Role of nitric oxide and KATP channel in the protective effect mediated by nicorandil in bile duct ligation-induced liver fibrosis in rats

Mohamed, Yasmin S.; Ahmed, Lamiaa A.; Salem, Hesham A.; Agha, Azza M.

doi:10.1016/j.bcp.2018.03.003

Cited by 16 publications

(12 citation statements)

References 39 publications

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“…Tissue NO has been shown to have protective effect on tissue injury and fibrosis in previous studies. For example, in the liver, NO plays a prominent role in the protective effect in bile duct ligation-induced liver fibrosis in rats [ 22 ]. In addition, a marked decrease in eNOS phosphorylation and NO level was involved in development of isoproterenol induced myocardial fibrosis [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

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Tissue-specific effects of targeted mutation of Mir29b1 in rats

et al. 2018

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Background miR-29 is a master regulator of extracellular matrix genes, but conflicting data on its anti-fibrotic effect have been reported. miR-29 improves nitric oxide (NO) production in arterioles by targeting Lypla1. Mir29b1 targeted mutation exacerbates hypertension in a model derived from the Dahl salt-sensitive rat. We examined the effect of Mir29b1 mutation on tissue fibrosis and NO levels with a focus on kidney regions. Methods Mir29b1 targeted mutant rats on the genetic background of SS-Chr13 BN rats were studied. Masson trichrome staining, molecular and biochemical assays, metabolic cage studies, and bioinformatic analysis of human genomic data were performed. Findings The abundance of miR-29b and the co-transcribed miR-29a was substantially lower in mutant rats. Tissue fibrosis was significantly increased in the renal outer medulla, but not in the renal cortex, heart or liver in mutant rats on a 0.4% NaCl diet. Lypla1 protein abundance was significantly higher and NO levels lower in the renal outer medulla, but not in the renal cortex. After 14 days of a 4% NaCl diet, 24 h urine volume and urinary sodium excretion was significantly lower in mutant rats, and tissue fibrosis became higher in the heart. NO levels were lower in the renal outer medulla and heart, but not in the renal cortex. Human miR-29 genes are located in proximity with blood pressure-associated single nucleotide polymorphisms. Interpretation The renal outer medulla might be particularly susceptible to the injurious effects of a miR-29 insufficiency, which might contribute to the development of hypertension in Mir29b1 mutant rats.

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Section: Discussionmentioning

confidence: 99%

“…Renal injury precedes overt hypertension in the SS rats [ 20 , 21 ]. NO has protective effects against tissue injury and fibrosis [ [22] , [23] , [24] ]. Renal NO inhibits tubular reabsorption of fluid and sodium, which may contribute to the anti-hypertensive effect of NO [ [25] , [26] , [27] ].…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific effects of targeted mutation of Mir29b1 in rats

et al. 2018

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“…14 It is well-known that K ATP channel openers can reduce oxidative stress and lipid peroxidation, maintain endogenous antioxidant defense, and mitigate inflammation. 15 In addition, it was reported that eNOS activators maintain microcirculation and decrease oxidative stress and apoptotic biomarkers. 16 Moreover, it was demonstrated that activation of TRPV1 can preserve antioxidant status and attenuate inflammation.…”

Section: Introductionmentioning

confidence: 99%

Hydrogen sulfide modulates IL-6/STAT3 pathway and inhibits oxidative stress, inflammation, and apoptosis in rat model of methotrexate hepatotoxicity

2019

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Methotrexate (MTX) is a commonly used anticancer and immunosuppressive agent. However, MTX can induce hepatotoxicity due to oxidative stress, inflammation, and apoptosis. Hydrogen sulfide (H2S), the endogenous gaseous molecule, has antioxidant, anti-inflammatory, and anti-apoptotic effects. The present work explored the probable protective effect of H2S against MTX hepatotoxicity in rats and also the possible mechanisms underlying this effect. MTX was given at a single intraperitoneal (i.p.) dose of 20 mg/kg. Sodium H2S (56 µmol /kg/day, i.p.), as H2S donor, was given for 10 days, starting 6 days before MTX administration. H2S significantly reduced serum alanine aminotransferase, hepatic malondialdehyde, interleukin 6, nuclear factor κB p65, cytosolic cytochrome c, phosphorylated signal transducer and activator of transcription 3, and Bax/Bcl-2 ratio and significantly increased hepatic total antioxidant capacity and endothelial nitric oxide synthase (eNOS) in rats received MTX. In addition, H2S minimized the histopathological injury and significantly decreased the expression of STAT3 in liver tissue of MTX-challenged rats. The effects of H2S were significantly antagonized by administration of glibenclamide as KATP channel blocker, Nω-nitro-l-arginine, as eNOS inhibitor, or ruthenium red, as transient receptor potential vanilloid 1 (TRPV1) antagonist. It was concluded that H2S provided significant hepatoprotection in MTX-challenged rats through its antioxidant, anti-inflammatory, anti-apoptotic effects. These effects are most probably mediated by the ability of H2S to act as IL-6/STAT3 pathway modulator, KATP channel opener, eNOS activator, and TRPV1 agonist.

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“…These data suggested that the protection revealed by nicorandil against hepatic fibrosis was related mainly to its action as a donor for NO and to a smaller extent to its KATP channel opening. [50]…”

Section: Different Mechanisms Involved In Different Diseased Conditionsmentioning

confidence: 99%

Nicorandil: A drug with ongoing benefits and different mechanisms in various diseased conditions

Ahmed

2019

Indian J Pharmacol

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Nicorandil is a well-known antianginal agent, which has been recommended as one of the second-line treatments for chronic stable angina as justified by the European guidelines. It shows an efficacy equivalent to that of classic antianginal agents. Nicorandil has also been applied clinically in various cardiovascular diseases such as variant or unstable angina and reperfusion-induced damage following coronary angioplasty or thrombolysis. Different mechanisms have been involved in the protective effects of nicorandil in various diseases through either opening of adenosine triphosphate-sensitive potassium (KATP) channel or donation of nitric oxide (NO). The predominance or participation of any of these proposed mechanisms depends on the dose of nicorandil used, the location of diseased conditions, and if this mechanism is still functioning or not. The protection afforded by nicorandil has been shown to be mainly attributed to KATP channel opening in experimental models of myocardial and pulmonary fibrosis as well as renal injury or glomerulonephritis, whereas NO donation predominates as a mechanism of protection in hepatic fibrosis and inflammatory bowel diseases. Therefore, in different diseased conditions, it is important to know which mechanism plays the major role in nicorandil-induced curative or protective effects. This can bring new insights into the proper use of selected medication and its recommended dose for targeting certain disease.

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Role of nitric oxide and KATP channel in the protective effect mediated by nicorandil in bile duct ligation-induced liver fibrosis in rats

Cited by 16 publications

References 39 publications

Tissue-specific effects of targeted mutation of Mir29b1 in rats

Tissue-specific effects of targeted mutation of Mir29b1 in rats

Hydrogen sulfide modulates IL-6/STAT3 pathway and inhibits oxidative stress, inflammation, and apoptosis in rat model of methotrexate hepatotoxicity

Nicorandil: A drug with ongoing benefits and different mechanisms in various diseased conditions

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