Improved Left Ventricular Function and Reduced Necrosis after Myocardial Ischemia/Reperfusion in Rabbits Treated with Ranolazine, an Inhibitor of the Late Sodium Channel

Hale, Sharon L.; Leeka, Justin; Kloner, Robert A.

doi:10.1124/jpet.106.103242

Cited by 64 publications

(52 citation statements)

References 31 publications

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“…Reperfusion is also thought to increase Na ϩ influx by washing out extracellular protons, which reactivates Na ϩ /H ϩ exchange, which has been attenuated by accumulation of extracellular protons after long-sustained ischemia. The contribution of these mechanisms of Na ϩ overload to myocardial necrosis has been supported by the findings that inhibition of the Na ϩ /H ϩ exchanger or Na ϩ channel during ischemia-reperfusion significantly limits myocardial infarct size (9,18).…”

Section: Contribution Of Suppression Of Gap Junction-meditated Injurymentioning

confidence: 52%

δ-Opioid receptor activation before ischemia reduces gap junction permeability in ischemic myocardium by PKC-ε-mediated phosphorylation of connexin 43

Miura

Yano²,

Naitoh³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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.-The aim of this study was to examine the hypothesis that ␦-opioid receptor activation before ischemia suppresses gap junction (GJ) permeability by PKC-mediated connexin 43 (Cx43) modulation, which contributes to infarct size limitation afforded by the ␦-opioid receptor activation. A ␦-opioid receptor agonist, [D-Ala 2 ,D-Leu 5 ]-enkephalin acetate (DADLE, 300 nM), was used in place of preconditioning (PC) ischemia to trigger PC mechanisms in rat hearts. GJ permeability during ischemia, which was assessed by Lucifer yellow, was reduced by DADLE to 47% of the control level, and this effect of DADLE was almost abolished by a PKC-ε inhibitor [PKC-ε translocation inhibitory peptide (PKC-ε-TIP)] but was not affected by a PKC-␦ inhibitor (rottlerin). After DADLE infusion, PKC-ε, but not PKC-␦, was coimmunoprecipitated with Cx43, and the level of phosphorylation of Cx43 at a PKCdependent site (Ser 368 ) was significantly elevated during ischemia. DADLE reduced infarct size after 35 min of ischemia followed by 2 h of reperfusion by 69%, and PKC-ε-TIP and rottlerin eliminated 48% and 63%, respectively, of the infarct size-limiting effect of DADLE. Infusion of a GJ blocker, heptanol, before reperfusion reduced infarct size by 36%, and this protection was not enhanced by preischemic infusion of rottlerin ϩ DADLE, which allows PKC-ε activation by DADLE. These results suggest that phosphorylation of Cx43 by PKC-ε plays a crucial role in ␦-opioid-induced suppression of GJ permeability in ischemic myocardium and that this modulation of the GJ is possibly an adjunct mechanism of infarct size limitation afforded by preischemic ␦-opioid receptor activation. infarct size; preconditioning PRECONDITIONING (PC) with brief ischemia substantially salvages the myocardium from necrosis after sustained ischemia and reperfusion (22,35). This cardioprotective effect of PC has been demonstrated not only in intact hearts, but also in isolated cardiomyocytes subjected to simulated ischemia, indicating that PC can directly protect each cardiomyocyte under ischemia-reperfusion. However, the extent of protection by PC is generally less in isolated cell preparations than in whole hearts (1,19,22,35). Furthermore, there is also evidence to suggest that a part of myocardial protection by PC in whole hearts is achieved by chemical uncoupling of cardiomyocytes during ischemia-reperfusion, resulting in suppressed extension of injury within the area at risk (8,20,23,28). In our recent studies (20, 23), both ischemic PC and an opener of the mitochondrial ATP-sensitive K ϩ (mK ATP ) channel, which is involved in the PC mechanism, significantly reduced gap junction permeability to a chemical tracer in the ischemic rabbit myocardium.

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Section: Contribution Of Suppression Of Gap Junction-meditated Injurymentioning

confidence: 52%

δ-Opioid receptor activation before ischemia reduces gap junction permeability in ischemic myocardium by PKC-ε-mediated phosphorylation of connexin 43

Miura

Yano²,

Naitoh³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…41 Furthermore, the pulmonary circulation would be affected by myocardial dysfunction after MIR. 8,42 Our hemodynamic findings indicating high LVEDP and the lung WD ratio suggest that pulmonary edema influences oxidative stress in the lungs after MIR, and our immunohistochemical studies using an anti-biopyrrin antibody revealed biopyrrin expression in relatively large mononuclear cells located in thickened alveolar walls. Because pulmonary oxidative stress is evoked by the NADPH pathway in cells of the alveolar wall after lung congestion, 43 lung edema could cause bilirubin oxidation by superoxide generated in mononuclear cells.…”

