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  • Interestingly myorelaxation and the stimulation of cGMP

    2022-08-05

    Interestingly, myorelaxation and the stimulation of cGMP production are properties also reported for sGC stimulators, such as YC-1 and BAY 41–2272 (i.e., indazole compounds that were discovered in the 1990s) [35]. They relax aortic ring contractions induced by phenylephrine, and their effects are significantly inhibited by ODQ. In contrast, the vasodilator actions of YC-1 and BAY 41–2272 clearly depend on the endothelial release of NO [36], [37], [38]. The lead compound, YC-1, also inhibits phosphodiesterase V, an action that may further induce an increase in cGMP levels [39]. The putative inhibitory effect of 1-nitro-2-phenylethane on phosphodiesterase function is unlikely because the vasodilator effects of most phosphodiesterase inhibitors are reduced as much by endothelium removal as by l-NAME treatment [40], [41], which strongly differed from the present findings for 1-nitro-2-phenylethane. Moreover, the median effective concentrations of 1-nitro-2-phenylethane were quite high. Notably, however, the IC50 values of ∼43 and ∼29μM observed in the present study in endothelium-intact and -denuded mesenteric arterial vessels, respectively, are comparable to the potency range for smooth muscle relaxation of sGC stimulators. For example, BAY 41–2272 relaxes the rat basilar artery with an IC50 of 0.1μM, whereas A-350619 relaxes the corpus cavernosum with an IC50 of 80μM [35]. The hypothesis that 1-nitro-2-phenylethane may exert direct sGC stimulation was addressed in the present study using in silico simulation of the molecular interaction between 1-nitro-2-phenylethane and (Ns) H-NOX, a heme protein obtained from symbiotic AG-126 Nostoc sp., which possesses high structural homology (approximately 35% sequence identity to the β-subunit found in mammalian sGC) and similar apparent in vivo function [42]. Such an approach revealed the existence of a main site that is able to dock 1-nitro-2-phenylethane based on at least 50 best conformations that were all consistently concentrated in a pocket of the macromolecule surface and displayed a main spatial orientation inside the pocket with the ring portion facing hydrophobic residues within the cavity. The portion with oxygen content bent to the external border, reclining within the proximity of the amino acid ARG116. Residues situated at a maximal distance of 5Å between the predicted binding site and docked molecule of 1-nitro-2-phenylethane were identified [43]. Because these residues were distributed into one main site in proximity to the heme group, perhaps 1-nitro-2-phenylethane could mediate crosstalk between non-heme groups that induce NO-independent but heme-dependent allosteric improvement of the guanylate cyclase's catalytic unity. Indeed, conventional guanylate cyclase stimulators, such as YC-1 and BAY 41–2272, appear to have a common allosteric site that targets their stimulatory actions on this enzyme [43], [44], [45]. Heme-dependency is characterized by the decreased stimulatory influence of sGC stimulators after heme removal or oxidation by ODQ, methylene blue, or ferri-cyanide [35]. Conversely, heme removal or oxidation does not interfere with the effects of BAY 58–2667, which may produce guanylate cyclase stimulation in a NO- and heme-independent manner. Substances that are able to increase cGMP levels by heme-independent stimulation of sGC prompted the formation of a novel class called “sGC activators” [35]. Altogether, if a direct stimulatory action on sGC can be confirmed using more appropriate methods, then 1-nitro-2-phenylethane may likely be characterized as a sGC stimulator rather than activator. Additional events may also contribute to the relaxant effects of 1-nitro-2-phenylethane, such as the opening of K+ channels in plasmalemma, a phenomenon apparently confirmed using K+ channel blockers, which significantly shifted the concentration-effect curve to the right in response to this nitro compound. Such findings are consistent with the hypothesis that 1-nitro-2-phenylethane stimulates the sGC pathway. Generally, sGC-derived cGMP will target three main cellular sites: cGMP-dependent protein kinases (PKGs), cGMP-gated cation channels, and phosphodiesterases [46]. Specifically, the opening of K+ channels is one of the possible events that result from cGMP accumulation in the cytoplasm, promoting subsequent vasodilation [47]. However, the present findings do not discard the putative hypothesis of a direct opening effect of 1-nitro-2-phenylethane on K+ channels.