Acidic infusion in early reperfusion affects the activity of antioxidant enzymes in postischemic isolated rat heart

Penna, Cláudia; Perrelli, Maria-Giulia; Tullio, Francesca; Angotti, Carmelina; Pagliaro, Pasquale

doi:10.1016/j.jss.2012.12.029

Cited by 11 publications

(15 citation statements)

References 37 publications

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“…Furthermore, Penna et al suggested that acid postC protected against myocardial I/R injury by activating ERK1/2-PKCε pathways in isolated rat hearts [26]. Though the differences of treatments (preC versus postC), dugs (morphine versus desflurane or acid perfusion), and animal models (in vitro versus in vivo) might account for the inconsistent observations, we cannot exclude the presumption that there might be an ERK1/2-PKCε positive feedback regulation in postC, namely, that PKCε dependently phosphorylates ERK1/2 while the phosphorylated ERK1/2 in turn activates PKCε because it has been shown that ERK 1/2 is both upstream and downstream of PKC in preC [27].…”

Section: Discussionmentioning

confidence: 99%

Morphine Postconditioning Protects Against Reperfusion Injury: the Role of Protein Kinase C-Epsilon, Extracellular Signal-Regulated Kinase 1/2 and Mitochondrial Permeability Transition Pores

Chen

Spahn

Zhang

et al. 2016

Cell Physiol Biochem

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Background/Aims: The purpose of this study was to investigate the implications of protein kinase C-epsilon (PKCε), Extracellular Signal-regulated Kinase 1/2 (ERK1/2) and mitochondrial permeability transition pore (mPTP) in myocardial protection induced by morphine postconditioning (MpostC). Methods: The isolated rat hearts were randomly assigned into one of eight groups. Hearts in time control (TC) group were constantly perfused for 105min. Hearts in ischemia-reperfusion (I/R) group were subjected to 45 min of ischemia followed by 1 h of reperfusion. MpostC was induced by 10 min of morphine administration at the onset of reperfusion. εV_1-2 (an inhibitor of PKCε) and PD (an inhibitor of ERK1/2) was administered with or without morphine during the first 10 min of reperfusion following the 45 min of ischemia. I/R injury was assessed by functional parameters, creatine kinase-MB (CK-MB) release and infarct size (IS/AAR). Additional hearts were excised at 20 min following reperfusion to detect the membrane-specific translocation of PKCε, ERK1/2 phosphorylation, mitochondrial permeability transition (MPT) and cytochrome C (Cyt-c) release. Results: MpostC markedly reduced infarct size (IS/AAR), CK-MB release, and improved cardiac function recovery. However, these protective effects were partly abolished in the presence of εV_1-2 or PD. Compared to TC group, the membrane translocation of PKCε, ERK1/2 phosphorylation, mPTP opening, and Cyt-c release were significantly increased in I/R hearts. MpostC further increased the membrane translocation of PKCε and ERK1/2 phosphorylation, and significantly inhibited mPTP opening and Cyt-c release. However, those protective effects induced by MpostC were abolished by εV_1-2 or PD, which, used alone, showed no influence on reperfusion injury. Conclusions: These findings suggest that MpostC protects isolated rat hearts against ischemia-reperfusion injury via activating PKCε-ERK1/2 pathway and inhibiting mPTP opening.

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Section: Discussionmentioning

confidence: 99%

Morphine Postconditioning Protects Against Reperfusion Injury: the Role of Protein Kinase C-Epsilon, Extracellular Signal-Regulated Kinase 1/2 and Mitochondrial Permeability Transition Pores

Chen

Spahn

Zhang

et al. 2016

Cell Physiol Biochem

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“…Mildly acid reperfusion is believed to act by delaying the restoration of physiological pH (Inserte et al, 2008, 2011), thereby prolonging the low-pH–induced inhibition of mPTP opening while reducing intracellular calcium overload and hypercontracture in the first minutes of reperfusion. Discrepant cardioprotective effects for mildly acidic reperfusion between previous studies (Inserte et al, 2008; Duan et al, 2011; Inserte et al, 2011; Penna et al, 2013; White et al, 2016) and ours are unlikely to be explained by differences in the acidic reperfusion conditions (previous studies used pH ranging from 6.4 to 6.8 for 2–3 min, while we used pH 6.8 for 3 min), but may be explained by differences in experimental conditions, as several previous studies used longer ischemic periods [30–40 min vs. 27 min in our study; (Inserte et al, 2008, 2011; Duan et al, 2011; Penna et al, 2013)] and/or higher buffer calcium concentrations 1.4–1.8 mM (Inserte et al, 2008, 2011; Duan et al, 2011) or lower (0.22 mmol/L) (White et al, 2016) vs. 1.25 mM in our study. Taken together, conditions in several previous reports are likely to generate a more severe ischemia than in our study, which may lead to conditions that are more damaging, but put hearts in a position to benefit from mildly acidic reperfusion.…”

Section: Discussionmentioning

confidence: 93%

“…Although it has been reported to improve hemodynamic recovery (Inserte et al, 2008, 2011; Duan et al, 2011; Penna et al, 2013; White et al, 2016), infarct size (Inserte et al, 2008; Penna et al, 2013), ATP levels (Inserte et al, 2008), and to decrease cyt c release and mitochondrial swelling (Duan et al, 2011) and markers of cell death (Inserte et al, 2008; Duan et al, 2011), we did not observe hemodynamic benefits, nor did we see a difference, compared to controls, in necrosis parameters. Although we measured higher oxygen consumption at 10 min reperfusion, we did not see other differences in metabolic recovery.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we decided to test the effects of no O 2 for 2 min in our model for its clinical practicality. Several acidic reperfusion strategies have also been tested, using with ranges of pH from 6.6 to 6.8 (Inserte et al, 2008, 2011; Duan et al, 2011; Penna et al, 2013; White et al, 2016); we decided to use a mildly acidic strategy, starting at pH 6.8 and then increasing with stepwise increments of 0.2 pH units per min to reach 7.4 after 3 min, as preliminary tests with lower pH levels and rapid normalization led to worse recovery compared with controls (data not shown).…”

