title: Mechanisms of nitric oxide independent activation of soluble guanylyl cyclase.
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 V(max). Combination of BAY 58-2667 and NO increased V(max) in an additive manner, whereas the synergistic effect of BAY 41-8543 and NO on enzyme activation was reflected in an overadditive increase of V(max). ODQ potentiated V(max) 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.
authors.affiliation: Institute of Cardiovascular Research, Bayer AG, Aprather Weg 18a, D-42096, Wuppertal, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schmidt
authors.forename: Matthias
authors.initials: M
authors.lastname: Schramm
authors.forename: Henning
authors.initials: H
authors.lastname: Schröder
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
mesh_terms: D001565:Benzoates / Q000378:metabolism; D004048:Diethylamines / Q000378:metabolism / Q000493:pharmacokinetics*; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase; D006418:Heme / Q000378:metabolism / Q000493:pharmacokinetics; D009025:Morpholines / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D009569:Nitric Oxide / Q000493:pharmacokinetics* / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000493:pharmacokinetics*; D009589:Nitrogen Oxides; D010069:Oxadiazoles / Q000378:metabolism / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000493:pharmacokinetics; D011810:Quinoxalines / Q000378:metabolism / Q000493:pharmacokinetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D013056:Spectrophotometry, Ultraviolet
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C450679:BAY 41-8543; D001565:Benzoates; D004048:Diethylamines; D009025:Morpholines; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D010069:Oxadiazoles; D011743:Pyrimidines; D011810:Quinoxalines; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; C480588:BAY 58-2667; D006418:Heme; C087229:diethylamine dinitric oxide adduct; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase