Enhanced cardioprotection against ischemia-reperfusion injury with a dipyridamole and low-dose atorvastatin combination

Ye, Yumei; Lin, Yu Li; Perez‐Polo, Regino; Huang, Ming He; Hughes, Michael G.; McAdoo, David J.; Manickavasagam, Saraswathy; Uretsky, Barry F.; Birnbaum, Yochai

doi:10.1152/ajpheart.00210.2007

Cited by 48 publications

(46 citation statements)

References 51 publications

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“…Indeed the combination of a statin with an inhibitor of adenosine uptake into the cell, dipyridamole and cilostazol, and subsequent increased extracellular adenosine concentrations potentiate the infarct size-limiting effect of statins in animals. 36,37 Our observations support caffeine abstinence in patients treated with a statin to fully utilize its clinical benefit. …”

Section: Perspectivessupporting

confidence: 59%

Upregulation of Ecto-5′-Nucleotidase by Rosuvastatin Increases the Vasodilator Response to Ischemia

et al. 2010

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Abstract-3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are effective in the primary and secondary prevention of cardiovascular events. Although originally developed to improve lipid profile, statins have demonstrated a surplus of beneficial pleiotropic effects, including improved endothelial function, reduced inflammation, and increased tolerance to ischemia-reperfusion injury. In preclinical studies, increased ecto-5Ј-nucleotidase activity, the key enzyme in extracellular adenosine formation, plays an important role in these effects. Because human data are absent, we explored the effects of rosuvastatin on ecto-5Ј-nucleotidase activity and the clinical relevance of increased extracellular adenosine during ischemia in humans in vivo. The forearm vasodilator responses to 3 increasing periods of forearm ischemia (2, 5, and 13 minutes) were determined during placebo and caffeine (an adenosine receptor antagonist) infusion into the brachial artery. At the end of an 8-day treatment period with rosuvastatin (20 mg per day), this whole procedure was repeated. During both experiments, ecto-5Ј-nucleotidase activity was determined. Vasodilator responses are expressed as the percentage increase in forearm blood flow ratio from baseline. Rosuvastatin increased ecto-5Ј-nucleotidase activity by 49Ϯ17% and enhanced the vasodilator response after 2, 5, and 13 minutes of ischemia in the absence (146Ϯ19, 330Ϯ26, and 987Ϯ133 to 312Ϯ77, 566Ϯ107, and 1533Ϯ267) but not in the presence of caffeine ( Key Words: adenosine Ⅲ ecto-5Ј-nucleotidase Ⅲ caffeine Ⅲ ischemia Ⅲ reactive hyperemia 3 -Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are effective in the primary and secondary prevention of cardiovascular events. 1,2 Although originally developed to improve lipid profile, statins have demonstrated a surplus of beneficial pleiotropic effects, including improved endothelial function, reduced inflammation, and increased tolerance to ischemia-reperfusion injury. [3][4][5][6][7] These effects are independent of plasma cholesterol lowering and improve outcome after cardiovascular events. 8,9 Increased extracellular adenosine formation has been implicated as one of the underlying mechanisms. This is supported by several preclinical studies demonstrating the activation of ecto-5Ј-nucleotidase (CD73) activity, increased stimulation of adenosine receptors, and adenosine-mediated protection against ischemia-reperfusion injury by statins. 10 -12 The enzyme CD73 dephosphorylates extracellular AMP, which forms the rate-limiting step in the formation of extracellular adenosine. 13 We recently demonstrated increased extracellular adenosine formation in healthy human volunteers after a 1-week treatment with rosuvastatin using a pharmacological approach. In addition, we demonstrated rosuvastatin-induced augmentation of postocclusive reactive hyperemia (PORH). 5 However, we did not assess CD73 activity as a potential source of extracellular adenosine, nor did we investigate the role of adenosine in rosuvasta...

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Section: Perspectivessupporting

confidence: 59%

Upregulation of Ecto-5′-Nucleotidase by Rosuvastatin Increases the Vasodilator Response to Ischemia

et al. 2010

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“…Mean±SEM. [4,6,20,21] . Similarly, acute pretreatment with highdose SIM (10 μmol/L) was shown to attenuate the ischemiareperfusion injury in isolated rat hearts, but chronic treatment of low-dose SIM did not [22] .…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Yang

Geng³

et al. 2012

Acta Pharmacol Sin

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Aim: The cholesterol-lowering drugs statins could enhance the activities of endothelial nitric oxide synthase (eNOS) and protect myocardium during ischemia and reperfusion. The aim of this study was to examine whether protein kinase A (PKA) was involved in statinmediated eNOS phosphorylation and cardioprotection. Methods: 6-Month-old Chinese minipigs (20-30 kg) underwent a 1.5-h occlusion and 3-h reperfusion of the left anterior descending coronary artery (LAD). In the sham group, the LAD was encircled by a suture but not occluded. Hemodynamic and cardiac function was monitored using a polygraph. Plasma activity of creatine kinase and the tissue activities of PKA and NOS were measured spectrophotometrically. p-CREB, eNOS and p-eNOS levels were detected using Western blotting. Sizes of the area at risk, the area of no-reflow and the area of necrosis were measured morphologically. Results: Pretreatment of the animals with simvastatin (SIM, 2 mg/kg, po) before reperfusion significantly decreased the plasma activity of creatine kinase, an index of myocardial necrosis, and reduced the no-reflow size (from 50.4%±2.4% to 36.1%±2.1%, P<0.01) and the infarct size (from 79.0%±2.7% to 64.1%±4.5%, P<0.01). SIM significantly increased the activities of PKA and constitutive NOS, and increased Ser 133 p-CREB protein, Ser 1179 p-eNOS, and Ser 635 p-eNOS in ischemic myocardium. Intravenous infusion of the PKA inhibitor H-89 (1 μg·kg -1 ·min -1 ) partially abrogated the SIM-induced cardioprotection and eNOS phosphorylation. In contrast, intravenous infusion of the eNOS inhibitor L-NNA (10 mg·kg -1 ) completely abrogated the SIM-induced cardioprotection and eNOS phosphorylation during ischemia and reperfusion, but did not affect the activity of PKA. Conclusion: Pretreatment with a single dose of SIM 2.5 h before reperfusion attenuates myocardial no-reflow and infarction through increasing eNOS phosphorylation at Ser 1179 and Ser 635 that was partially mediated via the PKA signaling pathway.

