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  • In contrast to sGC stimulators sGC activators

    2021-11-20

    In contrast to sGC stimulators, sGC activators promote enzymatic activity of sGC containing oxidized heme iron (Fe3+) or missing the heme group. A-350619 is one of the oldest activators of sGC to be discovered. A-350619 increased sGC activation in a non-additive manner with respect to YC-1, leading to vasorelaxation and indicating that A-350619 and YC-1 possess common binding sites [101]. In the presence of sodium nitroprusside, the vasorelaxation response to YC-1 and A-350619 increased further [101]. The A-350619 response was partially inhibited by ODQ. When employed in cavernosum tissue pretreated with an NO-synthase inhibitor, the YC-1 with A-350619 combination produced relaxation in a dose-dependent manner [101]. As previously discussed, protoporphyrin IX activated sGC and increased pulmonary artery vasorelaxation [66]. Application of ODQ inhibited sGC activation and attenuated the response to an NO donor without affecting aminolevulinic sh4 (ALA), the precursor to protoporphyrin IX [66]. Similar to BAY 41-2272, BAY 58-2667, also known as Cinaciguat, activated sGC in the presence of oxidized heme or a missing heme group [102] and helped protect cardiomyocytes [103]. Application of ODQ further enhanced Cinaciguat activation, indicating that oxidized sGC augments the effect of Cinaciguat [102]. These results demonstrate that Cinaciguat may have potential in treating cardiovascular conditions arising from oxidative stress, which would be an advantage over sGC stimulators that require reduced heme iron in sGC. In a similar fashion, HMR-1766, Ataciguat, significantly increased activation of sGC following pretreatment with an oxidizer, hydrogen peroxide [104]. Although HMR-1766 was more effective in activating heme-free sGC rather than wild-type sGC, hydrogen peroxide inhibited HMR-1766 in cells with heme-free sGC [104]. The effects of hydrogen peroxide seem to be contradictory and possibly warrant further study. HMR-1766 demonstrates potential in treating diseases with increased peripheral resistance and increased ROS production [104]. BAY 60-2770 was also found to activate oxidized heme or heme-free sGC sh4 in an NO-independent manner [105]. Data from the study demonstrated that BAY 60-2770 had increased vasodilator activity in the presence of ODQ and a nitric oxide synthase inhibitor, consistent with the properties of sGC activators [105]. In a more recent study, the drug gemfibrozil, part of a class of drugs known as fibrates, which are important in treating dyslipidemias, was found to reduce cardiovascular events by activating oxidized heme or heme-free sGC [106]. Deletion of the H-NOX domain of sGC prevented gemfibrozil activation of sGC, indicating that gemfibrozil may occupy the heme pocket such that the H-NOX domain of sGC stabilizes the molecule [106]. Upon co-treatment with other heme-independent activators such as Ataciguat and Cinaciguat, gemfibrozil was found to competitively bind to sGC, indicating that gemfibrozil and other sGC activators work in a similar manner [106]. Comparative in vivo studies of sGC stimulators and activators have the potential to provide insight into the molecular mechanisms underlying various sGC-associated diseases processes. In the case of sickle cell disease (SCD), findings from a preclinical placebo-controlled study of oral formulations of the sGC activator BAY 54-6544, sGC stimulator BAY 41-8543, and sildenafil in a transgenic mouse model of SCD were recently published [107]. BAY 54-6544 showed superior activity versus the other compounds for reversing the age-related cardiac and pulmonary pathology that spontaneously occurs in SCD. By doing so, the sGC activator demonstrates that the NO insensitivity that characterizes SCD pulmonary arterial hypertension is likely due to oxidative inactivation of the sGC heme in vascular smooth muscle [107]. These results indicate that the oral sGC activator BAY 54-6544 may have substantial therapeutic potential in treating SCD-associated pulmonary arterial hypertension (PAH) and cardiac remodeling [107].