Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway

Elrod, John W.; Greer, James J.M.; Lefer, David J.

doi:10.1152/ajpheart.00306.2006

Cited by 67 publications

(54 citation statements)

References 32 publications

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“…9 This is supported by compelling evidence from animal models indicating that the PDE5is such as sildenafil, tadalafil and vardenafil are cardioprotective in ischaemia-reperfusion injury (IRI) while suppressing cardiac arrhythmias and improving cardiac function. [10][11][12][13][14][15] Furthermore, small randomised controlled trials (RCTs) in systolic heart failure have shown an improvement in haemodynamic parameters and functional indices. 16 It is therefore important to establish whether there is benefit or harm in highrisk patients with ED.…”

mentioning

confidence: 99%

P6.11 Phosphodiesterase Type-5 Inhibitor Use in Type 2 Diabetes Is Associated With a Reduction in All Cause Mortality

Anderson¹,

Hutchings²,

Kwok³

et al. 2014

ARTRES

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Objective Experimental evidence has shown potential cardioprotective actions of phosphodiesterase type-5 inhibitors (PDE5is). We investigated whether PDE5i use in patients with type 2 diabetes, with high-attendant cardiovascular risk, was associated with altered mortality in a retrospective cohort study. Research design and methods Between January 2007 and May 2015, 5956 men aged 40-89 years diagnosed with type 2 diabetes before 2007 were identified from anonymised electronic health records of 42 general practices in Cheshire, UK, and were followed for 7.5 years. HRs from multivariable survival (accelerated failure time, Weibull) models were used to describe the association between on-demand PDE5i use and all-cause mortality.Results Compared with non-users, men who are prescribed PDE5is (n=1359) experienced lower percentage of deaths during follow-up (19.1% vs 23.8%) and lower risk of all-cause mortality (unadjusted HR=0.69 (95% CI: 0.64 to 0.79); p<0.001)). The reduction in risk of mortality (HR=0.54 (0.36 to 0.80); p=0.002) remained after adjusting for age, estimated glomerular filtration rate, smoking status, prior cerebrovascular accident (CVA) hypertension, prior myocardial infarction (MI), systolic blood pressure, use of statin, metformin, aspirin and β-blocker medication. PDE5i users had lower rates of incident MI (incidence rate ratio (0.62 (0.49 to 0.80), p<0.0001) with lower mortality (25.7% vs 40.1% deaths; age-adjusted HR=0.60 (0.54 to 0.69); p=0.001) compared with non-users within this subgroup. Conclusion In a population of men with type 2 diabetes, use of PDE5is was associated with lower risk of overall mortality and mortality in those with a history of acute MI.Erectile dysfunction (ED) is increasingly recognised as an early marker of cardiovascular disease (CVD).

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mentioning

confidence: 99%

P6.11 Phosphodiesterase Type-5 Inhibitor Use in Type 2 Diabetes Is Associated With a Reduction in All Cause Mortality

Anderson¹,

Hutchings²,

Kwok³

et al. 2014

ARTRES

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“…Interestingly, a low dose of sildenafil (0.06 mg/kg) given at reperfusion did not alter cGMP levels, but was able to reduce infarct size in the wild-type, eNOS null, and iNOS null mice after IR [214] .…”

Section: Effects Of Pde5 Inhibitors On Myocardial Ischemiareperfusionmentioning

confidence: 93%

“…Certain disease states may affect the cardioprotective effect of PDE5 inhibitors. In particular, the infarct size reducing effect of sildenafil in the heart is abolished in diabetic dogs [216] and mice [214] . This blunting effect may be a result of abolishment of sildenafil-induced enhancement of PKG expression in the diseased hearts [216] .…”

Section: Effects Of Pde5 Inhibitors On Myocardial Ischemiareperfusionmentioning

confidence: 95%

“…Flow-mediated dilation of the brachial artery was also improved by acute and long term treatment with sildenafil in patients with type 2 diabetes [232] . This is especially interesting because myocardial protection is lost in animal models of diabetes [205,214] . Very importantly, the sildenafil induced protection of the endothelium from IR injury was demonstrated in a study involving 10 healthy male volunteers [233] .…”

Section: Clinical Applications Of Pde5 Inhibitorsmentioning

confidence: 99%

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Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

Rao

2008

Acta Pharmacol Sin

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Phosphodiesterases (PDEs) are enzymes that degrade cellular cAMP and cGMP and are thus essential for regulating the cyclic nucleotides. At least 11 families of PDEs have been identified, each with a distinctive structure, activity, expression, and tissue distribution. The PDE type-3, -4, and -5 (PDE3, PDE4, PDE5) are localized to specific regions of the cardiomyocyte, such as the sarcoplasmic reticulum and Z-disc, where they are likely to influence cAMP/cGMP signaling to the end effectors of contractility. Several PDE inhibitors exhibit remarkable hemodynamic and inotropic properties that may be valuable to clinical practice. In particular, PDE3 inhibitors have potent cardiotonic effects that can be used for short-term inotropic support, especially in situations where adrenergic stimulation is insufficient. Most relevant to this review, PDE inhibitors have also been found to have cytoprotective effects in the heart. For example, PDE3 inhibitors have been shown to be cardioprotective when given before ischemic attack, whereas PDE5 inhibitors, which include three widely used erectile dysfunction drugs (sildenafil, vardenafil and tadalafil), can induce remarkable cardioprotection when administered either prior to ischemia or upon reperfusion. This article provides an overview of the current laboratory and clinical evidence, as well as the cellular mechanisms by which the inhibitors of PDE3, PDE4 and PDE5 exert their beneficial effects on normal and ischemic hearts. It seems that PDE inhibitors hold great promise as clinically applicable agents that can improve cardiac performance and cell survival under critical situations, such as ischemic heart attack, cardiopulmonary bypass surgery, and heart failure.

