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OtherGASTROINTESTINAL PHARMACOLOGY

The Role of Cyclic Guanylate Monophosphate in Nitric Oxide-Induced Injury to Rat Small Intestinal Epithelial Cells

B. L. Tepperman, T. D. Abrahamson and B. D. Soper
Journal of Pharmacology and Experimental Therapeutics March 1998, 284 (3) 929-933;
B. L. Tepperman
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T. D. Abrahamson
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Abstract

In our study we have examined the importance of cyclic guanylate monophosphate (cGMP) in NO-mediated intestinal cellular damage. Epithelial cells were harvested from a 20-cm segment of rat proximal small intestine by dispersion using citrate and ethylenediaminetetraacetic acid. Cell viability was assessed by trypan blue dye exclusion. Incubation of cells with the nitric oxide donors, S-nitroso-N-acetyl penicillamine (SNAP) or sodium nitroprusside (SNP) (10–1000 μM) produced a concentration-dependent increase in cell injury and an increase in cellular cGMP formation as determined by immunoassay. In addition, cell injury was also increased by treatment of cells with the cell permeable analogue, dibutryryl cGMP (db cGMP; 0.1–2.0 mM). Suppression of cellular cGMP production by incubating cells with the guanylate cyclase inhibitor LY83583 (5–20 μM) attenuated the damaging actions of SNAP or SNP. However, LY83583 treatment did not reduce ethanol-mediated (10% v/v) cell injury. Furthermore the cytotoxic actions of SNAP or SNP were enhanced by preincubation of cells with the selective cGMP phosphodiesterase inhibitor, zaprinast (10 mM). The damaging actions of SNAP, SNP and db cGMP were reduced by treating cells with superoxide dismutase (100 U/ml). Similarly SNAP, SNP and db cGMP treatments resulted in an increase in the in vitro production of reactive oxygen metabolites as assessed by the fluorescent probe 2′7′ dichlorofluoresein diacetate. These findings indicate that cGMP mediates intestinal cell injury in response to high levels of nitric oxide as produced by the nitric oxide donors, SNAP and SNP. Furthermore these data suggest that the cGMP-induced damage to intestinal epithelial cells involves the generation of reactive oxidants.

Footnotes

  • Send reprint requests to: Dr. B. L. Tepperman, Department of Physiology, The University of Western Ontario, London, Ontario Canada N6A 5C1.

  • ↵1 This work was supported by Grant MT 6426 from the Medical Research Council of Canada.

  • Abbreviations:
    NO
    nitric oxide
    cGMP
    cyclic guanylate monophosphate
    db cCMP
    dibutyryl cyclic cytidine monophosphate
    SNAP
    s-nitrosos-N-acetyl penicillamine
    SNP
    sodium nitroprusside
    Zap
    Zaprinast
    SOD
    superoxide dismutase
    PBS
    phosphate buffered saline
    DTT
    dithiothreitol
    EDTA
    ethylenediamine-tetraacetic acid
    • Received July 2, 1997.
    • Accepted November 3, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 284, Issue 3
1 Mar 1998
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OtherGASTROINTESTINAL PHARMACOLOGY

The Role of Cyclic Guanylate Monophosphate in Nitric Oxide-Induced Injury to Rat Small Intestinal Epithelial Cells

B. L. Tepperman, T. D. Abrahamson and B. D. Soper
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 929-933;

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OtherGASTROINTESTINAL PHARMACOLOGY

The Role of Cyclic Guanylate Monophosphate in Nitric Oxide-Induced Injury to Rat Small Intestinal Epithelial Cells

B. L. Tepperman, T. D. Abrahamson and B. D. Soper
Journal of Pharmacology and Experimental Therapeutics March 1, 1998, 284 (3) 929-933;
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