Sildenafil (Viagra) reduces arrhythmia severity during ischaemia 24 h after oral administration in dogs

Nagy, Orsolya; Hajnal, A.; Parratt, J. R.; Végh, Ágnes

doi:10.1038/sj.bjp.0705658

Cited by 47 publications

(33 citation statements)

References 18 publications

(27 reference statements)

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“…In the past decade, we have shown that PDE-5 inhibitors (including sildenafil, vardenafil and tadalafil) induce powerful cardioprotective effects against ischemia/reperfusion injury [30,37,42,44]. Our original findings are independently confirmed by several groups [12,36,46]. Moreover, PDE-5 inhibitors attenuate cardiac dysfunction in doxorubicin-induced cardiomyopathy [15,25,26], myocardial infarction-induced heart failure [43] and hypertrophy induced by pressure overload in mice [51].…”

Section: Introductionsupporting

confidence: 70%

Chronic treatment with long acting phosphodiesterase-5 inhibitor tadalafil alters proteomic changes associated with cytoskeletal rearrangement and redox regulation in Type 2 diabetic hearts

Koka

Kukreja

2012

Basic Res Cardiol

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Diabetic patients are prone to metabolic perturbations that progressively contribute to structural, functional and proteomic alterations in the myocardium. Phosphodiesterase-5 (PDE-5) inhibitors exhibit cardioprotective effects against ischemic/reperfusion injury, however the effects of chronic administration of PDE-5 inhibitors, particularly under diabetic conditions, remain unknown. Hence, the present study was designed to identify novel protein targets related to long-acting PDE-5 inhibitor tadalafil-induced cardioprotection in diabetes. Using two-dimensional differential in-gel electrophoresis with 3 CyDye labeling and MALDI-TOF/TOF tandem mass spectrometry we identified alterations in the expressions of cardiac proteins in diabetic db/db mice treated with tadalafil. Tadalafil reversed the coordinated alterations of cytoskeletal/contractile proteins such as myosin light chain (MLY) 2 and 4, myosin heavy chain α and myosin-binding protein C which contributes to contractile dysfunction. The expression of intermediate filament protein vimentin and extra-cellular matrix proteins like cysteine and glycine rich protein-3 and collagen type VI α were upregulated in db/db mice indicating cardiac remodeling in diabetes. These detrimental proteomic alterations were reflected in cardiac function which were reversed in tadalafil treated mice. Tadalafil also enhanced antioxidant enzyme glutathione S-transferase Kappa-1 (GSKT-1) and downregulated redox regulatory chaperones like heat shock protein 8 (HSPA8), and 75 kD glucose regulatory protein (75GRP). Furthermore, tadalafil treatment significantly attenuated GSSG/GSH ratio and improved the metabolic status of db/db mice. Chronic treatment with tadalafil in db/db mice modulates proteins involved in cytoskeletal rearrangement and redox signaling of the heart, which may explain the beneficial effects of PDE-5 inhibition in diabetes.

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Section: Introductionsupporting

confidence: 70%

Chronic treatment with long acting phosphodiesterase-5 inhibitor tadalafil alters proteomic changes associated with cytoskeletal rearrangement and redox regulation in Type 2 diabetic hearts

Koka

Kukreja

2012

Basic Res Cardiol

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“…Moreover, post conditioning, that is, administration of sildenafil or vardenafil at reperfusion, also induced significant cardioprotection, similar to the preconditioning-like effects (Salloum et al, 2007). Furthermore, a previous study by Nagy et al (2004) showed, in dogs, that orally administered sildenafil decreases the incidence of severe life-threatening ventricular arrhythmias, which arise early after coronary artery occlusion.…”

Section: Regional Myocardial Ischaemia/reperfusion Injurymentioning

confidence: 82%

Targeting phosphodiesterase 5 as a therapeutic option against myocardial ischaemia/reperfusion injury and for treating heart failure

