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      On a revised pharmacology of apo-soluble guanylate cyclase and its therapeutic implications

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            Nitric oxide (NO) is a widely distributed gasotransmitter binding to the heme of soluble guanylate cyclase (sGC) to stimulate the formation of the second messenger cyclic GMP. In disease, two pathomechanisms can occur, scavenging of NO by reactive oxygen species so that sGC is insufficiently stimulated, and oxidative damage of sGC resulting in heme loss and a NO-insensitive apo-form of sGC. To address this therapeutically, two pharmacological principles have entered the clinic or clinical development. sGC stimulators (sGCs) allosterically sensitize sGC for lower NO levels to reach physiological cGMP levels again; sGC activators (sGCa) bind to the empty heme pocket of apo-sGC to recover cGMP formation. Here we show in vitro and in vivo that this dichotomic pharmacology of sGCs/sGC and sGCa/apo-sGC is wrong. Instead apo-sGC is both activated by sGCa and allosterically modulated by sGC stimulators. The sGCs binding site in sGC and apo-sGC, however, is redox sensitive explaining why it has been previously missed in apo-sGC preparations generated for example by using heme oxidants such as 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Moreover, sGCs synergised with sGCa on apo-sGC in a supra-additive manner similar to the synergy between NO and sGCs on sGC. Our findings provide functional evidence including ischemic stroke, where apo-sGC rather than sGC is detectable, for identical modulation of sGC and apo-sGC by sGCs. This necessitates a revision of the dichotomic sGC/apo-sGC pharmacology and expands the therapeutic potential of sGCs and sGCa both individually and in combination.


            Author and article information

            30 January 2023
            [1 ] Department of Pharmacology and Personalized Medicine, MeHNS, Faculty of Health, Medicine and Life Science, Maastricht University, Maastricht, 6229 ER, the Netherlands. ( https://ror.org/02jz4aj89)
            [2 ] Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt. ( https://ror.org/053g6we49)
            [3 ] Department of Pharmacology and Personalized Medicine, MeHNS, Faculty of Health, Medicine and Life Science, Maastricht University, Maastricht, 6229 ER, the Netherlands.;
            [4 ] Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany;
            [5 ] Department of Neurology and Center for Translational Neuro- and Behavioural Sciences (C-TNBS), University Clinic Essen, Essen, Germany ( https://ror.org/02na8dn90)
            Author notes
            Author information

            This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

            : 30 January 2023
            Funded by: funder-id http://dx.doi.org/10.13039/501100007601, Horizon 2020;
            Award ID: 777111

            The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
            Pharmacology & Pharmaceutical medicine
            cyclic GMP,soluble guanylate cyclase stimulators,apo-soluble guanylate cyclase,apo-soluble guanylate cyclase activators,stroke


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