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, Matthias Schramm

Research output: Contribution to journalArticlepeer-review

439 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)212-215
Number of pages4
JournalNature
Volume410
Issue number6825
DOIs
StatePublished - Mar 8 2001

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