Skip Navigation LinksHome > February 2013 - Volume 39 - Issue 2 > Effects of Cyclosporine Pretreatment on Tissue Oxygen Levels...
Text sizing:
A
A
A
Shock:
doi: 10.1097/SHK.0b013e31828044f6
Basic Science Aspects

Effects of Cyclosporine Pretreatment on Tissue Oxygen Levels and Cytochrome Oxidase in Skeletal Muscle Ischemia and Reperfusion

Troitzsch, Dirk*†; Moosdorf, Rainer; Hasenkam, J. Michael*; Nygaard, Hans*; Vogt, Sebastian

Free Access
Article Outline
Collapse Box

Author Information

*Cardiovascular Program, Faculty of Health Sciences, Aarhus University and Aarhus University Hospital, Aarhus, Denmark; and Biomedical Research Center, Cardiovascular Research Lab, Department of Cardiac and Thoracic Vascular Surgery, University Medical Center, Philipps-University of Marburg/Lahn, Marburg/Lahn, Germany

Received 5 Aug 2012; first review completed 30 Aug 2012; accepted in final form 28 Nov 2012

Address reprint requests to Sebastian Vogt, Klinik für Herz- und thorakale Gefässchirurgie, Klinikum der Philipps-Universität, Baldinger Strasse 1, D-35043 Marburg, Germany. E-mail: vogts@med.uni-marburg.de.

The authors have no support or funding to report.

The authors have declared that no competing interests exist.

Collapse Box

Abstract

ABSTRACT: We hypothesized that pretreatment with single-dose cyclosporine (CsA) prevents alterations and improves tissue oxygen and mitochondrial cytochrome oxidase redox (CytOx) state in skeletal muscle ischemia and reperfusion-reoxygenation (I/R). Latissimus dorsi muscle was prepared and mobilized in New Zealand white rabbits. Ischemia was induced for 4 h, followed by 2 h of reperfusion. The animals were randomized to receive a 60-mg/kg intravenous bolus of CsA (CsA group, n = 10) or physiologic saline (control, n = 10) at 10 min before ischemia onset. Muscle tissue oxygen tension (PtO2) and mitochondrial CytOx were measured during I/R simultaneously. High-energy phosphate (HEP) levels were determined using high-field 31P magnetic resonance spectroscopy. Mitochondrial viability index and wet-to-dry ratio were used to assess the tissue viability between groups. Decreases in tissue oxygen levels and CytOx were slower during ischemia in the CsA group in comparison to control group, also the loss of phosphocreatine and adenosine triphosphate depletion. After ischemia, recovery of tissue oxygen, mitochondrial CytOx, and HEP was delayed in controls. Tissue PtO2 in the CsA group (P < 0.05) was significantly higher compared with that in the control group after I/R. Mitochondrial CytOx was also improved in the CsA group (P < 0.01 vs. control). Muscle HEP levels (phosphocreatine, adenosine triphosphate) were significantly preserved in the CsA group versus the control group (P < 0.01, P < 0.05). Mitochondrial viability index and wet-to-dry ratio confirmed significantly preserved tissue and lower edema formation in the CsA group. The pretreatment with single-dose CsA prevents alterations and improves tissue oxygenation and mitochondrial oxidation in skeletal muscle I/R.

Back to Top | Article Outline

INTRODUCTION

Ischemia and reperfusion-reoxygenation (I/R) induces cellular and subcellular changes characterized by impaired tissue oxygenation, decreased intracellular oxygen levels, interstitial edema, cellular swelling, alterations in high-energy phosphate (HEP) metabolism, and mitochondrial dysfunction (1–4). The pathophysiology of I/R becomes clinically apparent in different time intervals after surgery or intervention (3–6). Microsurgical skeletal muscle transplants may be particularly vulnerable to I/R because of prolonged ischemia during reconstructive surgery (3–7). Treatment aims to save initially viable tissue before it is compromised in secondary hypoxia or ischemia by decreased tissue oxygenation and disturbed cellular metabolism (5, 8). Although the ischemic muscle tissue is a target of therapy, the pathophysiology of tissue oxygenation and oxygen metabolism is of laboratory and clinical importance (3–5). Furthermore, monitoring tissue oxygenation will provide accurate values for evaluating emerging therapies in acute I/R-associated events. In previous studies, we found that the recovery muscle energetics and viability are directly related to oxygen availability at microvascular and cellular/mitochondrial level (8, 9). Local hypothermia and pharmacological interventions have been used to attenuate the I/R damage to tissue (4, 6, 10, 11). Pretreatment strategies such as cyclosporine (cyclosporin A, CsA) may be effective during ischemia and protective in the perioperative and postoperative period when reperfusion injury processes are the greatest (4, 6, 12–17). Suppression of the mitochondrial permeability transition (MPT) with CsA, a specific inhibitor of the MPT pore, may provide protection against such I/R-related injury and irreversible tissue damage (6, 12–17).

