Document Detail


A cardioprotective agent of a novel calpain inhibitor, SNJ-1945, exerts beta1 actions on left ventricular mechanical work and energetics.
MedLine Citation:
PMID:  20511411     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yoshiro Yoshikawa; Guo-Xing Zhang; Koji Obata; Hiroko Matsuyoshi; Keiji Asada; Shigeki Taniguchi; Miyako Takaki
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-28
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  299     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-30     Completed Date:  2010-08-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H396-401     Citation Subset:  IM    
Affiliation:
Dept. of Physiology II, Nara Medical Univ. School of Medicine, 840 Shijo-cho, Kashihara, Nara 634.8521, Japan.
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MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-Antagonists / pharmacology
Animals
Calpain / antagonists & inhibitors*,  metabolism
Carbamates / pharmacology*
Cardiotonic Agents / pharmacology*
Cysteine Proteinase Inhibitors / pharmacology*
Energy Metabolism / drug effects*
Excitation Contraction Coupling / drug effects
Heart Ventricles / drug effects*,  enzymology
Male
Oxygen Consumption / drug effects
Perfusion
Rats
Rats, Wistar
Receptors, Adrenergic, beta-1 / drug effects,  metabolism
Stroke Volume / drug effects
Time Factors
Ventricular Function, Left / drug effects*
Ventricular Pressure / drug effects
Chemical
Reg. No./Substance:
0/((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester; 0/Adrb1 protein, rat; 0/Adrenergic beta-Antagonists; 0/Carbamates; 0/Cardiotonic Agents; 0/Cysteine Proteinase Inhibitors; 0/Receptors, Adrenergic, beta-1; EC 3.4.22.-/Calpain

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