NO-independent regulatory site on soluble guanylate cyclase

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.

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Figure 1: In vitro effects of BAY 41-2272.
Figure 2: The NO-independent regulatory site of sGC.
Figure 3: In vivo effects of BAY 41-2272.

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Acknowledgements

We thank C. Robyr-Fürstner for the synthesis of YC-1; E. Bischoff for performing the PDE assays; and D. Wood for critical comments on the manuscript.

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Correspondence to Johannes-Peter Stasch.

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Stasch, JP., Becker, E., Alonso-Alija, C. et al. NO-independent regulatory site on soluble guanylate cyclase. Nature 410, 212–215 (2001). https://doi.org/10.1038/35065611

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