NO-independent regulatory site on soluble guanylate cyclase

Johannes-Peter Stasch (), Eva Maria Becker, Cristina Alonso-Alija, Heiner Apeler, Klaus Dembowsky, Achim Feurer, Rupert Gerzer, Torsten Minuth, Elisabeth Perzborn, Ulrich Pleiß, Henning Schröder, Werner Schroeder, Elke Stahl, Wolfram Steinke, Alexander Straub and Matthias Schramm
Additional contact information
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

Nature, 2001, vol. 410, issue 6825, 212-215

Abstract: 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.

Date: 2001
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DOI: 10.1038/35065611

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