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Suarez-Pierre A, Lui C, Zhou X, Kearney S, Jones M, Wang J, Thomas RP, Gaughan N, Metkus TS, Brady MB, Cho BC, Dodd-O JM, Lawton JS. Diazoxide preserves myocardial function in a swine model of hypothermic cardioplegic arrest and prolonged global ischemia. J Thorac Cardiovasc Surg 2022; 163:e385-e400. [PMID: 32977969 DOI: 10.1016/j.jtcvs.2020.08.069] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 08/18/2020] [Accepted: 08/18/2020] [Indexed: 10/23/2022]
Abstract
OBJECTIVE Adenosine triphosphate potassium sensitive channels provide endogenous myocardial protection via coupling of cell membrane potential to myocardial metabolism. Adenosine triphosphate potassium sensitive channel openers, such as diazoxide, mimic ischemic preconditioning, prevent cardiomyocyte swelling, preserve myocyte contractility after stress, and provide diastolic protection. We hypothesize that diazoxide combined with hyperkalemic cardioplegia provides superior myocardial protection compared with cardioplegia alone during prolonged global ischemia in a large animal model. METHODS Twelve pigs were randomized to global ischemia for 2 hours with a single dose of cold blood (4:1) hyperkalemic cardioplegia alone (n = 6) or with diazoxide (500 μmol/L) (n = 6) and reperfused for 1 hour. Cardiac output, myocardial oxygen consumption, left ventricular developed pressure, left ventricular ejection fraction, diastolic function, myocardial troponin, myoglobin, markers of apoptosis, and left ventricular infarct size were compared. RESULTS Four pigs in the cardioplegia alone group could not be weaned from cardiopulmonary bypass. There were no differences in myoglobin, troponin, or apoptosis between groups. Diazoxide preserved cardiac output versus control (74.5 vs 18.4 mL/kg/min, P = .01). Linear mixed regression modeling demonstrated that the addition of diazoxide to cardioplegia preserved left ventricular developed pressure by 36% (95% confidence interval, 9.9-61.5; P < .01), dP/dt max by 41% (95% confidence interval, 14.5-67.5; P < .01), and dP/dt min by 33% (95% confidence interval, 8.9-57.5; P = .01). It was also associated with higher (but not significant) myocardial oxygen consumption (3.7 vs 1.4 mL O2/min, P = .12). CONCLUSIONS Diazoxide preserves systolic and diastolic ventricular function in a large animal model of prolonged global myocardial ischemia. Diazoxide as an adjunct to hyperkalemic cardioplegia may allow safer prolonged ischemic times during increasingly complicated cardiac procedures.
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Affiliation(s)
| | - Cecillia Lui
- Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Xun Zhou
- Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Sean Kearney
- Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Melissa Jones
- Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Jie Wang
- Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Rosmi P Thomas
- Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Natalie Gaughan
- Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Thomas S Metkus
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Mary B Brady
- Division of Cardiac Anesthesiology, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Brian C Cho
- Division of Cardiac Anesthesiology, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Jeffrey M Dodd-O
- Division of Cardiac Anesthesiology, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Md
| | - Jennifer S Lawton
- Division of Cardiac Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Md.
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Relevance and Recommendations for the Application of Cardioplegic Solutions in Cardiopulmonary Bypass Surgery in Pigs. Biomedicines 2021; 9:biomedicines9091279. [PMID: 34572465 PMCID: PMC8464907 DOI: 10.3390/biomedicines9091279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/15/2021] [Accepted: 09/15/2021] [Indexed: 11/24/2022] Open
Abstract
Cardioplegic solutions play a major role in cardiac surgery due to the fact that they create a silent operating field and protect the myocardium against ischemia and reperfusion injury. For studies on cardioplegic solutions, it is important to compare their effects and to have a valid platform for preclinical testing of new cardioplegic solutions and their additives. Due to the strong anatomical and physiological cardiovascular similarities between pigs and humans, porcine models are suitable for investigating the effects of cardioplegic solutions. This review provides an overview of the results of the application of cardioplegic solutions in adult or pediatric pig models over the past 25 years. The advantages, disadvantages, limitations, and refinement strategies of these models are discussed.