Section: Methodsmentioning

confidence: 99%

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Controlled Reperfusion Strategies Improve Cardiac Hemodynamic Recovery after Warm Global Ischemia in an Isolated, Working Rat Heart Model of Donation after Circulatory Death (DCD)

et al. 2016

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Aims: Donation after circulatory death (DCD) could improve cardiac graft availability, which is currently insufficient to meet transplant demand. However, DCD organs undergo an inevitable period of warm ischemia and most cardioprotective approaches can only be applied at reperfusion (procurement) for ethical reasons. We investigated whether modifying physical conditions at reperfusion, using four different strategies, effectively improves hemodynamic recovery after warm ischemia.Methods and Results: Isolated hearts of male Wistar rats were perfused in working-mode for 20 min, subjected to 27 min global ischemia (37°C), and 60 min reperfusion (n = 43). Mild hypothermia (30°C, 10 min), mechanical postconditioning (MPC; 2x 30 s reperfusion/30 s ischemia), hypoxia (no O2, 2 min), or low pH (pH 6.8–7.4, 3 min) was applied at reperfusion and compared with controls (i.e., no strategy). After 60 min reperfusion, recovery of left ventricular work (developed pressure*heart rate; expressed as percent of pre-ischemic value) was significantly greater for mild hypothermia (62 ± 7%), MPC (65 ± 8%) and hypoxia (61 ± 11%; p < 0.05 for all), but not for low pH (45 ± 13%), vs. controls (44 ± 7%). Increased hemodynamic recovery was associated with greater oxygen consumption (mild hypothermia, MPC) and coronary perfusion (mild hypothermia, MPC, hypoxia), and with reduced markers of necrosis (mild hypothermia, MPC, hypoxia) and mitochondrial damage (mild hypothermia, hypoxia).Conclusions: Brief modifications in physical conditions at reperfusion, such as hypothermia, mechanical postconditioning, and hypoxia, improve post-ischemic hemodynamic function in our model of DCD. Cardioprotective reperfusion strategies applied at graft procurement could improve DCD graft recovery and limit further injury; however, optimal clinical approaches remain to be characterized.

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“…The methods were similar to those previously described [32][33][34][35]. In brief, animals were anaesthetized and treated for 10 min.…”

Section: Isolated Perfused Heartmentioning

confidence: 99%

Obestatin regulates cardiovascular function and promotes cardioprotection through the nitric oxide pathway

Penna

Tullio

Femminò

et al. 2017

J Cellular Molecular Medi

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Patients with ischaemic heart disease or chronic heart failure show altered levels of obestatin, suggesting a role for this peptide in human heart function. We have previously demonstrated that GH secretagogues and the ghrelin gene‐derived peptides, including obestatin, exert cardiovascular effects by modulating cardiac inotropism and vascular tone, and reducing cell death and contractile dysfunction in hearts subjected to ischaemia/reperfusion (I/R), through the Akt/nitric oxide (NO) pathway. However, the mechanisms underlying the cardiac actions of obestatin remain largely unknown. Thus, we suggested that obestatin‐induced activation of PI3K/Akt/NO and PKG signalling is implicated in protection of the myocardium when challenged by adrenergic, endothelinergic or I/R stress. We show that obestatin exerts an inhibitory tone on the performance of rat papillary muscle in both basal conditions and under β‐adrenergic overstimulation, through endothelial‐dependent NO/cGMP/PKG signalling. This pathway was also involved in the vasodilator effect of the peptide, used both alone and under stress induced by endothelin‐1. Moreover, when infused during early reperfusion, obestatin reduced infarct size in isolated I/R rat hearts, through an NO/PKG pathway, comprising ROS/PKC signalling, and converging on mitochondrial ATP‐sensitive potassium [mitoK(ATP)] channels. Overall, our results suggest that obestatin regulates cardiovascular function in stress conditions and induces cardioprotection by mechanisms dependent on activation of an NO/soluble guanylate cyclase (sGC)/PKG pathway. In fact, obestatin counteracts exaggerated β‐adrenergic and endothelin‐1 activity, relevant factors in heart failure, suggesting multiple positive effects of the peptide, including the lowering of cardiac afterload, thus representing a potential candidate in pharmacological post‐conditioning.

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Acidic infusion in early reperfusion affects the activity of antioxidant enzymes in postischemic isolated rat heart

Abstract: Background. Acidic-perfusion (AP) performed at the onset of reperfusion (i.e. acid-

Cited by 11 publications

References 37 publications

Morphine Postconditioning Protects Against Reperfusion Injury: the Role of Protein Kinase C-Epsilon, Extracellular Signal-Regulated Kinase 1/2 and Mitochondrial Permeability Transition Pores

Morphine Postconditioning Protects Against Reperfusion Injury: the Role of Protein Kinase C-Epsilon, Extracellular Signal-Regulated Kinase 1/2 and Mitochondrial Permeability Transition Pores

Controlled Reperfusion Strategies Improve Cardiac Hemodynamic Recovery after Warm Global Ischemia in an Isolated, Working Rat Heart Model of Donation after Circulatory Death (DCD)

Obestatin regulates cardiovascular function and promotes cardioprotection through the nitric oxide pathway

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