Consequently, we studied the effects of CsA on tissue oxygenation and mitochondrial cytochrome oxidase redox (CytOx) state to test the hypothesis that the pretreatment with single-dose CsA prevents alterations and improves tissue oxygen levels (PtO2) and mitochondrial CytOx in skeletal muscle I/R.

Back to Top | Article Outline

MATERIALS AND METHODS

Animals used in this study were handled in accordance with institutional and National Institutes of Health animal care and use guidelines. All animals received human care in accordance with the Principles of Laboratory Animal Care for the National Society for Medical Research and with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication 85-23, revised 1985).

Back to Top | Article Outline
Animal preparation

Male New Zealand white rabbits (Charles River Laboratories GmbH, Sulzfeld, Germany) were housed in a climate-controlled room (18°C–20°C, a humidity of 50%–60%, and a day-night rhythm of 12 h) and provided with standard rabbit pellets and water ad libitum. General anesthesia and surgical technique under aseptic conditions followed protocols as described previously (16,17). Briefly, in all animals, anesthesia was induced with intramuscular injection of ketamine (Ketanest, 50 mg kg/body weight) and xylazine (Rompun, 5 mg/kg body weight). After orotracheal intubation (Portex tube; Smiths Medical International, Keene, NH), mechanical ventilation providing the inspiratory oxygen fraction (FIO2) (Servo 900; Siemens, Bromma, Sweden) was performed. Refinements in mechanical ventilation were designed to preserve a pH of 7.35 to 7.45 and normocarbia (arterial carbon dioxide partial pressure [PaCO2] between 38 and 45 mmHg) using continuous end-tidal CO2 monitoring and arterial blood gas analysis. Pulse oximeter was used to monitor the heart rate and the level of oxygenation. After the placement of a central venous line, anesthesia was maintained by continuous intravenous infusion of fentanyl (100 μg · kg−1 · h−1) and midazolam (0.2 mg · kg−1 · h−1). A femoral artery catheter was placed for monitoring systemic arterial blood pressure and sampling blood for blood gas analysis. The animals were maintained at normothermia (38°C–39°C) using an air warming system (WarmTouch; Tyco Healthcare UK Ltd., Gosport, UK), and warmed physiologic saline was given at 5 mL · kg−1 · h−1 intravenously to replace insensible fluid loss.

Back to Top | Article Outline
Experimental groups

The rabbits (n = 20, 2.5 ± 0.5 kg) were divided into two groups. The animals were randomized to receive a 60-mg/kg intravenous single bolus of CsA (cyclosporin A, Sandimmun; Novartis Pharma GmbH, Nuernberg, Germany) (CsA group, n = 10) or physiologic saline (control group, n = 10) at 10 min before ischemia onset. After preparation of the vascular pedicle, ischemia was induced by clamping of the thoracodorsal artery and vein for 4 h, followed by 2 h of reperfusion. A small tissue oxygen (PtO2) microcatheter probe (CC1, Licox; Integra Neurosciences, Andover, UK) was inserted in the muscle tissue (distal part) and used to measure tissue oxygen simultaneously with mitochondrial CytOx state by noninvasive optical near-infrared (NIR) spectroscopic measurement (Fig. 1). During each experimental period, venous and arterial blood samples were obtained for blood gases and hemoglobin saturation to achieve stable experimental conditions.

