Mechanisms of nitric oxide independent activation of soluble guanylyl cyclase

Peter Schmidt, Matthias Schramm, Henning Schröder, Johannes Peter Stasch

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

The heterodimeric heme-protein soluble guanylyl cyclase (sGC) is the only proven receptor for nitric oxide (NO). Recently, two different types of NO-independent soluble guanylyl cyclase stimulators have been discovered. The heme-dependent stimulator 2-[1-[2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5(4- morpholinyl)-4,6-pyrimidinediamine (BAY 41-8543) stimulates the enzyme in a synergistic fashion when combined with NO, requires the presence of the heme group and can be blocked by the soluble guanylyl cyclase inhibitor 1H-(1,2,4)-Oxadiazole-(4,3-a)-quinoxalin-1-one (ODQ). The heme-independent activator 4-[((4-carboxybutyl){2-[(4-phenethylbenzol) oxy]phenethyl}amino)methyl[benzoic]acid (BAY 58-2667) activates soluble guanylyl cyclase even in the presence of ODQ or rendered heme-deficient. In the present study, BAY 41-8543, BAY 58-2667 and NO strongly increased Vmax. Combination of BAY 58-2667 and NO increased Vmax in an additive manner, whereas the synergistic effect of BAY 41-8543 and NO on enzyme activation was reflected in an overadditive increase of Vmax. ODQ potentiated Vmax of BAY 58-2667-stimulated soluble guanylyl cyclase. BAY 41-8543 prolonged the half-life of the nitrosyl-heme complex of NO-activated enzyme, an effect that was not observed with BAY 58-2667. These results show the different activation patterns of both compounds and demonstrate their value as tools to investigate the mechanisms that underlie soluble guanylyl cyclase activation.

Original languageEnglish (US)
Pages (from-to)167-174
Number of pages8
JournalEuropean Journal of Pharmacology
Volume468
Issue number3
DOIs
StatePublished - May 16 2003
Externally publishedYes

Keywords

  • BAY 41-8543
  • BAY 58-2667
  • Heme
  • Kinetics
  • Nitric oxide (NO)
  • Soluble guanylyl cyclase

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