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OtherCARDIOVASCULAR PHARMACOLOGY

Evidence against a Cytochrome P450-Derived Reactive Oxygen Species as the Mediator of the Nitric Oxide-Independent Vasodilator Effect of Bradykinin in the Perfused Heart of the Rat

D. Fulton, J. C. McGiff, M. S. Wolin, P. Kaminski and J. Quilley
Journal of Pharmacology and Experimental Therapeutics February 1997, 280 (2) 702-709;
D. Fulton
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J. C. McGiff
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M. S. Wolin
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P. Kaminski
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J. Quilley
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Abstract

The coronary vasodilator effect of bradykinin (BK) in the rat is independent of NO but dependent on activation of phospholipases with involvement of cytochrome P450 mono-oxygenase (P450) and stimulation of Ca++-activated K+ channels, implicating an unidentified hyperpolarizing factor generated via P450 metabolism of arachidonic acid (AA). Because P450 activity also generates free radicals, such as superoxide, which can lead to the formation of hydrogen peroxide and hydroxyl radicals, which are vasoactive, we addressed the contribution of superoxide to the vasodilator effect of BK in the rat heart. Using rat renal microsomes as a source of P450, we verified that P450-dependent metabolism of AA generated superoxide, as detected by chemiluminescence with lucigenin. The signal was almost abolished by inhibition of P450 with clotrimazole and the superoxide scavenger 4,5-dihydroxy-1,3-benzene sulfonic acid. However, base-line superoxide formation, detected by chemiluminescence, in cardiac slices and perfused hearts was unchanged in response to BK or AA. Furthermore, in perfused hearts treated with nitroarginine and indomethacin to eliminate NO and prostaglandins and elevate perfusion pressure, dose-dependent vasodilator responses to BK were unaffected by superoxide dismutase plus catalase, a combination that abolished dilator responses to hydrogen peroxide. Similarly, the superoxide scavengers 4,5-dihydroxy-1,3-benzene sulfonic acid and 4-hydroxy-2,2,6,6-tetramethylpiperidine-noxyl were without effect on vasodilator responses to BK. Thus, the coronary vasodilator action of BK is independent of superoxide or its derivatives, which can be excluded as hyperpolarizing factors mediating NO-independent vasodilation in the rat.

Footnotes

  • Send reprint requests to: Dr. J. Quilley, Department of Pharmacology, New York Medical College, Valhalla, NY 10595.

  • ↵1 This work was supported by National Institutes of Health grants RO1–25394, RO1–49275 and PO1–43023 and AHA grant 940–318.

  • Abbreviations:
    BK
    bradykinin
    P450
    cytochrome P450
    AA
    arachidonic acid
    SOD
    superoxide dismutase
    TEMPO
    4-hydroxy-2,2,6,6-tetramethylpiperidine-noxyl
    NO
    nitric oxide
    EET
    epoxyeicosatrienoic acid
    Tiron
    4,5-dihydroxy-1,3-benzene sulfonic acid
    HEPES
    4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
    • Received August 8, 1996.
    • Accepted October 28, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 2
1 Feb 1997
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OtherCARDIOVASCULAR PHARMACOLOGY

Evidence against a Cytochrome P450-Derived Reactive Oxygen Species as the Mediator of the Nitric Oxide-Independent Vasodilator Effect of Bradykinin in the Perfused Heart of the Rat

D. Fulton, J. C. McGiff, M. S. Wolin, P. Kaminski and J. Quilley
Journal of Pharmacology and Experimental Therapeutics February 1, 1997, 280 (2) 702-709;

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OtherCARDIOVASCULAR PHARMACOLOGY

Evidence against a Cytochrome P450-Derived Reactive Oxygen Species as the Mediator of the Nitric Oxide-Independent Vasodilator Effect of Bradykinin in the Perfused Heart of the Rat

D. Fulton, J. C. McGiff, M. S. Wolin, P. Kaminski and J. Quilley
Journal of Pharmacology and Experimental Therapeutics February 1, 1997, 280 (2) 702-709;
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