Section: Discussionmentioning

confidence: 98%

Biphasic Elevation of Bilirubin Oxidation During Myocardial Ischemia Reperfusion

Yamamoto

Maeda

Hirose

et al. 2008

Circ J

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lthough therapeutic intervention or coronary artery bypass grafting can recover coronary blood flow, myocardial damage after blood flow reperfusion, namely myocardial ischemia reperfusion (MIR) injury, remains to be resolved. Among the factors affecting MIR, oxidative stress might play an important role in both the myocardial injury and the cardiac events after reperfusion therapy. 1 Oxidative stress induced by superoxide generated via the xanthine oxidase system and infiltrating inflammatory cells is the major proposed mechanism of MIR progression. [2][3][4][5] We have reported that reactive oxygen species (ROS) influence the opening of the mitochondrial permeability transition pore in myocardial cells, which led to progression of myocardial infarction (MI) in a rat MIR model. 6 Moreover, total nitric oxide (NO) synthesis in the reperfused heart was increased in previous investigations. 7-9 Physiological concentrations of NO produced from endothelial NO synthase (eNOS) or NO donors exert significant cardioprotective effects, whereas the reaction between NO and ROS produces peroxynitrite and results in oxidative and nitrative tissue injury. [7][8][9][10][11][12][13] Evidence from several model systems supports the notion that NO radicals cause myocardial damage in MIR, 7,8,[12][13][14][15] whereas a small amount of NO exerts a cytoprotective effect in the reperfused heart. 11,12,16,17 The dynamics of oxidative stress up to 48 h after MIR remain unclear because of the difficulties associated with monitoring oxidation in vivo. This period is considered critical in both cardiac surgery and therapeutic intervention, so more sensitive and reliable markers of in vivo oxidative stress are required.Bilirubin is an intrinsic antioxidant that quenches radicals under several inflammatory conditions. 18-21 Its synthesis is regulated by the rate-limiting enzyme, heme oxygenase-1 (HO-1), which is rapidly induced by oxidative stress and inflammatory reactions caused by factors such as cytokines, ischemia and NO. [22][23][24][25][26][27][28][29] Bilirubin generates several hydrophilic metabolites called biopyrrins upon oxidation and these can be detected using the anti-bilirubin monoclonal antibody 24G7. 30,31 Biopyrrins are immediately excreted in urine because of their hydrophilic properties and thus can reflect the severity of oxidative stress. 25,[32][33][34][35][36][37][38] Biopyrrin synthesis reflects NO radicals, 25 so urinary biopyrrin levels can indicate ongoing changes in oxidative stress in vivo and thus function as a marker of oxidative stress.The time course of urinary and tissue biopyrrin levels in rat models of cardiac transplantation and hepatic ischemia reperfusion has been investigated. 25,32 A cardiac transplantation study showed that levels of urinary biopyrrins become more rapidly and sensitively elevated than either urinary 8-hydroxy-2'-deoxyguanosine or serum troponin-T during Biphasic Elevation of Bilirubin Oxidation During Myocardial Ischemia ReperfusionMasaki Yamamoto, MD; Hironori Maeda, MD; Nobuyuki...

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“…This could be achieved by inhibiting I NHE or late I Na . Both approaches were cardioprotective in experimental models of ischemia/ reperfusion, since in this situation, an excessive increase of [Na + ] i contributes to progressive cytosolic and mitochondrial Ca 2+ -overload and thus, the induction of apoptosis through activation of the mitochondrial PTP [78,135,168,189]. Also in animal models of heart failure, both the inhibition of I NHE by cariporide and of late I Na by ranolazine reduced [Na + ] i and improved EC coupling and LV remodeling [6,34,38,62,163,202].…”

Section: Discussionmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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Improved Left Ventricular Function and Reduced Necrosis after Myocardial Ischemia/Reperfusion in Rabbits Treated with Ranolazine, an Inhibitor of the Late Sodium Channel

Cited by 64 publications

References 31 publications

δ-Opioid receptor activation before ischemia reduces gap junction permeability in ischemic myocardium by PKC-ε-mediated phosphorylation of connexin 43

δ-Opioid receptor activation before ischemia reduces gap junction permeability in ischemic myocardium by PKC-ε-mediated phosphorylation of connexin 43

Biphasic Elevation of Bilirubin Oxidation During Myocardial Ischemia Reperfusion

Excitation-contraction coupling and mitochondrial energetics

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