NO-independent regulatory site on soluble guanylate cyclase |
| |
Authors: | Stasch J P Becker E M Alonso-Alija C Apeler H Dembowsky K Feurer A Gerzer R Minuth T Perzborn E Pleiss U Schröder H Schroeder W Stahl E Steinke W Straub A Schramm M |
| |
Institution: | Pharma Research Center, Bayer AG, Aprather Wey 18a, D-42096 Wuppertal, Germany. johannes-peter.stasch.js@bayer-ag.de |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|