Vascular dysfunction induced by hypochlorite is improved by the selective phosphodiesterase-5-inhibitor vardenafil

Radovits, Tamás; Arif, Rawa; Bömicke, Timo; Korkmaz, Sevil; Barnucz, Enikő; Kretzler, Matthias; Merkely, Béla; Szabó, Gábor

doi:10.1016/j.ejphar.2013.04.012

Cited by 16 publications

(25 citation statements)

References 41 publications

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“…Vardenafil treatment significantly inhibited oxidative stress and restored the antioxidant parameters, suggesting that the drug is a powerful inhibitor of LCA-induced hepatic oxidative damage. This finding corresponds with previous investigations that showed the ability of vardenafil to suppress nitro-oxidative damage in the aortic endothelium and rat ovary [24,25]. Additionally, other PDE-5 inhibitors have been reported to have potential antioxidative effects in other models of oxidative injury [26][27][28][29].…”

Section: Discussionsupporting

confidence: 79%

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

El‐Agamy

Almaramhy

Ahmed

et al. 2018

Cell Physiol Biochem

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Background/Aims: Phosphodiesterase-5 inhibitors have beneficial effects in multiple liver diseases possibly through the reduction of oxidative stress and inflammatory response. However, these effects have not yet been examined in cholestatic liver dysfunction. Hence, this study aimed to explore the ability of vardenafil, a known phosphodiesterase-5 inhibitor, to repress lithocholic acid (LCA)-induced cholestatic liver injury and investigate the possible molecular pathways. Methods: Male Swiss albino mice were treated with LCA (0.125 mg/g) twice daily for 7 days to induce cholestatic liver damage. Vardenafil was administered 3 days before and throughout the administration of LCA. Serum markers of hepatotoxicity and hepatic nitro-oxidative stress along with antioxidant parameters were measured, and the histopathology of liver tissues was assessed. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes was examined using PCR. The activation of nuclear factor kappa-B (NF-κB) and the levels of inflammatory cytokines were determined. NLRP3 inflammasome and its components were studied by PCR and western blot. Results: LCA induced marked cholestatic liver damage as demonstrated by increased serum transaminases, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin, and bile acids. Examination of liver specimens confirmed the biochemical results. Nitro-oxidative stress parameters were significantly elevated along with reduced antioxidant capacity in hepatic tissue following LCA administration. LCA suppressed Nrf2 and its target genes and decreased the mRNA expression and binding capacity of Nrf2 as well as the mRNA expression of GCLm, GCLc, Nqo1, and HO-1. Additionally, LCA enhanced the activation of NF-κB, which was accompanied by elevations of inflammatory cytokines. Importantly, LCA induced the activation of NLRP3 inflammasome. LCA increased the expression of NLRP3, ASC, caspase-1, and IL-1β genes and proteins in hepatic tissue. The activities of IL-1β and caspase-1 were increased in the LCA group. Interestingly, vardenafil ameliorated LCA-induced hepatic injury and alleviated all biochemical, histopathological, and inflammatory parameters. Conclusions: These data elucidated the effects of Nrf2 inhibition and NLRP3 inflammasome activation in LCA-induced liver injury. The hepatoprotective activity of vardenafil in LCA-induced cholestatic damage may result from the drug’s ability to activate Nrf2 signaling and prevent the activation of NLRP3, which could suppress the inflammatory responses in hepatic tissue. Thus, vardenafil can be considered a novel anti-inflammatory remedy for cholestatic liver damage.

