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Related Experiment Videos

Characterization of guanoxabenz reducing activity in rat brain

M Dambrova1, S Uhlén, J E Wikberg

  • 1Department of Pharmaceutical Biosciences, Uppsala University, Sweden.

Pharmacology & Toxicology
|November 20, 1998
PubMed
Summary

Rat spleen and brain enzymes activate guanoxabenz, forming high-affinity alpha 2-adrenoceptor ligands. Brain activation differs from spleen, suggesting distinct enzymatic pathways for this antihypertensive drug metabolite.

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Area of Science:

  • Pharmacology
  • Neuroscience
  • Biochemistry

Background:

  • Guanoxabenz and guanabenz are centrally acting antihypertensive drugs.
  • Rat spleen enzymes, identified as xanthine oxidase, N-reduce guanoxabenz to the active guanabenz, enhancing alpha 2-adrenoceptor binding.
  • The spleen enzyme activity is activated by xanthine and inhibited by allopurinol.

Purpose of the Study:

  • To investigate the enzymatic activation of guanoxabenz in rat brain membranes.
  • To characterize the mechanism and identify enzymes involved in guanoxabenz activation in the brain.
  • To compare the brain activation pathway with the previously identified spleen pathway.

Main Methods:

  • Incubation of rat brain membranes with guanoxabenz and NADH/NADPH cofactors.

Related Experiment Videos

  • Assessment of high-affinity guanoxabenz binding to alpha 2-adrenoceptors.
  • Testing the effects of inhibitors (allopurinol, carbon monoxide, SKF525A, menadione, dicumarol) and activators (xanthine) on enzymatic activity.

    • Main Results:

    • High-affinity guanoxabenz binding was induced in rat brain membranes with NADH/NADPH.
    • The brain activation mechanism was not inhibited by allopurinol, carbon monoxide, or SKF525A, ruling out xanthine oxidase and cytochrome P450.
    • Menadione and dicumarol blocked the brain enzymatic activity, indicating a distinct pathway from the spleen.

    Conclusions:

    • Rat cerebral cortex possesses an enzymatic activity that activates guanoxabenz into a metabolite with high affinity for alpha 2-adrenoceptors.
    • This brain enzymatic activity is distinct from the xanthine oxidase-mediated pathway found in the rat spleen.
    • The findings suggest tissue-specific mechanisms for guanoxabenz activation and potential implications for its antihypertensive effects.