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  • In contrast the sGC activator BAY relaxed

    2022-06-23

    In contrast, the sGC activator BAY 58-2667 relaxed the CC in a concentration-dependent manner (Figure 4B), a response that was significantly increased in the CC of sGCβ1ki/ki mice compared with WT mice. The finding that BAY 58-2667 also possessed a corporal relaxing effect in WT mice is suggestive because, even in healthy mice, a subset of the available sGC pool is free of heme and responsive to sGC activators. To our surprise, the ability of BAY 58-2667 to activate sGC was less pronounced in sGCβ1ki/ki mice than in WT mice, a finding that is in contrast with our functional test results (Figure 5) and previously reported findings. A potential explanation for this discrepancy could be that the protein levels of at least one sGC subunit is lower in the CC of sGCβ1ki/ki mice, an observation previously noted for cardiovascular tissues.19, 35 Another possibility is that BAY 58-2667 exerts sGC-independent effects resulting in vascular and corporal smooth muscle relaxation. Our functional data clearly illustrate the potential of BAY 58-2667 to ameliorate erectile function in mice expressing apo-sGC. From a clinical point of view, this finding is of major importance. Many diseases Novobiocin Sodium australia associated with ED are characterized by increased oxidative stress. This leads to lower NO bioavailability and an alteration in the redox state of sGC through oxidation of the heme iron hampering its activation by NO.36, 37 For those patients, PDE-5 inhibitors will offer little therapeutic advantage in treating ED because only low concentrations of cGMP are produced. As shown by this study, sGC stimulators fail to activate oxidized sGC and thus provide no or limited advantage over PDE-5 inhibitors in restoring erectile function. The finding that BAY 58-2667 was more potent in relaxing corporal tissue expressing apo-sGC provides a solid scientific Novobiocin Sodium australia for the further development of this new class of drugs because they might have advantages over current therapies for treating ED. This conclusion also is supported by the enhanced erectile responses seen with the administration of a different sGC activator (BAY 60-2270) after sGC oxidation and its ability to restore erectile function in obese mice and in a rat model of cavernosal nerve injury.10, 12, 38 Moreover, Frey et al presented clinical evidence that sGC activators possess erectile properties because they found that spontaneous penile erection was one of the most frequent treatment-emergent adverse events after intake of BAY 58-2667. Similar responses of CC in sGCβ1+/+ and sGCβ1ki/ki mice to 8-pCPT-cGMP and forskolin showed that the pathway downstream of sGC was intact in sGCβ1ki/ki mice (Figures 3 and 7). These results further illustrate that the abolished sGC-related responses are not due to an aspecific impairment of relaxation related to structural damage or to intrinsic changes in the relaxing properties of sGCβ1ki/ki smooth muscle cells. Furthermore, these data exclude a compensatory role for the adenylate cyclase and cyclic adenosine monophosphate signaling pathway.
    Conclusion This article describes the penile vascular phenotype of a mouse model that allowed us to distinguish between the sGC-dependent and sGC-independent effects of NO. Our data provide evidence that NO exerts its erectile properties solely through sGC activation. The present data also show the therapeutic potential of compounds able to activate apo-sGC in the setting of ED. In addition, our results suggest an important contribution of the lower expressed sGCα2β1 isoform in penile erection. This finding supports the idea of developing agents specifically targeting the sGCα2β1 isoform because this might limit potential side effects and thus provide a therapeutic advantage. The potential of sGC activators to ameliorate erectile function in several disease models and the physiologic pathways involved require further investigation.
    Statement of authorship
    Acknowledgments
    Introduction Calcium signaling plays a crucial role in regulation of different aspects of neuronal function. Changes in the intracellular Ca concentration ([Ca]free) in neurons give rise to diverse physiological responses via activation of EF-hand-type Ca-sensor proteins including members of the neuronal Ca-sensor (NCS) protein family (for review, see [1], [2]). The human genome encodes 14 members of the NCS family that can be divided into five groups: frequenins, visinin-like proteins (VILIPs), recoverins, guanylate cyclase-activating proteins (GCAPs) and K+-channels interacting proteins (KChIPs). Some of these proteins such as NCS1 (frequenin) are widely distributed within the nervous system and display multidirectional activity. The expression pattern of other NCSs is restricted to certain neuronal tissue, where they often have more specialized functions. The latter NCS group includes recoverin and GCAPs, which are present predominantly in photoreceptor cells of the retina. Recoverin is implicated in rhodopsin desensitization by inhibiting rhodopsin kinase (RK, also known as GRK1) in the dark-adapted state at high [Ca]free and releasing the enzyme at decreased Ca levels after illumination (for review, see [3]). GCAP1 and GCAP2 regulate cGMP synthesis of photoreceptor guanylate cyclases 1 and 2 (ROS-GC1 and ROS-GC2, also known as RetGC1 and RetGC2 or GC-E and GC-F, respectively) in a Ca-relay manner, i.e. sequentially switching from a ROS-GC-inhibitor to a ROS-GC-activator conformation following illumination-induced decrease in intracellular [Ca]free (for review, see [4]).