Effect of Sildenafil on Reperfusion Function, Infarct Size, and Cyclic Nucleotide Levels in the Isolated Rat Heart Model

Toit, Eugene F. Du; Rossouw, E; Salie, Ruduwaan; Opie, Lionel H.; Lochner, Amanda

doi:10.1007/s10557-005-6894-2

Cited by 54 publications

(52 citation statements)

References 24 publications

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“…24 The PDE 5 inhibitor sildenafil decreases infarct size, and this protection is associated with increased myocardial cyclic guanosine monophosphate and reduced cAMP levels in isolated rat hearts. 25 On the whole, the by-now well-founded concept of localized signaling through cAMP provides an attractive avenue for more specific drug therapy and, in the present study by Takahasi et al, 5 provides a potential explanation for an additive protection by AC overexpression and propranolol.…”

Section: Article P 388mentioning

confidence: 55%

Cyclic Adenosine Monophosphate in Acute Myocardial Infarction With Heart Failure

2006

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C yclic adenosine monophosphate (cAMP) is a tightly regulated second messenger that is critically involved in many intracellular processes. In cardiomyocytes, the activation of a number of membrane receptors, notably ␤-receptors and muscarinic receptors, acts through stimulatory or inhibitory G-proteins (G␣s/G␣i) on adenylyl cyclase (AC), which synthesizes cAMP from ATP. cAMP is degraded by phosphodiesterases (PDE). Thereafter, cAMP activates protein kinase A (PKA), which, in turn, through phosphorylation of L-type calcium channels, ryanodine receptors, phospholamban, and troponin I, improves excitationcontraction coupling and increases heart rate, as well as contraction amplitude and relaxation. PKA also phosphorylates nuclear cAMP-response element binding proteins to activate transcription. 1 There are at least 9 isoforms of AC; the mammalian myocardium expresses mainly AC V and VI. AC V is the predominant isoform in adult cardiac tissue, whereas AC VI expression decreases with age. Both isoforms are phosphorylated by PKA and thereby inhibited, thus providing a feedback regulation and potential desensitization pathway. 2,3 Transgenic mice with cardiac-directed overexpression of AC VI have normal cAMP and cardiac function at rest but increased responses in both cAMP and function to ␤-adrenergic stimulation, 4 as confirmed in the present study by Takahasi et al. 5 Article p 388The prevailing notion is that increased myocardial cAMP in settings of acute myocardial ischemia is detrimental. In fact, ␤-adrenergic agonists that increase cAMP formation disrupt perfusion-contraction matching and promote infarction in controlled animal models of myocardial ischemia, both by increasing myocardial energetic requirements and by an unfavorable flow redistribution away from the ischemic subendocardium. 6 Apart from increasing infarct size, cAMP promotes ventricular tachyarrhythmias in ischemia/reperfusion. 7 Although increased cAMP acutely increases left ventricular function in heart failure, most trials with either ␤-adrenergic agonists or PDE inhibitors have revealed increased mortality, possibly secondary to tachyarrhythmias. 1 The present article by Takahashi et al 5 challenges the concept that cAMP in subacute myocardial infarction with heart failure is bad. They subjected transgenic mice with cardiac-directed overexpression of AC VI to permanent coronary ligation and found 17-fold-elevated AC protein content and 4.3-fold-increased cAMP formation, along with reduced mortality, over a 1-week observation period. The reduced mortality in the AC VI-overexpressing mice was associated with a nonsignificant increase in ventricular extrasystoles but reduced bradyarrhythmias. The better conduction properties in the AC VI-overexpressing mice were not mechanistically explained but are possibly related to connexin 43 expression, which is reduced in heart failure 8 and increased by catecholamines in a PKA-dependent manner. 9 Reduced mortality is a robust and undisputable end point in mice and humans, and in this respect, the present...

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Section: Article P 388mentioning

confidence: 55%

Cyclic Adenosine Monophosphate in Acute Myocardial Infarction With Heart Failure

2006

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“…By selectively inhibiting phosphodiesterase type-5 (PDE-5) and thus effectively reducing the breakdown of cGMP, sildenafil administration can markedly improve pulmonary and cardiac functional capacity, and hemodynamics (du Toit et al, 2005;Traverse et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Angiogenesis and improved cerebral blood flow in the ischemic boundary area detected by MRI after administration of sildenafil to rats with embolic stroke

Li¹,

Jiang²,

Zhang³

et al. 2007

Brain Research

106

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To dynamically investigate the long-term response of an ischemic lesion in rat brain to the administration of sildenafil, male Wistar rats subjected to embolic stroke were treated with sildenafil (n=11) or saline (n=10) at a dose of 10mg/Kg administered subcutaneously 24-hours after stroke and daily for an additional 6-days. Magnetic resonance images were acquired and functional performance was measured in all animals at 1-day, 2-days and weekly for 6-weeks post-stroke. All rats were sacrificed 6-weeks after stroke and endothelial barrier antigen immunostaining was employed for morphological analysis and quantification of cerebral vessels. Map-ISODATA was computed from T 1 , T 2 and T 1sat maps. ISODATA derived tissue signatures characterize the degree of ischemic injury. Based on the map-ISODATA calculated at 6-weeks, the ischemic lesion for each animal was divided into two specific regions, the ischemic boundary and ischemic core. The temporal profiles of cerebral blood flow (CBF) and tissue signature were retrospectively tracked in these two regions and were compared with histological evaluation and functional outcome. After 1-week of sildenafil treatment, the ischemic lesion exhibited two significantly different regions, with higher CBF level and correspondingly, lower tissue signature value in the boundary region than in the core region. Sildenafil treatment did not significantly reduce the lesion size, but did enhance angiogenesis. Functional performance was significantly increased after sildenafil treatment compared with the control group. Administration of sildenafil to rats with embolic stroke enhances angiogenesis and selectively increases the CBF level in the ischemic boundary, and improves neurological functional recovery compared to saline-treated rats.

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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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Effect of Sildenafil on Reperfusion Function, Infarct Size, and Cyclic Nucleotide Levels in the Isolated Rat Heart Model

Cited by 54 publications

References 24 publications

Cyclic Adenosine Monophosphate in Acute Myocardial Infarction With Heart Failure

Cyclic Adenosine Monophosphate in Acute Myocardial Infarction With Heart Failure

Angiogenesis and improved cerebral blood flow in the ischemic boundary area detected by MRI after administration of sildenafil to rats with embolic stroke

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

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