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Research ArticleCARDIOVASCULAR

A Metabolic Fragment of Bradykinin, Arg-Pro-Pro-Gly-Phe, Protects against the Deleterious Effects of Lipopolysaccharide in Rats

Thomas A. Morinelli, Jerry G. Webb, Ayad A. Jaffa, Philip J. Privitera and Harry S. Margolius
Journal of Pharmacology and Experimental Therapeutics January 2001, 296 (1) 71-76;
Thomas A. Morinelli
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Jerry G. Webb
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Ayad A. Jaffa
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Philip J. Privitera
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Harry S. Margolius
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Abstract

Extensive research has provided few therapeutic agents for the treatment of septicemia. Bradykinin, an endogenous vasodepressor hormone, is a key mediator in the hypotension seen with septicemia. The present investigation shows that a stable metabolic fragment of bradykinin, arginine-proline-proline-glycine-phenylalanine (RPPGF), prevents the deleterious effects of endotoxin [lipopolysaccharide (LPS); a component of the membrane of Gram negative bacteria], the signaling agent responsible for the effects of septicemia, in both anesthetized rats and in isolated rat aortic segments. Survival time of rats treated with LPS (12 mg/kg) was significantly (p < 0.05) prolonged by pretreatment with RPPGF [140.3 ± 16 min (n = 10)] compared with rats receiving saline and LPS [93.2 ± 8 min (n = 39)]. Prolongation of survival was not seen when rats were pretreated with either bradykinin or with PRGFP (proline-arginine-glycine-phenylalanine-proline). Isolated aortic segments treated with LPS (30 μg/ml) showed a significantly reduced ability to contract in response to phenylephrine compared with control segments not receiving LPS. Pretreatment of the segments with RPPGF significantly reversed the LPS-induced reduction in contractile response of the segments. Removal of the endothelial layer did not alter the protection provided by RPPGF. These results demonstrate the ability of a stable metabolic fragment of bradykinin, RPPGF, to protect against the deleterious effects produced by LPS. The findings presented here may provide the basis for a new developmental area for novel therapeutic agents in the treatment of septicemia.

Footnotes

  • Send reprint requests to: Thomas A. Morinelli, Ph.D., Department of Cell and Molecular Pharmacology and Experimental Therapeutics, 175 Ashley Ave., P.O. Box 250505, Charleston, SC 29425. E-mail: morinelt{at}musc.edu

  • This work was provided in part by a grant from the Medical University of South Carolina's Foundation for Research Development.

  • Abbreviations:
    LPS
    lipopolysaccharide
    BK
    bradykinin
    LBK
    kallidin
    RPPGF (BK1-5)
    arginine-proline-proline-glycine-phenylalanine
    nNOS
    neuronal nitric-oxide synthase
    PE
    phenylephrine
    MABP
    mean arterial blood pressure
    PRGFP
    Pro-Arg-Gly-Phe-Pro
    • Received July 24, 2000.
    • Accepted September 29, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 296 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 296, Issue 1
1 Jan 2001
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Research ArticleCARDIOVASCULAR

A Metabolic Fragment of Bradykinin, Arg-Pro-Pro-Gly-Phe, Protects against the Deleterious Effects of Lipopolysaccharide in Rats

Thomas A. Morinelli, Jerry G. Webb, Ayad A. Jaffa, Philip J. Privitera and Harry S. Margolius
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 71-76;

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Research ArticleCARDIOVASCULAR

A Metabolic Fragment of Bradykinin, Arg-Pro-Pro-Gly-Phe, Protects against the Deleterious Effects of Lipopolysaccharide in Rats

Thomas A. Morinelli, Jerry G. Webb, Ayad A. Jaffa, Philip J. Privitera and Harry S. Margolius
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 71-76;
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