Frequent biomarker analysis in the isolated perfused heart reveals two distinct phases of reperfusion injury

Povlsen, Jonas Agerlund; Løfgren, Bo; Dalgas, Christian; Jespersen, Nichlas Riise; Johnsen, Jacob; Bøtker, Hans Erik

doi:10.1016/j.ijcard.2013.11.035

Cited by 16 publications

(21 citation statements)

References 41 publications

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“…In agreement with previous studies (Murry et al, 1986;Povlsen et al, 2014), a protective effect of IPC was found in our study. ATP-sensitive K channels have been suggested to be involved in the cardioprotective effects of IPC (Liu et al, 1998;Kristiansen et al, 2005), whereas the role of K V 7 channels has not previously been investigated.…”

Section: Discussionsupporting

confidence: 94%

“…The heart and femoral vein were exposed and heparin (1000 IU/kg) was administered intravenously, followed by insertion of a custom-made cannula in the ascending aorta and immediate initiation of retrograde perfusion of the heart. The heart was perfused with a Krebs-Henseleit (KH) solution (containing118 mM NaCl 2 , 4.9 mM KCl, 27.2 mM NaHCO 3 , 1.2 mM MgCl 2 , 1.0 mM KH 2 PO 4 , 2.0 mM CaCl 2 , and 11.0 mM glucose) as described in detail previously (Povlsen et al, 2014). The perfusion protocol consisted of 15 minutes of stabilization; 25 minutes of infusion with K V 7 channel blockers or openers, respectively; 40 minutes of global no-flow ischemia; and 120 minutes of reperfusion.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury

Hedegaard

Johnsen

Povlsen

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The voltage-gated K V 7 (KCNQ) potassium channels are activated by ischemia and involved in hypoxic vasodilatation. We investigated the effect of K V 7 channel modulation on cardiac ischemia and reperfusion injury and its interaction with cardioprotection by ischemic preconditioning (IPC). Reverse-transcription polymerase chain reaction revealed expression of K V 7.1, K V 7.4, and K V 7.5 in the left anterior descending rat coronary artery and all K V 7 subtypes (K V 7.1-K V 7.5) in the left and right ventricles of the heart. Isolated hearts were subjected to no-flow global ischemia and reperfusion with and without IPC. Infarct size was quantified by 2,3,5-triphenyltetrazolium chloride staining. Two blockers of K V 7 channels, XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone] (10 mM) and linopirdine (10 mM), reduced infarct size and exerted additive infarct reduction to IPC. An opener of K V 7 channels, flupirtine (10 mM) abolished infarct size reduction by IPC. Hemodynamics were measured using a catheter inserted in the left ventricle and postischemic left ventricular recovery improved in accordance with reduction of infarct size and deteriorated with increased infarct size. XE991 (10 mM) reduced coronary flow in the reperfusion phase and inhibited vasodilatation in isolated small branches of the left anterior descending coronary artery during both simulated ischemia and reoxygenation. K V 7 channels are expressed in rat coronary arteries and myocardium. Inhibition of K V 7 channels exerts cardioprotection and opening of K V 7 channels abrogates cardioprotection by IPC. Although safety issues should be further addressed, our findings suggest a potential role for K V 7 blockers in the treatment of ischemiareperfusion injury.

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Section: Discussionsupporting

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury

Hedegaard

Johnsen

Povlsen

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…In our previous protocol, insulin had decreased the release of TNF-α into the coronary efferent fluid 5 min after reperfusion, while no effect was seen 15 min later [3]. In the current study myocardial TNF-α was measured 20 min after reperfusion only, supporting the previously made observation in a myocardial infarction heart model of two phases of reperfusion injury, an early one within the first 3 min and a later phase after 40–60 min [20]. …”

Section: Discussionsupporting

confidence: 86%

Glycemia and the cardioprotective effects of insulin pre-conditioning in the isolated rat heart

Nakadate

Sato

Oguchi

et al. 2017

Cardiovasc Diabetol

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BackgroundWhile acute hyperglycemia has been shown to mitigate the beneficial effects of ischemic preconditioning, its effect on insulin-induced preconditioning remains unclear.MethodsThe study was designed to test the hypothesis that acute hyperglycemia diminishes the cardioprotective effects following a 20-min pre-ischemic pre-conditioning with insulin in the isolated rat heart using the Langendorff system. Forty hearts were assigned to receive modified Krebs–Henseleit (KH) buffer containing 0.5 U/L insulin and 100 mg/dL glucose (InsG100, n = 10), KH buffer with 100 mg/dL glucose (G100, n = 10), KH buffer supplemented with 0.5 U/L insulin and 600 mg/dL glucose (InsG600, n = 10), or with 600 mg/dL glucose (G600, n = 10). To match the osmotic pressure of the InsG600 group, 27.5 mmol/L of mannitol was added to KH solution in the InsG100 and G100 group. The four groups were perfused with each solution for 20 min prior to 15 min of no-flow ischemia, and during 20 min of reperfusion. Only during the ischemic period the heart was paced at 222 beats/min. Measurements of heart rate, coronary flow and maximum of LV derivative of pressure development (dP/dt max) were recorded. Myocardial phospho-protein kinase B (p-Akt) and tumor necrosis factor-α (TNF-α) levels were assayed by enzyme-linked immunosorbent assay and sandwich ELISA, respectively following reperfusion.ResultsAfter reperfusion, LV dP/dt max and heart rate in the InsG100 group was significantly higher than that in the other three groups. The myocardial p-Akt level in the InsG100 group was significantly elevated when compared to the InsG600 group at the end of reperfusion. The p-Akt levels in the InsG600 and InsG100 group were significantly higher than in the corresponding non-insulin groups.ConclusionsAcute hyperglycemia diminishes the cardioprotective effects of insulin preconditioning in the isolated rat heart, possibly mediated through the suppression of myocardial Akt phosphorylation.

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“…For the rat heart, 60–120 min of reperfusion is mandatory. Frequent analysis of biomarkers reveals two distinct phases of reperfusion injury [342]. With the mouse heart, there is no detectable difference in infarct size following 30 or 60 min reperfusion [136, 325, 376, 408].…”

Section: Isolated Perfused Heartsmentioning

confidence: 99%

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

et al. 2018

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Frequent biomarker analysis in the isolated perfused heart reveals two distinct phases of reperfusion injury

Cited by 16 publications

References 41 publications

Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury

Inhibition of KV7 Channels Protects the Rat Heart against Myocardial Ischemia and Reperfusion Injury

Glycemia and the cardioprotective effects of insulin pre-conditioning in the isolated rat heart

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

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