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27 April 2024 |
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NO-independent regulatory site on soluble guanylate cyclase | | J P Stasch
; E M Becker
; C Alonso-Alija
; H Apeler
; K Dembowsky
; A Feurer
; R Gerzer
; T Minuth
; E Perzborn
; U Pleiss
; H Schröder
; W Schroeder
; E Stahl
; W Steinke
; A Straub
; M Schramm
; | | Date: |
8 Mar 2001 | | Journal: | Nature, 410 (6825), 212-5 | | Abstract: | Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles. 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 (alpha/beta) 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 alpha1-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. | | Source: | PubMed, pmid11242081 doi: 10.1038/35065611 | | Services: | Forum | Review | Favorites | |
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