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Research ArticleCARDIOVASCULAR

Metabolism of Bradykinin In Vivo in Humans: Identification of BK1-5 as a Stable Plasma Peptide Metabolite

Laine J. Murphey, David L. Hachey, John A. Oates, Jason D. Morrow and Nancy J. Brown
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 263-269;
Laine J. Murphey
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David L. Hachey
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John A. Oates
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Jason D. Morrow
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Nancy J. Brown
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Abstract

Studies investigating the role of bradykinin in disease states such as hypertension, sepsis, and asthma have been confounded by difficulties in measuring the concentration of this short-lived peptide. The purpose of this study was to determine a stable metabolite of bradykinin in the systemic circulation of humans. Bradykinin (containing trace concentrations of [3H]bradykinin) was administered i.v. into three human volunteers in increasing amounts up to a maintenance rate of 200 ng/kg/min until a total dose of 1 mg was given. Metabolic products were purified and identified by HPLC and by electrospray ionization mass spectrometry. Infused bradykinin was rapidly degraded, such that no exogenous bradykinin was detected in venous plasma sampled during infusion. BK1-5 (Arg-Pro-Pro-Gly-Phe), the 1-to-5 amino acid fragment of bradykinin, was identified as a major stable plasma metabolite of bradykinin. Plasma concentrations of BK1-5 correlated with dose of bradykinin infused and concentrations at the end of bradykinin infusion were 1510 to 4600 fmol/ml of blood. BK1-5 was cleared from blood with a terminal half-life of 86 to 101 min. Thus, in humans, bradykinin is rapidly degraded in vivo to BK1-5, a stable metabolite. Measurement of this metabolite could provide a tool to assess pathophysiologic and pharmacologic alterations in systemic bradykinin generation associated with human disease.

Footnotes

  • Send reprint requests to: Nancy J. Brown, M.D., Division of Clinical Pharmacology, Vanderbilt University Medical Center, 560 MRB-1, Nashville, TN 37232-6602. E-mail:nancy.brown{at}mcmail.vanderbilt.edu

  • ↵1 This study was supported by National Institutes of Health Grants HL56963, GM07569, DK48831, GM42056, GM15431, DK26657, CA68485, CA77839, and RR00095. J.D.M. is the recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.

  • Abbreviations:
    ACE
    angiotensin-converting enzyme
    LC
    liquid chromatography
    MS
    mass spectrometry
    ESI
    electrospray ionization
    BK1-5
    Arg-Pro-Pro-Gly-Phe
    TFA
    trifluoroacetic acid
    CID
    collision-induced dissociation
    • Received February 3, 2000.
    • Accepted March 21, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Research ArticleCARDIOVASCULAR

Metabolism of Bradykinin In Vivo in Humans: Identification of BK1-5 as a Stable Plasma Peptide Metabolite

Laine J. Murphey, David L. Hachey, John A. Oates, Jason D. Morrow and Nancy J. Brown
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 263-269;

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Research ArticleCARDIOVASCULAR

Metabolism of Bradykinin In Vivo in Humans: Identification of BK1-5 as a Stable Plasma Peptide Metabolite

Laine J. Murphey, David L. Hachey, John A. Oates, Jason D. Morrow and Nancy J. Brown
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 263-269;
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