A cardioprotective agent of a novel calpain inhibitor, SNJ-1945, exerts beta1 actions on left ventricular mechanical work and energetics.
We have previously shown that a newly developed calpain inhibitor, SNJ-1945 (SNJ), with good aqueous solubility prevents the heart from KCl arrest-reperfusion injury associated with the impairment of total Ca(2+) handling by inhibiting the proteolysis of alpha-fodrin as a cardioplegia. The aim of the present study was to investigate certain actions of this calpain inhibitor, SNJ, on left ventricular (LV) mechanical work and energetics in cross-circulated excised rat hearts undergoing blood perfusion with 40 microM SNJ. Mean end-systolic pressure at midrange LV volume and systolic pressure-volume area (PVA) at mLVV (a total mechanical energy/beat) were significantly increased by SNJ perfusion (P < 0.01). Mean myocardial oxygen consumption per beat (Vo(2)) intercepts (Vo(2) for the total Ca(2+) handling in excitation-contraction coupling and basal metabolism) of Vo(2)-PVA linear relations were significantly increased (P < 0.01) with unchanged mean slopes of Vo(2)-PVA linear relations. Pretreatment with the selective beta(1)-blocker landiolol (10 microM) blocked these effects of SNJ perfusion. There were no significant differences in mean basal metabolic oxygen consumption among normal, 40 microM SNJ, and 10 microM landiolol + 40 microM SNJ groups. Our results indicate that water-soluble SNJ exerted positive actions on mechanical work and energetics mediated via beta(1)-adrenergic receptors associated with the enhancement of total Ca(2+) handling in excitation-contraction coupling and with unchanged contractile efficiency. In clinical settings, this pharmacological action of SNJ is beneficial as an additive agent for cardioplegia.
Dept. of Physiology II, Nara Medical Univ. School of Medicine, 840 Shijo-cho, Kashihara, Nara 634.8521, Japan.
Yoshiro
Y
Yoshikawa
Guo-Xing
GX
Zhang
Koji
K
Obata
Hiroko
H
Matsuyoshi
Keiji
K
Asada
Shigeki
S
Taniguchi
Miyako
M
Takaki
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D056966:Excitation Contraction Coupling / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*; D017725:Ventricular Pressure / Q000187:drug effects
C515164:((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester; C547789:Adrb1 protein, rat; D000319:Adrenergic beta-Antagonists; D002219:Carbamates; D002316:Cardiotonic Agents; D015853:Cysteine Proteinase Inhibitors; D018342:Receptors, Adrenergic, beta-1; D002154:Calpain