Norfloxacin Reduces Aortic NO Synthases and Proinflammatory Cytokine Up-Regulation in Cirrhotic Rats: Role of Akt Signaling

Tazi, Khalid A.; Moreau, Richard; Hervé, Philippe; Dauvergne, Agnès; Cazals–Hatem, Dominique; Bert, Frédéric; Poirel, Odile; Rabiller, Anne; Lebrec, Didier

doi:10.1053/j.gastro.2005.04.016

Cited by 74 publications

(73 citation statements)

References 51 publications

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“…*P Ͻ 0.05. factor alpha (TNF-␣) in the aortas of BDL rats. 53,54 As well, in spite of the inhibition of NO by L-NAME, fasudil tended to decrease MAP in BDL rats (Fig. 3D,E).…”

Section: Discussionmentioning

confidence: 64%

Defective endothelial nitric oxide synthase signaling is mediated by rho-kinase activation in rats with secondary biliary cirrhosis

et al. 2007

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In liver cirrhosis, down-regulation of endothelial nitric oxide synthase (eNOS) has been implicated as a cause of increased intrahepatic resistance. We investigated whether Rhokinase activation is one of the molecular mechanisms involved in defective eNOS signaling in secondary biliary cirrhosis. Liver cirrhosis was induced by bile duct ligation (BDL). We measured mean arterial pressure (MAP), portal venous pressure (PVP), and hepatic tissue blood flow (HTBF) during intravenous infusion of saline (control), 0.3, 1, or 2 mg/kg/hour fasudil for 60 minutes. In BDL rats, 1 and 2 mg/kg/hour fasudil significantly reduced PVP by 20% compared with controls but had no effect on HTBF. MAP was significantly reduced in response to 2 mg/kg/hour fasudil. In the livers of BDL rats, 1 and 2 mg/kg/hour fasudil significantly suppressed Rho-kinase activity and significantly increased eNOS phosphorylation, compared with controls. P ortal hypertension is a common clinical syndrome associated with liver cirrhosis and characterized by increased intrahepatic resistance and elevated splanchnic blood flow, leading to a pathological increase in portal pressure and the development of portosystemic collaterals such as esophagogastric varices. 1-6 Pharmacological therapy for portal hypertension should be aimed at reducing intrahepatic vascular tone or elevated splanchnic blood flow. However, the only available treatment is a nonselective beta-blocker that reduces portal venous pressure (PVP) by decreasing cardiac output and splanchnic blood flow. 7 Several randomized trials indicate that a nonselective beta-blocker is the first choice for primary and secondary prophylaxis against esophageal variceal bleeding. [8][9][10] However, the mean decrease in PVP in response to beta-blockers is only approximately 15%. Moreover, 15% of patients with cirrhosis are beta-blocker intolerant, whereas another approximately 30% do not respond to betablockers despite adequate blockade. 11 Therefore, there is a pressing need for a more effective pharmacological therapy for portal hypertension.Previous studies have shown that hepatic stellate cells (HSCs) through their contraction play a crucial role in regulating sinusoidal vascular tone. 12 The contractility of HSCs is regulated by the balance of vasoactive agents such as endothelin-1, and vasorelaxing agents such as nitric oxide (NO). 13 Recent studies have shown that the production of NO by endothelial nitric oxide synthase (eNOS) in hepatic sinusoidal endothelial cells (SECs) is Abbreviations: ␣-SMA, alpha-smooth muscle actin;

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“…*P Ͻ 0.05. factor alpha (TNF-␣) in the aortas of BDL rats. 53,54 As well, in spite of the inhibition of NO by L-NAME, fasudil tended to decrease MAP in BDL rats (Fig. 3D,E).…”

Section: Discussionmentioning

confidence: 64%

Defective endothelial nitric oxide synthase signaling is mediated by rho-kinase activation in rats with secondary biliary cirrhosis

et al. 2007

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“…Importantly, the aortic wall pro-inflammatory phenotype is abolished after five-day norfloxacin therapy. Moreover, norfloxacin dramatically reduces aortic NO production [45,46]. These findings suggest that BT via PAMPs induces systemic and local pro-inflammatory responses that increase arterial NO production.…”

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confidence: 78%

“…Therefore, BT via PAMPs and/or systemic TNF-α may explain the increased eNOS activity in mesenteric arterioles. Interestingly, aortic walls from cirrhotic rats overexpress pro-inflammatory cytokines, contributing to both iNOS induction and eNOS hyperactivity [45]. Importantly, the aortic wall pro-inflammatory phenotype is abolished after five-day norfloxacin therapy.…”

mentioning

confidence: 99%

Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis

Bernardi

Moreau

Angeli

et al. 2015

Journal of Hepatology

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506

451

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“…Norfloxacin decontaminates the intestine and is well established in the prophylaxis of spontaneous bacterial peritonitis. In addition to targeting translocation from the gut, it may also ameliorate hyperdynamic circulatory changes in cirrhosis [26][27][28].…”

Section: Treatment Strategiesmentioning

confidence: 99%

Hepatic encephalopathy in acute-on-chronic liver failure

Lee

2015

Hepatol Int

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The presence of hepatic encephalopathy (HE) within 4 weeks is part of the criteria for defining acute-on-chronic liver failure (ACLF). The pathophysiology of HE is complex, and hyperammonemia and cerebral hemodynamic dysfunction appear to be central in the pathogenesis of encephalopathy. Recent data also suggest that inflammatory mediators may have a significant role in modulating the cerebral effect of ammonia. Multiple prospective and retrospective studies have shown that hepatic encephalopathy in ACLF patients is associated with higher mortality, especially in those with grade III-IV encephalopathy, similar to that of acute liver failure (ALF). Although significant cerebral edema detected by CT in ACLF patients appeared to be less common, specialized MRI imaging was able to detect cerebral edema even in low grade HE. Ammonia-focused therapy constitutes the basis of current therapy, as in the treatment of ALF. Emerging treatment strategies focusing on modulating the gut-liver-circulation-brain axis are discussed.

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Norfloxacin Reduces Aortic NO Synthases and Proinflammatory Cytokine Up-Regulation in Cirrhotic Rats: Role of Akt Signaling

Cited by 74 publications

References 51 publications

Defective endothelial nitric oxide synthase signaling is mediated by rho-kinase activation in rats with secondary biliary cirrhosis

Defective endothelial nitric oxide synthase signaling is mediated by rho-kinase activation in rats with secondary biliary cirrhosis

Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis

Hepatic encephalopathy in acute-on-chronic liver failure

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