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Salameh A, Dhein S. Strategies for Pharmacological Organoprotection during Extracorporeal Circulation Targeting Ischemia-Reperfusion Injury. Front Pharmacol 2015; 6:296. [PMID: 26733868 PMCID: PMC4686733 DOI: 10.3389/fphar.2015.00296] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 12/02/2015] [Indexed: 01/28/2023] Open
Abstract
Surgical correction of congenital cardiac malformations or aortocoronary bypass surgery in many cases implies the use of cardiopulmonary-bypass (CPB). However, a possible negative impact of CPB on internal organs such as brain, kidney, lung and liver cannot be neglected. In general, CPB initiates a systemic inflammatory response (SIRS) which is presumably caused by contact of blood components with the surface of CPB tubing. Moreover, during CPB the heart typically undergoes a period of cold ischemia, and the other peripheral organs a global low flow hypoperfusion. As a result, a plethora of pro-inflammatory mediators and cytokines is released activating different biochemical pathways, which finally may result in the occurrence of microthrombosis, microemboli, in depletion of coagulation factors and haemorrhagic diathesis besides typical ischemia-reperfusion injuries. In our review we will focus on possible pharmacological interventions in patients to decrease negative effects of CPB and to improve post-operative outcome with regard to heart and other organs like brain, kidney, or lung.
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Affiliation(s)
- Aida Salameh
- Clinic for Pediatric Cardiology, Heart Centre University of Leipzig Leipzig, Germany
| | - Stefan Dhein
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, University of Leipzig Leipzig, Germany
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Activation of Adenosine Triphosphate-regulated Potassium Channels during Reperfusion Restores Isoflurane Postconditioning-induced Cardiac Protection in Acutely Hyperglycemic Rabbits. Anesthesiology 2015; 122:1299-311. [PMID: 25812079 DOI: 10.1097/aln.0000000000000648] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Hyperglycemia is known to inhibit myocardial anesthetic postconditioning. The authors tested whether activation of adenosine triphosphate-regulated potassium (KATP) channels would restore anesthetic postconditioning during acute hyperglycemia. METHODS Rabbits subjected to 40-min myocardial ischemia and 3-h reperfusion (ischemia-reperfusion [I/R]) were assigned to groups (n = 10 in each group) with or without isoflurane postconditioning (2.1% for 5 min) in the presence or absence of hyperglycemia and/or the KATP channel agonist diazoxide. Creatine kinase MB fraction and infarct size were measured. Phosphorylated protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) were assessed. Oxidative stress was evaluated by measuring malondialdehyde, and apoptosis was assessed by dUTP nick-end labeling and activated caspase-3. RESULTS Postconditioning significantly reduced myocardial infarct size (26 ± 4% in the isoflurane [ISO] group vs. 53 ± 2% in the I/R group; P = 0.007); whereas, hyperglycemia inhibited this effect (infarct size: 47 ± 2%, P = 0.02 vs. the ISO group). Phosphorylated and eNOS levels increased, whereas malondialdehyde and myocardial apoptosis were significantly lower after isoflurane postconditioning compared with I/R. These effects were inhibited by acute hyperglycemia. Diazoxide restored the protective effect of isoflurane in the hyperglycemic animals (infarct size: 29 ± 2%; P = 0.01 vs. the I/R group), reduced malondialdehyde levels and myocardial apoptosis, but did not affect the expression of phosphorylated Akt or eNOS. CONCLUSIONS KATP channel activation restored anesthetic postconditioning-induced myocardial protection under acute hyperglycemia. This effect occurred without increasing Akt or eNOS phosphorylation, suggesting that KATP channels are located downstream to Akt and eNOS in the pathway of isoflurane-induced myocardial postconditioning.
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Characterization of the apoptotic response induced by the cyanine dye D112: a potentially selective anti-cancer compound. PLoS One 2015; 10:e0125381. [PMID: 25927702 PMCID: PMC4415924 DOI: 10.1371/journal.pone.0125381] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 03/23/2015] [Indexed: 01/01/2023] Open
Abstract
Chemotherapeutic drugs that are used in anti-cancer treatments often cause the death of both cancerous and noncancerous cells. This non-selective toxicity is the root cause of untoward side effects that limits the effectiveness of therapy. In order to improve chemotherapeutic options for cancer patients, there is a need to identify novel compounds with higher discrimination for cancer cells. In the past, methine dyes that increase the sensitivity of photographic emulsions have been investigated for anti-cancer properties. In the 1970's, Kodak Laboratories initiated a screen of approximately 7000 dye structural variants for selective toxicity. Among these, D112 was identified as a promising compound with elevated toxicity against a colon cancer cell line in comparison to a non-transformed cell line. Despite these results changing industry priorities led to a halt in further studies on D112. We decided to revive investigations on D112 and have further characterized D112-induced cellular toxicity. We identified that in response to D112 treatment, the T-cell leukemia cell line Jurkat showed caspase activation, mitochondrial depolarization, and phosphatidylserine externalization, all of which are hallmarks of apoptosis. Chemical inhibition of caspase enzymatic activity and blockade of the mitochondrial pathway through Bcl-2 expression inhibited D112-induced apoptosis. At lower concentrations, D112 induced growth arrest. To gain insight into the molecular mechanism of D112 induced mitochondrial dysfunction, we analyzed the intracellular localization of D112, and found that D112 associated with mitochondria. Interestingly, in the cell lines that we tested, D112 showed increased toxicity toward transformed versus non-transformed cells. Results from this work identify D112 as a potentially interesting molecule warranting further investigation.
