NO-independent regulatory site on soluble guanylate cyclase

Nature. 2001 Mar 8;410(6825):212-5. doi: 10.1038/35065611.

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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antihypertensive Agents / therapeutic use
  • Binding Sites
  • Blood Pressure / drug effects
  • Cyclic N-Oxides / pharmacology
  • Cysteine / chemistry
  • Disease Models, Animal
  • Enzyme Activation
  • Female
  • Guanylate Cyclase / chemistry*
  • Guanylate Cyclase / metabolism
  • Heme / chemistry
  • Humans
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Indazoles / pharmacology
  • Molecular Sequence Data
  • Nitric Oxide / chemistry*
  • Photoaffinity Labels
  • Platelet Aggregation Inhibitors / pharmacology
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Solubility

Substances

  • 3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
  • Antihypertensive Agents
  • Cyclic N-Oxides
  • Imidazoles
  • Indazoles
  • Photoaffinity Labels
  • Platelet Aggregation Inhibitors
  • Pyrazoles
  • Pyridines
  • pyrazolopyridine
  • 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
  • 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide
  • Nitric Oxide
  • Heme
  • Guanylate Cyclase
  • Cysteine