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“…However, in another study, we 5 demonstrated that the PDE5 inhibitor tadalafil, which was administrated by gastric gavage (10 mg/kg) 2 hours before coronary occlusion, reduced myocardial infarct size in a rat myocardial ischemia/reperfusion model. Moreover, Salloum et al 6 and Elrod et al 7 reported that treatment with sildenafil at 5 minutes before coronary reperfusion significantly reduced myocardial infarct size in rabbits or mice subjected to ischemia induced by 30 minutes of left coronary artery occlusion followed by coronary reperfusion. In a cell culture experiment, Das et al 8 treated cultured adult mouse ventricular myocytes with sildenafil for 1 hour before 40 minutes of simulated ischemia followed by 18 hours of reoxygenation.…”

Section: Cardioprotection Of Pde5 Inhibitors In Experimental Acute Mymentioning

confidence: 99%

Is Inhibition of Phosphodiesterase Type 5 by Sildenafil a Promising Therapy for Volume-Overload Heart Failure?

Dai

Kloner

2012

Circulation

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Phosphodiesterase type 5 (PDE5) is an enzyme that belongs to a large family of cyclic nucleotide PDEs that catalyze cAMP and cGMP. cAMP and cGMP are 2 essential intracellular second messengers regulating many different cellular functions of living cells. PDE5 specifically breaks down the substrate cGMP. Inhibition of PDE5 increases intracellular cGMP levels by inhibiting its degradation. Sildenafil (Viagra) is a potent and selective inhibitor of cGMPspecific PDE5 and is the first oral treatment for men with erectile dysfunction; it was approved by Food and Drug Administration on March 27, 1998. Sildenafil binds to the catalytic site of PDE5 and inhibits the degradation of intracellular cGMP in smooth muscle within the corpus cavernosum, resulting in increased levels of cGMP, which cause smooth muscle cell relaxation and vasodilation and improve erectile function. 1,2 Article see p 1390 Cardioprotection of PDE5 Inhibitors in Experimental Acute Myocardial InfarctionIn recent years, there has been growing interest in therapeutic applications of PDE5 inhibitors for cardiovascular diseases other than erectile dysfunction. Some experimental studies demonstrated direct cardioprotective effects of inhibition of PDE5 in experimental acute myocardial infarction models. In 2002, Ockaili et al 3 treated rabbits with sildenafil (0.7 mg/kg given as an intravenous bolus) either 30 minutes or 24 hours before coronary occlusion. The rabbits were then subjected to 30 minutes of left anterior descending coronary artery occlusion followed by 3 hours of reperfusion, and the infarct size was measured by tetrazolium staining. The results demonstrated for the first time that sildenafil had a powerful preconditioning-like effect against myocardial ischemia/reperfusion injury. Our research group 4 injected 1.45 mg/kg intravenous sildenafil or saline 30 minutes before ischemia in anesthetized open-chest rabbits subjected to 30 minutes of left anterior descending coronary occlusion followed by 3 hours of reperfusion. Compared with saline, sildenafil significantly decreased coronary resistance in the ischemic risk area, slightly increased regional myocardial blood flow, and significantly decreased left ventricular end-diastolic pressure, although it did not attenuate acute ischemic left ventricular dilation or reduce infarct size. However, in another study, we 5 demonstrated that the PDE5 inhibitor tadalafil, which was administrated by gastric gavage (10 mg/kg) 2 hours before coronary occlusion, reduced myocardial infarct size in a rat myocardial ischemia/reperfusion model. Moreover, Salloum et al 6 and Elrod et al 7 reported that treatment with sildenafil at 5 minutes before coronary reperfusion significantly reduced myocardial infarct size in rabbits or mice subjected to ischemia induced by 30 minutes of left coronary artery occlusion followed by coronary reperfusion. In a cell culture experiment, Das et al 8 treated cultured adult mouse ventricular myocytes with sildenafil for 1 hour before 40 minutes of simulated ischemia followed by 18...

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Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway

Abstract: Elrod JW, Greer JJM, Lefer DJ. Sildenafil-mediated acute cardioprotection is independent of the NO/cGMP pathway.

Cited by 67 publications

References 32 publications

P6.11 Phosphodiesterase Type-5 Inhibitor Use in Type 2 Diabetes Is Associated With a Reduction in All Cause Mortality

P6.11 Phosphodiesterase Type-5 Inhibitor Use in Type 2 Diabetes Is Associated With a Reduction in All Cause Mortality

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

Is Inhibition of Phosphodiesterase Type 5 by Sildenafil a Promising Therapy for Volume-Overload Heart Failure?

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