Korkmaz‐Icöz

Radovits

Szabó

2017

British J Pharmacology

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Phosphodiesterase type 5 (PDE5) selectively hydrolyses the second messenger cGMP into 5 0 -GMP, thereby regulating its intracellular concentrations. Dysregulation of the cGMP-dependent pathway plays a significant role in various cardiovascular diseases. Therefore, its modulation by drugs, such as PDE5 inhibitors, may represent an effective therapeutic approach. There are currently four PDE5 inhibitors available for the treatment of erectile dysfunction: sildenafil, vardenafil, tadalafil and avanafil. Sildenafil and tadalafil have also received Food and Drug Administration approval for the treatment of pulmonary arterial hypertension. This review summarizes the pharmacological aspects and clinical potential of PDE5 inhibition for the treatment of myocardial ischaemia/reperfusion injury and heart failure.This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc Abbreviations Bcl 2, B-cell lymphoma 2; HF, heart failure; IR, ischemia/reperfusion; KCa, calcium-activated potassium channel; LAD, left anterior descending artery; PGC-1α, PPAR gamma coactivator 1-alpha; SIRT1, sirtuin 1 LINKED ARTICLES

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“…22 Recent research in animal models has reported that sildenafil administration, probably by reducing cGMP catabolism and therefore increasing intracellular bioavailability of this mediator, is associated with a significant reduction of myocardial infarct size and incidence of arrhythmias after coronary artery ligation, an effect that appears to mimic ischemic preconditioning. 10,11,23 Of note, controversial results have also been reported, 12 and, most importantly, the possibility of modulating endothelial sensitivity to IR via changes in cGMP bioavailability has never been tested in humans.…”

Section: Discussionmentioning

confidence: 99%

Sildenafil Prevents Endothelial Dysfunction Induced by Ischemia and Reperfusion via Opening of Adenosine Triphosphate–Sensitive Potassium Channels

et al. 2005

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Background— Animal studies have demonstrated that administration of sildenafil can limit myocardial damage induced by prolonged ischemia, an effect that appears to be mediated by opening of adenosine triphosphate–sensitive potassium (K ATP ) channels. No study has investigated whether sildenafil can also prevent the impairment in endothelium-dependent vasodilatation induced by ischemia-reperfusion (IR) in humans. Methods and Results— In a double-blind, placebo-controlled, crossover design, 10 healthy male volunteers (25 to 45 years old) were randomized to oral sildenafil (50 mg) or placebo. Two hours later, endothelium-dependent, flow-mediated dilatation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion). Seven days later, subjects received the other treatment (ie, placebo or sildenafil) and underwent the same protocol. Pre-IR radial artery diameter and FMD, as well as baseline radial artery diameter after IR, were similar between visits ( P =NS). After placebo administration, IR significantly blunted FMD (before IR: 7.9±1.1%; after IR: 1.2±0.7%, P <0.01). Importantly, sildenafil limited this impairment in endothelium-dependent vasodilatation (before IR: 7.0±0.9%; after IR: 6.2±1.1%, P =NS; P <0.01 compared with placebo). In a separate protocol, this protective effect was completely prevented by previous administration of the sulfonylurea glibenclamide (glyburide, 5 mg), a blocker of K ATP channels (n=7; FMD before IR: 10.3±1.5%; after IR: 1.3±1.4%, P <0.05). Conclusions— In humans, oral sildenafil induces potent protection against IR-induced endothelial dysfunction through opening of K ATP channels. Further studies are needed to test the potential clinical implications of this finding.

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Sildenafil (Viagra) reduces arrhythmia severity during ischaemia 24 h after oral administration in dogs

Cited by 47 publications

References 18 publications

Chronic treatment with long acting phosphodiesterase-5 inhibitor tadalafil alters proteomic changes associated with cytoskeletal rearrangement and redox regulation in Type 2 diabetic hearts

Chronic treatment with long acting phosphodiesterase-5 inhibitor tadalafil alters proteomic changes associated with cytoskeletal rearrangement and redox regulation in Type 2 diabetic hearts

Targeting phosphodiesterase 5 as a therapeutic option against myocardial ischaemia/reperfusion injury and for treating heart failure

Sildenafil Prevents Endothelial Dysfunction Induced by Ischemia and Reperfusion via Opening of Adenosine Triphosphate–Sensitive Potassium Channels

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