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    • The following are the supplementary data

    2022-09-16

    The following are the supplementary data related to this article.
    Transparency Document
    Acknowledgements
    Introduction Nitric oxide (NO) is an important signaling molecule mediating several physiological functions including vasodilation, platelet anti-aggregation, inhibition of interstitial fibrosis, and smooth muscle anti-proliferation. NO exerts its diverse effects mainly through the activation of soluble guanylate cyclase (sGC) and its subsequent cGMP production [1]. NO activates sGC by binding to its reduced (Fe2+) heme moiety, and is unable to activate sGC if it contains an oxidized (Fe3+) heme moiety or if the heme group is missing altogether [2]. This sGC redox equilibrium is disrupted under stress conditions [3] and could decrease NO bioavailability. Pulmonary CPTH2 hydrochloride (PH) is associated with impaired NO bioavailability, and thus, drugs targeting the NO/sGC/cGMP pathway are clinically used to treat PH [4]. Several hypotheses have been made as to underlying mechanisms by which NO bioavailability decreases during PH and they include: (1) the suppression of NO production in the pulmonary endothelium [5,6], (2) the scavenging of NO by the superoxide anion generated at the site of the lesion [7,8], and (3) the stimulation of cGMP degradation in the lung and pulmonary circulation [9,10]. However, there is no concrete evidence that indicates that the sGC redox state, or the balance between NO-sensitive and -insensitive forms, is altered in the pulmonary vessels during the progression of PH. The therapeutic efficacy of exogenously administered NO-enhancing drugs against PH remains controversial. The inhalation of nebulized nitrite [11] or the daily intraperitoneal administration of inorganic nitrite [12] has been demonstrated to reverse established PH induced by a monocrotaline (MCT) injection in rats. Additionally, continuous subcutaneous infusion of molsidomine [13], daily oral administration of isosorbide dinitrate [14], or gavage treatment with pentaerythritol tetranitrate [15] prevented the development of MCT-induced PH. Conversely, chronic NO inhalation did not exert such beneficial effects [16,17]. Furthermore, patients with PH are sometimes refractory to the therapeutic action of NO supplementation [18,19].
    Materials and methods
    Results
    Discussion The redox state of sGC heme is a crucial determinant of vascular NO bioavailability and is related to the progression of various cardiovascular diseases [21]. This study indicated, for the first time, the sGC redox state in the pulmonary artery of rats with PH. Briefly, the responsiveness of rat pulmonary arteries to the reduced sGC stimulant BAY 41-2272 and the oxidized/heme-free sGC stimulant BAY 60-2770 were normal at 14 days after MCT injection. Given the fact that only pulmonary arterial medial thickening was observed at this time point, it is suggested that in the early stage of PH, the sGC redox state, or the balance between NO-sensitive and -insensitive forms, remains normal. This conclusion is supported by previous studies showing that NO donors normally relax pulmonary arteries when the period after MCT injection is short [22,23]. Therefore, NO-enhancing drugs are considered to be able to work normally in the pulmonary circulatory system in the early stage of PH. Chronic treatment with isosorbide mononitrate or sodium nitrite from the early stage of MCT-induced PH prevented the subsequent RVSP elevation and pulmonary arterial medial thickening. However, these preventive effects were not observed in rats treated with the high dose of isosorbide mononitrate or sodium nitrite. Of course, it is well known that NO has both beneficial and detrimental effects depending on its concentration [24]. In fact, Sahara et al. [14] showed that an appropriate dose range of isosorbide dinitrate to treat MCT-injected rats is not broad and that too high a dose worsens the disease. In light of this and our findings, it is no wonder that there are conflicting reports showing protective [[11], [12], [13],15] and non-protective effects [16,17] of NO supplementation on MCT-induced PH.