Fig. 1
Fig. 1
Image Tools
Back to Top | Article Outline
Operative procedures

A circumferential skin incision was made to expose the latissimus dorsi (LD) muscle. After dissection of the myocutaneous LD muscle flap, the dominant vascular pedicle was prepared, the muscle mobilized, and the thoracodorsal nerve was transected. The exposed LD muscle was reimplanted to the site using standard microsurgical techniques, and the overlying skin was closed with Prolene sutures. A small opening access was used for clamping of the vascular pedicle to induce muscle ischemia.

Back to Top | Article Outline
Tissue oxygen (PO2) measurement

After surgical preparation and dissection, a small and highly flexible oxygen microcatheter probe (CC1, 500-μm diameter, Licox; Integra Neurosciences) was inserted into the muscle tissue (distal part of the LD muscle) using a guide cannula and connected to a digital monitor (Licox CMP; Integra Neurosciences). The microcatheter sensor utilizes the Clark-type polarographic electrode technique, providing a real-time quantitative local oxygen tension (PtO2) measurement in the muscle tissue. An integrated temperature sensor compensates the values for regional muscle tissue temperature, providing an accurate assessment of oxygen levels.

Back to Top | Article Outline
NIR optical spectroscopy

Mitochondrial cytochrome oxidase redox state was measured with a research-based modified NIR spectroscopy system (Critikon; Johnson and Johnson Medical, Berks, UK). The used miniaturized sensor consists of a laser emitter, two light detectors, and a light-emitting diode for compensating differences in coupling. A full spectral charge-coupled device spectrometer system (wavelength range λ = 720–920 nm) was used. The changes in chromospheres concentration of mitochondrial CytOx were converted to units of concentration (i.e., μmol/L of tissue). The noninvasive NIR spectroscopic probe was positioned adjacent to the tissue oxygen microcatheter sensor on the surface of the prepared LD muscle (Fig. 1) and fixed by sutures. The differential path length has been determined specifically for the rabbit LD muscle and was used in all animals for quantitative measurements. All PtO2 and CytOx data were measured continuously with 5-s resolution and averaged in 2-min blocks, processed, and stored on a computer system for subsequent analysis.

Back to Top | Article Outline
31P magnetic resonance spectroscopy

Data were acquired at high-field Bruker magnetic resonance spectrometer (4.7 T, BioSpec; Bruker BioSpin GmbH, Rheinstetten, Germany) using a surface coil (10/18 mm) placed directly on the muscle adjacent to the NIR optical probe. Shimming for optimizing magnetic field homogeneity and pulse power adjusting for deep tissue acquisition of 31P spectra were performed. The positioning of the coil over the muscle was confirmed by T1-weighed 1H images in the axial plane. The pulse width that optimized the phosphocreatine (PCr) signal was chosen for each study. Spectra (repetition time = 5 s, four averages) were measured at baseline, before ischemia, end of ischemia, and end of reperfusion. All spectra were computed and analyzed using a peak fitting routine with least-squares program. The calculated levels of PCr and adenosine triphosphate (ATP) determined from the spectra peak intensity were normalized to 100% by using as reference the average value obtained during the baseline measurements.

Back to Top | Article Outline
Tissue edema

The extent of skeletal muscle edema was measured in tissue samples by the wet-to-dry weight technique. Immediately after harvesting, muscle tissue specimens were blotted, weighed, and placed in a drying oven at 60°C until a constant weight was obtained. Samples were then weighed again, and wet-to-dry weight ratio was estimated.

Back to Top | Article Outline
Mitochondrial viability index

Mitochondrial viability was assessed by the reduction of tetrazolium salt to water-insoluble colored formazan crystals by electron carriers and oxidative enzymes in the mitochondria of the tissue specimens. At the end of the experiment, the LD muscles were harvested, and the tissue was cut into pieces to increase surface area and tissue uptake of the tetrazolium salt. Each piece was weighed and placed in a small tube supplemented with 300 μL of 1 mg/mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (Sigma, St Louis, Mo). The samples were then incubated for 3 h at 37°C in the dark on a rotating mixer. Subsequently, they were removed, washed with distilled water, and blotted dry. The water-insoluble formazan salt was extracted in 3 mL of 2-propanol for 6 h at 37°C in the dark on a rotating mixer. Two-hundred-microliter aliquots were removed, and the absorbance was determined at 570 nm using a microplate reader. The tissue samples were then dried at 90°C for 24 h. The mitochondrial viability index was expressed as percentage of OD570 relative to dry tissue weight in the muscle (percentage viability index of fresh and nonischemic sample considered as 100% viability).

