Different Influences of Extracellular and Intracellular Superoxide on Relaxation Through the NO/sGC/cGMP Pathway in Isolated Rat Iliac Arteries

Tawa, Masashi; Shimosato, Takashi; Iwasaki, Hiromichi; Imamura, Teruhiko; Okamura, Tomio

doi:10.1097/fjc.0000000000000173

Cited by 14 publications

(18 citation statements)

References 40 publications

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“…In the previous study, we have shown that superoxide, a precursor of peroxynitrite, has an ability to shift the sGC redox equilibrium toward the NO-insensitive form in isolated endothelium-denuded monkey coronary [22] and rat iliac arteries [21]. Based on this observation, we next examined whether superoxide contributes to the effects of peroxynitrite on the relaxant responses to BAY compounds.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Peroxynitrite on Relaxation through the NO/sGC/cGMP Pathway in Isolated Rat Iliac Arteries

et al. 2014

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Background/Aims: The present study investigated the mechanism by which peroxynitrite impairs vascular function through the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP pathway. Methods: Mechanical responses of rat external iliac arteries without endothelium were studied under exposure to peroxynitrite. cGMP concentrations were determined by enzyme immunoassay. Results: Relaxation induced by BAY 41-2272 (sGC stimulator) was impaired under exposure to peroxynitrite, whereas that by BAY 60-2770 (sGC activator) was enhanced. These responses were correlated with tissue levels of cGMP. Effects of peroxynitrite on the relaxant responses to BAY compounds were also observed in the presence of superoxide dismutase (SOD) or tempol, both of which scavenge a certain kind of reactive molecules other than peroxynitrite. As is the case with the relaxant response to BAY 41-2272, acidified NaNO₂- and nitroglycerin-induced relaxations were markedly attenuated by exposing the arteries to peroxynitrite, which was not abolished by preincubation with SOD or tempol. On the other hand, peroxynitrite exposure had no effect on the 8-Br-cGMP-induced vasorelxation. Conclusion: These findings suggest that peroxynitrite interferes with the NO/sGC/cGMP pathway by altering the redox state of sGC. It is likely that peroxynitrite can shift the sGC redox equilibrium to the NO-insensitive state in the vasculature.

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Section: Discussionmentioning

confidence: 99%

“…Briefly, these drugs were added to the bathing solution just before exposure to peroxynitrite. The concentration of these drugs was determined based on a previous work [21]. Incidentally, the incubated drugs such as ODQ, peroxynitrite, SOD and tempol were maintained in the bath throughout the experiment.…”

Section: Methodsmentioning

confidence: 99%

Effects of Peroxynitrite on Relaxation through the NO/sGC/cGMP Pathway in Isolated Rat Iliac Arteries

et al. 2014

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“…; Tawa et al. ,b, ,b; Goulopoulou et al. ), two different NO‐independent stimulants acting on sGC were used in this study as valuable tools for indirectly assessing the redox state of the enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…) and iliac arteries (Tawa et al. , ) or in cultured sheep pulmonary artery smooth muscle cells (Zhou et al. ).…”

Section: Introductionmentioning

confidence: 99%

Soluble guanylate cyclase redox state under oxidative stress conditions in isolated monkey coronary arteries

Tawa

Okamura

2016

Pharmacology Res & Perspec

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Coronary artery disease is associated with oxidative stress due to the excessive generation of free radicals in the vascular wall. This study investigated the impact of tert‐butyl hydroperoxide (t‐BuOOH), a peroxyl radical generator, on the redox state of soluble guanylate cyclase (sGC) in isolated monkey coronary arteries. Helically cut strips of endothelium‐intact monkey coronary arteries treated with the nitric oxide synthase inhibitor NG‐nitro‐L‐arginine (10 μmol/L) were exposed for approximately 60 min to either no drug or t‐BuOOH (100 μmol/L) in the presence and absence of α‐tocopherol (300 μmol/L). Relaxation and cGMP levels in response to the sGC stimulator BAY 41‐2272 and the sGC activator BAY 60‐2770 were assessed by organ chamber technique and enzyme immunoassay, respectively. The relaxant response to BAY 41‐2272 was significantly impaired by the exposure to t‐BuOOH, whereas the response to BAY 60‐2770 was significantly augmented. In addition, vascular cGMP accumulation caused by BAY 41‐2272 was decreased by the exposure to t‐BuOOH, whereas for BAY 60‐2770, it was increased. These effects of t‐BuOOH were abolished by coincubation with α‐tocopherol. Furthermore, correlations were observed between BAY compound‐induced relaxant magnitudes and cGMP levels. Therefore, it is concluded that increased oxidative stress leads to disruption of the sGC redox state in monkey coronary arteries. This finding is of great importance for understanding coronary physiology in primates.