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“…Further studies are probably needed to search for alternative mode of administration (chewable, intravenous, or even higher loading dose) to achieve effective ticagrelor blood levels by the time reperfusion occurs. Additional studies are needed to evaluate the effects of ticagrelor treatment on cardiac remodeling and heart function after myocardial infarction.In addition to ticagrelor, 2 other antiplatelet agents, dipyridamole 51,52 and cilostazol, 53 also prevent the reuptake of adenosine and have been shown to limit myocardial IS. However, both also inhibit phosphodiesterase-III, increasing intracellular levels of cAMP making comparisons difficult.…”

mentioning

confidence: 99%

Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

Ye¹,

Birnbaum

Perez‐Polo

et al. 2015

ATVB

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108

111

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Objective-In addition to P2Y 12 receptor antagonism, ticagrelor inhibits adenosine cell uptake. Prior data show that 7-day pretreatment with ticagrelor limits infarct size. We explored the acute effects of ticagrelor and clopidogrel on infarct size and potential long-term effects on heart function. Approach and Results-Rats underwent 30-minute ischemia per 24-hour reperfusion. (1) Ticagrelor (10 or 30 mg/kg) or clopidogrel (12.5 mg/kg) was given via intraperitoneal injection 5 minutes before reperfusion. (2) Rats received ticagrelor acute (intraperitoneal; 30 mg/kg), chronic (oral; 300 mg/kg per day) for 4 weeks starting 1 day after reperfusion or the combination (acute+chronic). Another group received clopidogrel (intraperitoneal [12.5 mg/kg]+oral [62.5 mg/kg per day]) for 4 weeks.(1) Ticagrelor dose-dependently reduced infarct size, 10 mg/kg (31.5%±1.8%; P<0.001) and 30 mg/ kg (21.4%±2.6%; P<0.001) versus control (45.3±1.7%), whereas clopidogrel had no effect (42.4%±2.6%). Ticagrelor, but not clopidogrel, increased myocardial adenosine levels, increased phosphorylation of Akt, endothelial NO synthase, and extracellular-signal-regulated kinase 1/2 4 hours after reperfusion and decreased apoptosis. (2) After 4 weeks, left ventricular ejection fraction was reduced in the vehicle-treated group (44.8%±3.5%) versus sham (77.6%±0.9%).All ticagrelor treatments improved left ventricular ejection fraction, acute (69.5%±1.6%), chronic (69.2%±1.0%), and acute+chronic (76.3%±1.2%), whereas clopidogrel had no effect (37.4%±3.7%). Ticagrelor, but not clopidogrel, attenuated fibrosis and decreased collagen-III mRNA levels 4 weeks after ischemia/reperfusion. Ticagrelor, but not clopidogrel, attenuated the increase in proinflammatory tumor necrosis factor-α, interleukin-1β, and interleukin-18, and increased anti-inflammatory 15-epi-lipoxin-A 4 levels. Conclusions-Ticagrelor, but not clopidogrel, administered just before reperfusion protects against reperfusion injury. This acute treatment or chronic ticagrelor for 4 weeks or their combination improved heart function, whereas clopidogrel, despite achieving a similar degree of platelet inhibition, had no effect. addition to platelet inhibition, ticagrelor, but not clopidogrel, has protective effects against ischemia-reperfusion that may help explain the differences in clinical benefit in the PLATO trial. 7,8 However, a recent multicenter, randomized, double-blind clinical trial did not show a clear clinical benefit in patients with STEMI receiving ticagrelor en route to the hospital versus in the catheterization laboratory. 16 As the study was not powered for benefit on cardiovascular events, it is inconclusive about the hypothesis that administration of ticagrelor after onset of ischemia (in contrast to pretreatment just before reperfusion) can ameliorate reperfusion injury. In addition, as the median time difference between the prehospital and the in-hospital ticagrelor administration groups was only 31 minutes, 16 it is plausible that ticagrelor absorption was insufficient an...

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Enhanced cardioprotection against ischemia-reperfusion injury with a dipyridamole and low-dose atorvastatin combination

Cited by 48 publications

References 51 publications

Upregulation of Ecto-5′-Nucleotidase by Rosuvastatin Increases the Vasodilator Response to Ischemia

Upregulation of Ecto-5′-Nucleotidase by Rosuvastatin Increases the Vasodilator Response to Ischemia

Phosphorylation of endothelial NOS contributes to simvastatin protection against myocardial no-reflow and infarction in reperfused swine hearts: partially via the PKA signaling pathway

Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

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