TY - JOUR
T1 - NO-independent regulatory site on soluble guanylate cyclase
AU - Stasch, Johannes Peter
AU - Becker, Eva Maria
AU - Alonso-Alija, Cristina
AU - Apeler, Heiner
AU - Dembowsky, Klaus
AU - Feurer, Achim
AU - Gerzer, Rupert
AU - Minuth, Torsten
AU - Perzborn, Elisabeth
AU - Pleiß, Ulrich
AU - Schröder, Henning
AU - Schroeder, Werner
AU - Stahl, Elke
AU - Steinke, Wolfram
AU - Straub, Alexander
AU - Schramm, Matthias
PY - 2001/3/8
Y1 - 2001/3/8
N2 - 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.
AB - 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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U2 - 10.1038/35065611
DO - 10.1038/35065611
M3 - Article
C2 - 11242081
AN - SCOPUS:0035826261
SN - 0028-0836
VL - 410
SP - 212
EP - 215
JO - Nature
JF - Nature
IS - 6825
ER -