-reperfusion injury associated with the impairment of total Ca(2+) handling by directly inhibiting the proteolysis of alpha-fodrin.
authors.affiliation: Dept. of Physiology II, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Hiroji
authors.initials: H
authors.lastname: Hagihara
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Ohga
authors.forename: Chikako
authors.initials: C
authors.lastname: Nakajima-Takenaka
authors.forename: Ken-ya
authors.initials: KY
authors.lastname: Murata
authors.forename: Shigeki
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Miyako
authors.initials: M
authors.lastname: Takaki
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006023:Glycoproteins / Q000494:pharmacology*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D013049:Spectrin
chemical_list: D002118:Calcium; D000252:Calcium-Transporting ATPases; D002316:Cardiotonic Agents; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; D019344:Lactic Acid; D008840:Microfilament Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019831:Sodium-Calcium Exchanger; D000254:Sodium-Potassium-Exchanging ATPase; D013049:Spectrin; C039304:calpain inhibitors