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NO-independent regulatory site on soluble guanylate cyclase

Author

Listed:
  • Johannes-Peter Stasch

    (Pharma Research Center, Bayer AG)

  • Eva Maria Becker

    (Pharma Research Center, Bayer AG)

  • Cristina Alonso-Alija

    (Pharma Research Center, Bayer AG)

  • Heiner Apeler

    (Pharma Research Center, Bayer AG)

  • Klaus Dembowsky

    (Pharma Research Center, Bayer AG)

  • Achim Feurer

    (Pharma Research Center, Bayer AG)

  • Rupert Gerzer

    (DLR, Institute of Aerospace Medicine)

  • Torsten Minuth

    (Pharma Research Center, Bayer AG)

  • Elisabeth Perzborn

    (Pharma Research Center, Bayer AG)

  • Ulrich Pleiß

    (Pharma Research Center, Bayer AG)

  • Henning Schröder

    (Martin Luther University, School of Pharmacy)

  • Werner Schroeder

    (Pharma Research Center, Bayer AG)

  • Elke Stahl

    (Pharma Research Center, Bayer AG)

  • Wolfram Steinke

    (Pharma Research Center, Bayer AG)

  • Alexander Straub

    (Pharma Research Center, Bayer AG)

  • Matthias Schramm

    (Pharma Research Center, Bayer AG)

Abstract

Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles1. Research in the field of NO appears to have followed a straightforward path, and the findings have been progressive: NO and cyclic GMP are involved in vasodilatation; glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO; mammalian cells synthesize NO; and last, NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC), a heterodimeric (α/β) haem protein that converts GTP to cGMP2–4. Here we report the discovery of a regulatory site on sGC. Using photoaffinity labelling, we have identified the cysteine 238 and cysteine 243 region in the α1-subunit of sGC as the target for a new type of sGC stimulator. Moreover, we present a pyrazolopyridine, BAY 41-2272, that potently stimulates sGC through this site by a mechanism that is independent of NO. This results in antiplatelet activity, a strong decrease in blood pressure and an increase in survival in a low-NO rat model of hypertension, and as such may offer an approach for treating cardiovascular diseases.

Suggested Citation

  • Johannes-Peter Stasch & Eva Maria Becker & Cristina Alonso-Alija & Heiner Apeler & Klaus Dembowsky & Achim Feurer & Rupert Gerzer & Torsten Minuth & Elisabeth Perzborn & Ulrich Pleiß & Henning Schröde, 2001. "NO-independent regulatory site on soluble guanylate cyclase," Nature, Nature, vol. 410(6825), pages 212-215, March.
    • Handle: RePEc:nat:nature:v:410:y:2001:i:6825:d:10.1038_35065611
    DOI: 10.1038/35065611
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