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Section: Discussionsupporting

confidence: 79%

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

El‐Agamy

Almaramhy

Ahmed

et al. 2018

Cell Physiol Biochem

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“…The restoration of NO‐cGMP‐PKG axis has been proven to be cytoprotective in different cardiovascular diseases6, 17, 18 including diabetic cardiomyopathy 5, 6, 12. Phosphodiesterase‐5A inhibitors block one of the main regulator of cGMP degradation thereby preserving and/or increasing intracellular cGMP concentration 4.…”

Section: Discussionmentioning

confidence: 99%

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

Mátyás

Németh

Oláh

et al. 2016

European J of Heart Fail

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AimsHeart failure with preserved ejection fraction (HFpEF) has a great epidemiological burden. The pathophysiological role of cyclic guanosine monophosphate (cGMP) signalling has been intensively investigated in HFpEF. Elevated levels of cGMP have been shown to exert cardioprotective effects in various cardiovascular diseases, including diabetic cardiomyopathy. We investigated the effect of long‐term preventive application of the phosphodiesterase‐5A (PDE5A) inhibitor vardenafil in diabetic cardiomyopathy‐associated HFpEF.Methods and resultsZucker diabetic fatty (ZDF) rats were used as a model of HFpEF and ZDF lean rats served as controls. Animals received vehicle or 10 mg/kg body weight vardenafil per os from weeks 7 to 32 of age. Cardiac function, morphology was assessed by left ventricular (LV) pressure–volume analysis and echocardiography at week 32. Cardiomyocyte force measurements were performed. The key markers of cGMP signalling, nitro‐oxidative stress, apoptosis, myocardial hypertrophy and fibrosis were examined. The ZDF animals showed diastolic dysfunction (increased LV/cardiomyocyte stiffness, prolonged LV relaxation time), preserved systolic performance, decreased myocardial cGMP level coupled with impaired protein kinase G (PKG) activity, increased nitro‐oxidative stress, enhanced cardiomyocyte apoptosis, and hypertrophic and fibrotic remodelling of the myocardium. Vardenafil effectively prevented the development of HFpEF by maintaining diastolic function (decreased LV/cardiomyocyte stiffness and LV relaxation time), by restoring cGMP levels and PKG activation, by lowering apoptosis and by alleviating nitro‐oxidative stress, myocardial hypertrophy and fibrotic remodelling.ConclusionsWe report that vardenafil successfully prevented the development of diabetes mellitus‐associated HFpEF. Thus, PDE5A inhibition as a preventive approach might be a promising option in the management of HFpEF patients with diabetes mellitus.

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“…The discovery of compounds such as haem-dependent sGC stimulators and haem-independent sGC activators that can stimulate the enzyme in a • NO-independent manner has led to the development of a clinical programme for the treatment of patients with pulmonary (arterial) hypertension (Ghofrani et al, 2013a), chronic thromboembolic pulmonary hypertension (Ghofrani et al, 2013b) and heart failure (Lapp et al, 2009) (for review see (Evgenov et al, 2006)). The sGC activator cinaciguat normalized vascular oxidative stress and coronary endothelial function in a rat model of myocardial infarction (Korkmaz et al, 2009b), a canine model of cardiopulmonary bypass (Radovits et al, 2011) and prevented endothelial dysfunction of isolated rat aorta when challenged with peroxynitrite (Korkmaz et al, 2013). Inhibitors of phosphodiesterases (PDE) act down-stream of sGC to increase cGMP levels and are used for multiple indications (for review see (Boswell-Smith et al, 2006)).…”

Section: Repair Therapy With Pharmacological Agentsmentioning

confidence: 99%

“…Likewise, therapy with the PDE5 inhibitor vardenafil prevented cardiovascular dysfunction in a rat model of T1DM ) and a canine model of cardiopulmonary bypass with hypothermic cardiac arrest . Vardenafil also improved endothelial function of isolated rat aorta upon ex vivo challenges with peroxynitrite (Korkmaz et al, 2009a) and hypochlorite (Radovits et al, 2013).…”

Section: Repair Therapy With Pharmacological Agentsmentioning

confidence: 99%

Targeting vascular (endothelial) dysfunction

Daiber

Steven

Weber

et al. 2016

British J Pharmacology

381

334

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Vascular dysfunction induced by hypochlorite is improved by the selective phosphodiesterase-5-inhibitor vardenafil

Cited by 16 publications

References 41 publications

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

Prevention of the development of heart failure with preserved ejection fraction by the phosphodiesterase‐5A inhibitor vardenafil in rats with type 2 diabetes

Targeting vascular (endothelial) dysfunction

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