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Research ArticleTOXICOLOGY

Efficacy of Novel Calpain Inhibitors in Preventing Renal Cell Death

Jay F. Harriman, Shayla Waters-Williams, Der-Lun Chu, James C. Powers and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics September 2000, 294 (3) 1083-1087;
Jay F. Harriman
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Shayla Waters-Williams
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Der-Lun Chu
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James C. Powers
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Rick G. Schnellmann
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Abstract

Inhibitors of calpains, calcium-activated neutral proteases, protect against cell death produced by anoxia and a variety of toxicants both in vitro and in vivo. The problems with known calpain inhibitors are a lack of specificity, low membrane permeability, and/or low potency. The goal of this study was to determine the effects of seven novel dipeptide and tripeptide calpain inhibitors on calpain activity and antimycin A-induced cell death in rabbit renal proximal tubule (RPT) suspensions. We chose the compounds based on their inhibitory constants for μ- versus m-calpain, specificity of the inhibitors for calpain, and membrane permeability. Only three of the compounds inhibited calpain in RPT and were cytoprotective (Z-Leu-Phe-COOH, Z-Leu-Abu-CONH-CH2-CH(OH)-Ph, and Z-Leu-Phe-CONH-Et). Interestingly, Z-Leu-Phe-COOEt, Z-Leu-Abu-CONH-CH2-CH(OH)-C6F5, and Z-Leu-Abu-CONH-CH2-2-quinolinyl were greater than 60% cytoprotective but did not inhibit calpain in RPT. Z-Leu-Abu-CONH(CH2)3-morpholine was neither cytoprotective nor inhibited calpain. Although these results suggest that six of the seven peptide calpain inhibitors are cell permeable, only three of them inhibited calpain activity in RPT and were cytoprotective. Their ability to inhibit calpain or produce cytoprotection did not correlate with their ability to selectively inhibit purified μ- or m-calpain. Thus it remains to be determined whether they inhibit μ-calpain, m-calpain, or both in RPT. These results also suggest that inhibition of other protease(s) in addition to calpains may be responsible for the cytoprotective actions of some compounds.

Footnotes

  • Send reprint requests to: Rick G. Schnellmann, Ph.D., Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Slot 638, Little Rock, AR 72205-7199. E-mail: Rschnell{at}biomed.uams.edu

  • ↵1 This publication was made possible by Grant ES-09129 from the National Institute of Environmental Health Sciences, National Institutes of Health. J.F.H. was supported by an American Heart Association Heartland Affiliate Predoctoral Fellowship and University of Arkansas for Medical Sciences Graduate Student Research Funds.

  • ↵2 Current address: Center for Toxicology and Environmental Health, 4301 W. Markham St., Slot 767, Little Rock, AR 72205-7199.

  • Portions of this work were presented at the 36th Annual Meeting of the Society of Toxicology in Cincinnati, OH on March 9–13, 1997.

  • Abbreviations:
    RPT
    renal proximal tubule(s)
    LDH
    lactate dehydrogenase
    AMC
    7-amido-4-methyl coumarin
    SLLVY-AMC
    N-succinyl-Leu-Leu-Val-Tyr-AMC
    calpain inhibitor 1
    N-acetyl-Leu-Leu-norleucinal
    calpain inhibitor 2
    N-acetyl-Leu-Leu-methioninal
    DCI
    dichloroisocoumarin
    TLCK
    N-p-tosyl-l-lysine chloromethyl ketone
    MG132
    carbobenzoxy-l-leucyl-l-leucyl-l-leucinal
    β-LAC
    clasto-lactacystin β-lactone
    caspase 1 inhibitor V
    Z-VAD-FMK, Z-Val-Ala-Asp(OMe)-CH2F
    • Received February 16, 2000.
    • Accepted May 24, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 3
1 Sep 2000
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Research ArticleTOXICOLOGY

Efficacy of Novel Calpain Inhibitors in Preventing Renal Cell Death

Jay F. Harriman, Shayla Waters-Williams, Der-Lun Chu, James C. Powers and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 1083-1087;

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Research ArticleTOXICOLOGY

Efficacy of Novel Calpain Inhibitors in Preventing Renal Cell Death

Jay F. Harriman, Shayla Waters-Williams, Der-Lun Chu, James C. Powers and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 1083-1087;
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