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Nogueira MA, Coelho AMM, Sampietre SN, Patzina RA, Pinheiro da Silva F, D'Albuquerque LAC, Machado MCC. Beneficial effects of adenosine triphosphate-sensitive K+ channel opener on liver ischemia/reperfusion injury. World J Gastroenterol 2014; 20:15319-15326. [PMID: 25386080 PMCID: PMC4223265 DOI: 10.3748/wjg.v20.i41.15319] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 05/28/2014] [Accepted: 07/11/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of diazoxide administration on liver ischemia/reperfusion injury. METHODS Wistar male rats underwent partial liver ischemia performed by clamping the pedicle from the medium and left anterior lateral segments for 1 h under mechanical ventilation. They were divided into 3 groups: Control Group, rats submitted to liver manipulation, Saline Group, rats received saline, and Diazoxide Group, rats received intravenous injection diazoxide (3.5 mg/kg) 15 min before liver reperfusion. 4 h and 24 h after reperfusion, blood was collected for determination of aspartate transaminase (AST), alanine transaminase (ALT), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), nitrite/nitrate, creatinine and tumor growth factor-β1 (TGF-β1). Liver tissues were assembled for mitochondrial oxidation and phosphorylation, malondialdehyde (MDA) content, and histologic analysis. Pulmonary vascular permeability and myeloperoxidase (MPO) were also determined. RESULTS Four hours after reperfusion the diazoxide group presented with significant reduction of AST (2009 ± 257 U/L vs 3523 ± 424 U/L, P = 0.005); ALT (1794 ± 295 U/L vs 3316 ± 413 U/L, P = 0.005); TNF-α (17 ± 9 pg/mL vs 152 ± 43 pg/mL, P = 0.013; IL-6 (62 ± 18 pg/mL vs 281 ± 92 pg/mL); IL-10 (40 ± 9 pg/mL vs 78 ± 10 pg/mL P = 0.03), and nitrite/nitrate (3.8 ± 0.9 μmol/L vs 10.2 ± 2.4 μmol/L, P = 0.025) when compared to the saline group. A significant reduction in liver mitochondrial dysfunction was observed in the diazoxide group compared to the saline group (P < 0.05). No differences in liver MDA content, serum creatinine, pulmonary vascular permeability and MPO activity were observed between groups. Twenty four hours after reperfusion the diazoxide group showed a reduction of AST (495 ± 78 U/L vs 978 ± 192 U/L, P = 0.032); ALT (335 ± 59 U/L vs 742 ± 182 U/L, P = 0.048), and TGF-β1 (11 ± 1 ng/mL vs 17 ± 0.5 ng/mL, P = 0.004) serum levels when compared to the saline group. The control group did not present alterations when compared to the diazoxide and saline groups. CONCLUSION Diazoxide maintains liver mitochondrial function, increases liver tolerance to ischemia/reperfusion injury, and reduces the systemic inflammatory response. These effects require further evaluation for using in a clinical setting.
