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Research ArticleArticle

Tissue Selectivity of Antidiabetic Agent Nateglinide: Study on Cardiovascular and β-Cell KATP Channels

Shiling Hu, Shuya Wang and Beth E. Dunning
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1372-1379;
Shiling Hu
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Shuya Wang
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Beth E. Dunning
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Abstract

Nateglinide (NAT) stimulates insulin secretion from pancreatic β-cells by closing KATP channels. Because KATP channels are widely distributed in cardiovascular (CV) tissues, we assessed the tissue specificity of NAT by examining its effect on KATP channels in enzymatically isolated rat β-cells, rat cardiac myocytes, and smooth muscle cells from porcine coronary artery and rat aorta with the patch-clamp method. The selectivity of known antidiabetic agents glyburide (GLY) and repaglinide (REP) was also studied for comparison. NAT was found to inhibit KATP channels in the cells from porcine coronary artery and rat aorta with IC50s of 2.3 and 0.3 mM, respectively, compared with 7.4 μM in rat β-cells, indicating a respective 311- and 45-fold selectivity (p < .01) for β-cells. With an IC50 of 5.0 nM in β-cells, REP displayed an ∼16-fold (p < .05) selectivity for β-cells over both types of vascular cells. GLY was nonselective between vascular and β-cells. At equipotent concentrations (2× respective IC50s in β-cells), NAT, GLY, and REP all caused 62% reduction of pancreatic KATP current but a respective 39, 55, and 66% inhibition of cardiac KATPcurrent. These data collectively indicate that NAT, when compared with GLY and REP, at concentrations effective in stimulating insulin secretion is least likely to cause detrimental CV effects via blockade of CV KATP channels.

Footnotes

  • Send reprint requests to: Shiling Hu, Metabolic and Cardiovascular Diseases, Novartis Institute for Biomedical Research, 556 Morris Av., Summit, NJ 07901-1027. E-mail:hiling.hu{at}pharma.novartis.com

  • Abbreviations:
    GLY
    glyburide
    NAT
    nateglinide
    REP
    repaglinide
    CV
    cardiovascular
    SU
    sulfonylurea
    SUR
    sulfonylurea receptor
    RA
    rat aorta
    PCA
    porcine coronary artery
    • Received June 16, 1999.
    • Accepted August 23, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Tissue Selectivity of Antidiabetic Agent Nateglinide: Study on Cardiovascular and β-Cell KATP Channels

Shiling Hu, Shuya Wang and Beth E. Dunning
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1372-1379;

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Research ArticleArticle

Tissue Selectivity of Antidiabetic Agent Nateglinide: Study on Cardiovascular and β-Cell KATP Channels

Shiling Hu, Shuya Wang and Beth E. Dunning
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1372-1379;
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