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Research ArticleArticle

Noncompetitive Inhibition of Glycylsarcosine Transport by Quinapril in Rabbit Renal Brush Border Membrane Vesicles: Effect on High-Affinity Peptide Transporter

Wiyada Akarawut, Chun-Jung Lin and David E. Smith
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 684-690;
Wiyada Akarawut
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Chun-Jung Lin
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David E. Smith
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Abstract

Angiotensin converting enzyme (ACE) inhibitors are important therapeutic agents for treating patients with hypertension and cardiovascular diseases. Although most ACE inhibitors are cleared by the kidney via glomerular filtration and tubular secretion, little is known about their reabsorption potential. In particular, it is believed that while certain ACE inhibitors are transported by the intestinal peptide transporter (PepT1), these same compounds do not interact with the renal peptide transporter (PepT2). In the present study, we examined the interaction of quinapril with the high-affinity peptide transporter, PepT2. Studies were performed in rabbit renal brush border membrane vesicles in which the uptake of [14C]glycylsarcosine (GlySar), at low substrate concentrations, was examined in the absence and presence of quinapril (and other ACE inhibitors). We found that quinapril was capable ofcis-inhibiting the uptake of GlySar and in a concentration-dependent manner. While theKi for quinapril (≈1 mM) was several-fold higher than the Km for GlySar (≈ 160 μM), the interaction was unique in that inhibition of PepT2 was of a noncompetitive type. Overall, the data suggest that quinapril is a low-affinity inhibitor of the renal peptide transporter and that it binds to a site distinct from that of the GlySar binding site.

Footnotes

  • Send reprint requests to: David E. Smith, Ph.D., Upjohn Center for Clinical Pharmacology, 1310 E. Catherine Street, The University of Michigan, Ann Arbor, MI 48109-0504. E-mail:smithb{at}umich.edu

  • ↵1 This work was supported in part by the Upjohn Research Award Fund, College of Pharmacy, The University of Michigan and by Grant R01 GM35498 from the National Institutes of Health.

  • Abbreviations:
    ACE
    angiotensin converting enzyme
    BBMV
    brush border membrane vesicles
    GlySar
    glycylsarcosine
    SITS
    4-acetamido-4′-isothiocyanato-stilbene-2,2′-disulfonic acid
    Tris
    tris(hydroxymethyl)aminomethane
    HEPES
    N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid)
    ALP
    alkaline phosphatase
    Mes
    2-(N-morpholino)ethanesulfonic acid
    • Received February 17, 1998.
    • Accepted June 4, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

Noncompetitive Inhibition of Glycylsarcosine Transport by Quinapril in Rabbit Renal Brush Border Membrane Vesicles: Effect on High-Affinity Peptide Transporter

Wiyada Akarawut, Chun-Jung Lin and David E. Smith
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 684-690;

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Research ArticleArticle

Noncompetitive Inhibition of Glycylsarcosine Transport by Quinapril in Rabbit Renal Brush Border Membrane Vesicles: Effect on High-Affinity Peptide Transporter

Wiyada Akarawut, Chun-Jung Lin and David E. Smith
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 684-690;
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