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“…BAY 58–2770 (cinaciguat) and HMR-1766 (ataciguat) have been studied in the progression of cardiovascular disease due to their roles as activators of oxidized sGC [8, 9]. Moreover, the therapeutic potency of the sGC activator BAY 60–2770 (4-[[[4-carboxybutyl] [2-[5-fluoro-2-[[4’-[trifluoromethyl] biphenyl-4-yl] methoxy] phenyl] ethyl] amino] methyl] benzoic acid) has been elucidated in nitrate-tolerant arteries [10, 11], obesity [12, 13], platelet activity [14] and asthma [15]. Despite studies investigating the protective role of BAY 60–2770 in coronary artery occlusion [16], few studies have focused on mitochondrial ROS in cardiac IR injury.…”

Section: Introductionmentioning

confidence: 99%

Cardioprotective effects of PKG activation by soluble GC activator, BAY 60-2770, in ischemia-reperfusion-injured rat hearts

Lee

Cho

et al. 2017

PLoS ONE

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Soluble guanylate cyclase (sGC) has been suggested as a therapeutic target for cardiac ischemia-reperfusion (IR) injury. Until now, the molecular mechanism of BAY 60–2770, a sGC activator, in cardiac IR injury has not been assessed. To identify the cardioprotective effects of BAY 60–2770 in IR-injured rat hearts, IR injury was established by occlusion of LAD for 40 min and reperfusion for 7 days, and the effects of BAY 60–2770 on myocardial protection were assessed by echocardiography and TTC staining. 5 nM and 5 μM of BAY 60–2770 were perfused into isolated rat hearts in a Langendorff system. After 10- or 30-min reperfusion with BAY 60–2770, cGMP and cAMP concentrations and PKG activation status were examined. Hearts were also perfused with 1 μM KT5823 or 100 μM 5-HD in conjunction with 5 nM Bay 60–2770 to evaluate the protective role of PKG. Mitochondrial oxidative stress was investigated under hypoxia-reoxygenation in H9c2 cells. In IR-injured rat hearts, BAY 60–2770 oral administration reduced infarct size by TTC staining and improved left ventricular function by echocardiography. Tissue samples from BAY 60-2770-perfused hearts had approximately two-fold higher cGMP levels. BAY 60–2770 increased PKG activity in the myocardium, and the reduced infarct area by BAY 60–2770 was abrogated by KT-5823 in isolated myocardium. In H9c2 cardiac myoblasts, hypoxia-reoxygenation-mediated mitochondrial ROS generation was diminished with BAY 60–2770 treatment, but was recovered by pretreatment with KT-5823. BAY 60–2770 demonstrated a protective effect against cardiac IR injury via mitoKATP opening and decreased mitoROS by PKG activation. BAY 60–2770 has a protective effect against cardiac IR injury via mitoKATP opening and decreased mitoROS by PKG activation. These results demonstrated that BAY 60–2770 may be used as a therapeutic agent for cardiac IR injury.

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Different Influences of Extracellular and Intracellular Superoxide on Relaxation Through the NO/sGC/cGMP Pathway in Isolated Rat Iliac Arteries

Cited by 14 publications

References 40 publications

Effects of Peroxynitrite on Relaxation through the NO/sGC/cGMP Pathway in Isolated Rat Iliac Arteries

Effects of Peroxynitrite on Relaxation through the NO/sGC/cGMP Pathway in Isolated Rat Iliac Arteries

Soluble guanylate cyclase redox state under oxidative stress conditions in isolated monkey coronary arteries

Cardioprotective effects of PKG activation by soluble GC activator, BAY 60-2770, in ischemia-reperfusion-injured rat hearts

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