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Enhancement of liver regeneration by adenosine triphosphate-sensitive K⁺ channel opener (diazoxide) after partial hepatectomy. Transplantation 2012; 93:1094-100. [PMID: 22466787 DOI: 10.1097/tp.0b013e31824ef1d1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Enhancement of liver regeneration is a matter of importance after partial liver transplantation including small-for-size grafting. Mitochondrial adenosine triphosphate (ATP)-sensitive K⁺ (mitoKATP) channel plays an important role in mitochondrial bioenergetics, which is a prerequisite for liver regeneration. However, the ATP-sensitive K⁺ (KATP) channel in hepatocytes is incompletely understood. We investigated the KATP channel in hepatocytes and examined the effects of diazoxide, a potent KATP channel opener, on liver regeneration using a rat model. METHODS Using rat primary hepatocytes, expression and localization of KATP channel subunits, Kir6.x and sulfonylurea receptor (SUR)x, were studied by polymerase chain reaction, Western blotting, and immunostaining. To investigate the role of KATP channel openers in liver regeneration, we allocated rats into four groups: control (vehicle) (n=24), diazoxide (n=24), vehicle plus channel blocker (n=6), and diazoxide plus channel blocker (n=6) groups. After 70% partial hepatectomy, hepatic tissue ATP levels, liver-to-body weight ratio, and proliferation rate of hepatocytes were examined. RESULTS KATP channel subunits, Kir6.1 and SUR1, were detected on hepatic mitochondria. During liver regeneration, liver-to-body weight ratio, proliferation rate of hepatocytes, and the hepatic ATP level were significantly higher in the diazoxide group than the control group at 2 days after partial hepatectomy. These effects of diazoxide were neutralized by a KATP channel blocker. CONCLUSIONS We demonstrated the existence of a mitoKATP channel in hepatocytes composed of Kir6.1 and SUR1. Diazoxide could enhance liver regeneration by keeping a higher ATP content of the liver tissue. These results suggest that diazoxide will sustain the mitochondrial energetics through the mitoKATP channel opening.
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CARDIAC role of the mitochondrial Ca2+ transporters in the high-[K+](o) cardioprotection of rat hearts under ischemia and reperfusion: a mechano-energetic study. J Cardiovasc Pharmacol 2010; 54:213-22. [PMID: 19597370 DOI: 10.1097/fjc.0b013e3181b04ce3] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
UNLABELLED The role of mitochondrial transporters in the cardioprotection of rat hearts exposed to high [K+]-low [Ca2+]-cardioplegia (CPG) and ischemia and reperfusion (I/R) was studied through the mechano-energetic consequences of target drugs. The total heat rate (Ht) and the left intraventricular pressure (LVP) were simultaneously measured in isolated perfused hearts (30 degrees C and 1 Hz) inside a flow-calorimeter during 45 minutes of no-flow I and 45 minutes of R. After stabilization (C) they were pretreated with CPG and 100 microM 5-hydroxidecanoate (5HD, selective mKATP blocker) without and with 10 or 30 microM clonazepam (Clzp, mNCX inhibitor), 30 microM diazoxide (Dzx, selective mKATP opener), 1 microM Ru360 (selective Ca-uniporter blocker), and 0.2 microM cyclosporine-A, (mPTP inhibitor, before I and during R). Before I, 5-hydroxydecanoate in CPG increased the resting heat rate (17.83 +/- 3.55 mW/g) without changing the stunning. Clzp 30 microM + CPG + 5-hydroxydecanoate reduced the postischemic P with diastolic contracture and high Ht. Dzx protected C-hearts from stunning but increased it in CPG hearts with low economy (P/Ht) as well as Ru360. Cyclosporine-A did not modify the stunning of C or CPG ischemic hearts, suggesting that the mPTP was not opened. CONCLUSIONS Mitochondria have a precise role for determining cardioprotection or stunning in high-K+ cardioplegic rat hearts under I/R. Known protective drugs, such as Dzx and Ru360, which reduce the mitochondrial Ca2+-uptake, increased the stunning of CPG-rat hearts and reduced muscle economy, whereas 5-hydroxydecanoate and Clzp together increased the stunning by inducing mitochondrial Ca2+ overload.
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Wang L, Oka N, Tropak M, Callahan J, Lee J, Wilson G, Redington A, Caldarone CA. Remote ischemic preconditioning elaborates a transferable blood-borne effector that protects mitochondrial structure and function and preserves myocardial performance after neonatal cardioplegic arrest. J Thorac Cardiovasc Surg 2008; 136:335-42. [DOI: 10.1016/j.jtcvs.2007.12.055] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2007] [Revised: 10/24/2007] [Accepted: 12/18/2007] [Indexed: 10/22/2022]
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Inhibition of mitochondrial remodeling by cyclosporine A preserves myocardial performance in a neonatal rabbit model of cardioplegic arrest. J Thorac Cardiovasc Surg 2008; 135:585-93. [PMID: 18329475 DOI: 10.1016/j.jtcvs.2007.09.023] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2007] [Revised: 09/12/2007] [Accepted: 09/24/2007] [Indexed: 11/22/2022]
Abstract
OBJECTIVE Mitochondrial permeability transition pore opening is associated with apoptotic signaling and alterations in mitochondrial structure and function. We tested whether inhibition of mitochondrial permeability transition pore opening with cyclosporine A preserved mitochondrial structure and function after cardioplegic arrest and whether this preservation is associated with improved myocardial performance. METHODS Langendorff-perfused neonatal rabbit hearts were perfused for 30 minutes with Krebs-Henseleit buffer (CCP; n = 6) or Krebs-Henseleit buffer containing 2 mumol/L of cyclosporine A (CCP+CsA; n = 6) followed by 60 minutes of normothermic crystalloid cardioplegia (CCP) and 60 minutes of reperfusion. Control hearts (non-CCP; n = 6) were constantly perfused for 150 minutes without cardioplegic arrest. RESULTS In comparison with non-CCP, CCP was associated with Bax translocation to the mitochondria, cytochrome c release, and greater frequency of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive myocytes These changes were also associated with deficits in isolated mitochondrial oxygen consumption at complex I. CsA pretreatment minimized or prevented all these findings. Myocardial performance (systolic pressure, maximum positive and negative dP/dt, and elevated left ventricular end-diastolic pressure) at 5, 15, 30, and 60 minutes after reperfusion was diminished in CCP hearts when compared with non-CPB, and these deficits could be minimized with cyclosporine A pretreatment. (P < .05 all comparisons) CONCLUSIONS Cyclosporine A prevents apoptosis-related mitochondrial permeabilization and dysfunction after cardioplegic arrest. This protection is associated with improved myocardial performance. Prevention of mitochondrial permeability transition pore opening is a valuable target for mitochondrial (and myocardial) preservation after neonatal cardioplegic arrest.
