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Vol. 294, Issue 1, 263-269, July 2000
Division of Clinical Pharmacology (L.J.M., J.A.O., J.D.M., N.J.B)
and Mass Spectrometry Research Center (D.L.H.), Departments of Medicine
(L.J.M., J.A.O., J.D.M., N.J.B) and Pharmacology (L.J.M., D.L.H.,
J.A.O., J.D.M., N.J.B.), Vanderbilt University Medical Center,
Nashville, Tennessee
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.
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