2. Academic Validation
  3. Revisiting soluble guanylate cyclase pharmacology: Additive potential of stimulators and activators

Revisiting soluble guanylate cyclase pharmacology: Additive potential of stimulators and activators

  • Biomed Pharmacother. 2025 Dec:193:118762. doi: 10.1016/j.biopha.2025.118762.
Alexandra Petraina 1,  Mahmoud H Elbatreek 2,  Christopher T Neullens 1,  Theodora Saridaki 1,  Vu Thao-Vi Dao 3,  Rebecca D Szepanowski 4,  Emil Martin 5,  Wolfgang Sippl 6,  Ana I Casas 7,  Harald H H W Schmidt 8
Affiliations

Affiliations

  • 1 Department of Pharmacology and Personalized Medicine, Faculty of Health, Medicine and Life Science, Maastricht University, Maastricht 6229ER, the Netherlands.
  • 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
  • 3 Department of Pharmacology and Personalized Medicine, Faculty of Health, Medicine and Life Science, Maastricht University, Maastricht 6229ER, the Netherlands; Department of Paediatrics, Clinic Hanau, Hanau 63450, Germany.
  • 4 Department of Neurology and Center for Translational Neuro-, and Behavioural Sciences (C-TNBS), University Clinic Essen, Essen 45147, Germany.
  • 5 McGovern Medical School, Internal Medicine, UTHealth Houston, Houston, TX 77030, USA.
  • 6 Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-Universitaet Halle-Wittenberg, Halle/Saale, Germany.
  • 7 Department of Pharmacology and Personalized Medicine, Faculty of Health, Medicine and Life Science, Maastricht University, Maastricht 6229ER, the Netherlands; Department of Neurology and Center for Translational Neuro-, and Behavioural Sciences (C-TNBS), University Clinic Essen, Essen 45147, Germany. Electronic address: [email protected].
  • 8 Department of Pharmacology and Personalized Medicine, Faculty of Health, Medicine and Life Science, Maastricht University, Maastricht 6229ER, the Netherlands. Electronic address: [email protected].
PMID: 41252787 DOI: 10.1016/j.biopha.2025.118762
Abstract

Nitric oxide (NO) is a key gasotransmitter that binds to soluble Guanylate Cyclase (sGC), thereby stimulating cGMP production. Under disease conditions, Reactive Oxygen Species disrupt this signaling by either: (1) scavenging NO, or (2) promoting heme-free, NO-insensitive apo-sGC due to impaired heme incorporation or oxidative damage. To counteract these conditions, two pharmacological approaches have emerged: sGC stimulators, which allosterically enhance sGC sensitivity to low NO levels; and sGC activators, which directly activate apo-sGC (heme-free sGC) by binding to its empty heme pocket, inducing a conformation that mimics NO-bound sGC. Thus, sGC stimulators are thought to target only sGC. Instead, we here show both in vitro and in vivo that sGC stimulators also modulate apo-sGC and - together with sGC activators - exert additive effects on apo-sGC. This newly identified activity of sGC stimulators on apo-sGC appears to be redox-sensitive. Indeed, when inactive sGC (ferric heme sGC) is generated by the commonly used oxidant 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), the stimulatory effect of sGC stimulators is abolished. The potential in vivo relevance of this mechanism was further demonstrated in a mouse model of ischemic stroke, wherein sGC is known to be predominantly NO-insensitive, yet sGC stimulators remain protective. Altogether, these findings challenge the current pharmacological paradigm of sGC modulation, revealing that both sGC and apo-sGC can be stimulated by sGC stimulators, whereas sGC activators remain specific to apo-sGC. This expanded understanding highlights the therapeutic potential of sGC stimulators, both as standalone treatments and in combination with sGC activators.

Keywords

CGMP; Guanylate cyclase; SGC activator; SGC stimulator; Stroke.

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