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Oka N, Wang L, Mi W, Zhu W, Honjo O, Caldarone CA. Cyclosporine A prevents apoptosis-related mitochondrial dysfunction after neonatal cardioplegic arrest. J Thorac Cardiovasc Surg 2008; 135:123-30, 130.e1-2. [PMID: 18179928 DOI: 10.1016/j.jtcvs.2007.05.009] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2007] [Revised: 04/27/2007] [Accepted: 05/02/2007] [Indexed: 12/01/2022]
Abstract
OBJECTIVE Mitochondrial permeability transition pore opening plays a critical role in mediating the mitochondrial response to ischemia/reperfusion injury and initiation of apoptosis. We tested whether inhibition of mitochondrial permeability transition pore opening with cyclosporine A prevented apoptosis-related alterations in mitochondrial structure and function after cardioplegic arrest. METHODS Newborn piglets (age approximately 14 days) underwent cardiopulmonary bypass, cardioplegic arrest (60 minutes), weaning from bypass, and 6-hour reperfusion. Comparison was made among cold crystalloid cardioplegia (n = 5), cold crystalloid cardioplegia with cyclosporine A pretreatment (n = 5), and noncardiopulmonary bypass (n = 5) groups. RESULTS Early apoptosis signaling events (Bax translocation to the mitochondria) were prominent in cold crystalloid cardioplegia and prevented in cold crystalloid cardioplegia + cyclosporine A myocardium. Mitochondrial release of cytochrome c, determined by Western blot of cytosolic fractions and confocal quantitative colocalization analysis, was also prominent in cold crystalloid cardioplegia but prevented in cold crystalloid cardioplegia + cyclosporine A myocardium. Electron microscopy of isolated mitochondria demonstrated subjective alterations in mitochondrial architecture in cold crystalloid cardioplegia mitochondria, which were prevented by cyclosporine A. Deficiency of isolated mitochondrial oxygen consumption at Complex I was present in cold crystalloid cardioplegia mitochondria and prevented by cyclosporine A (P < .01). The frequency of deoxyuride-5'-triphosphate biotin nick end labeling-positive myocytes was diminished in cold crystalloid cardioplegia + cyclosporine A myocardium (P < .05). Mitochondrial resistance to calcium-mediated mitochondrial permeability transition pore opening was not different in cold crystalloid cardioplegia and noncardiopulmonary bypass mitochondria, suggesting that calcium overload is not solely responsible for the observed deficits in mitochondrial function. CONCLUSIONS Cyclosporine A pretreatment prevents postcardioplegia alterations in mitochondrial structure and function in a clinically relevant model of neonatal cardiac surgery. Prevention of mitochondrial permeability transition pore opening and apoptosis signaling events (Bax translocation and mitochondrial permeabilization) are associated with superior mitochondrial preservation.
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Affiliation(s)
- Norihiko Oka
- Division of Cardiovascular Surgery, the Hospital for Sick Children, University of Toronto, Ontario, Canada
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Camerino DC, Desaphy JF, Tricarico D, Pierno S, Liantonio A. Therapeutic Approaches to Ion Channel Diseases. ADVANCES IN GENETICS 2008; 64:81-145. [DOI: 10.1016/s0065-2660(08)00804-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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