The contralateral LD muscle served as nonischemic control and was also instrumented except that no ischemia was applied. After finishing the experimental protocol, the animals were killed with an overdose sodium pentobarbital (200 mg/kg intravenously administered) under anesthesia.

Back to Top | Article Outline
Statistical analysis

Data were analyzed statistically using the SigmaStat (version 2.03) statistical software (SPSS, Inc, San Rafael, Calif). The calculated sample size to achieve sufficient power was n = 7 for each group. The following tests were carried out: Kolmogorov-Smirnov to assess the normality of variable distribution, descriptive analysis of data with values reported as means ± SD, repeated two-way analysis of variance for comparisons between baseline and post–ischemia-reperfusion values, one-way analysis of variance for comparison of groups at baseline, and χ2 and Goodman tests to compare proportions. Percent changes (Δ) of all variables were calculated. The Pearson or Spearman coefficient of correlation was used to assess correlation between values. P < 0.05 was considered significant.

Back to Top | Article Outline

RESULTS

There were no significant differences among the two groups in baseline hemodynamic and blood gas data (Table 1). Mean arterial pressure and tissue PtO2 tended to increase after intravenous application of CsA in the CsA group, but were not significantly changed.

Table 1
Table 1
Image Tools

Baseline values of tissue PtO2 were comparable between the groups and show no significant difference (Fig. 2). After vascular clamping and induction of ischemia, PtO2 declined rapidly in the first 10 min, and then the decrease slowed, and reached their lowest levels at end of ischemia (Fig. 2). The tissue PtO2 values in the CsA group tended to be higher than the corresponding values in the control group during ischemia and were significantly different at 5 and 15 min of ischemia (Fig. 2). During ischemia, tissue PtO2 decreased precipitously followed by a decrease in mitochondrial CytOx in all LD muscles (Figs. 2 and 3). After ischemia, tissue PtO2 recovered with an overshoot and remained significantly low in the control group (Fig. 2). In the CsA group, the tissue PtO2 levels reach nearly baseline after 1 h of reperfusion (Fig. 2). During reperfusion and reoxygenation, tissue PtO2 values were significantly different in both groups (P < 0.05; Fig. 2). At the end of reperfusion, recovery of tissue PtO2 was significantly improved in the CsA group compared with the control group (CsA group: 31.5 ± 4.6 mmHg vs. control group: 13.9 ± 3.1 mmHg; P < 0.05) (Fig. 2).

Fig. 2
Fig. 2
Image Tools
Fig. 3
Fig. 3
Image Tools

During ischemia, the decline of mitochondrial CytOx and the recovery during reperfusion were significantly different in the CsA group versus control (P < 0.05; Fig. 3). A significant difference in mitochondrial CytOx values between the two groups was found, and the difference progressively increased during last time interval of ischemia and during reperfusion (P < 0.01; Fig. 3). During reperfusion and reoxygenation, the recovery of mitochondrial CytOx in the CsA group was very rapid with evident two-step phases (Fig. 3). Near-baseline CytOx values were reestablished at 60 min of reperfusion (Fig. 3). In contrast, the recovery of mitochondrial CytOx during reperfusion was much lower and significantly different (P < 0.01) in the control group compared with the CsA group (Fig. 3). The mitochondrial CytOx values at the end of reperfusion were significantly different in the groups (CsA group: +0.2 ± 0.04 μmol/L compared with the control group: −1.7 ± 0.08 μmol/L, P < 0.01; Fig. 3).

There were no significant differences in the mean PCr or ATP between the control group and the CsA group before ischemia (Figs. 4 and 5). Ischemia caused a decline in HEPs to levels that were higher in the CsA group than in the control group at the end of ischemia period (Figs. 4 and 5). Muscle PCr was significantly better preserved during ischemia in the CsA group compared with the control group (P < 0.01; Fig. 4). The ATP levels were also significantly higher at the end of ischemia (P < 0.05; Fig. 5). By the end of postischemic reperfusion, the mean percent PCr (P < 0.01) and ATP (P < 0.05) were significantly improved in the CsA group than in controls (Figs. 4 and 5).

Fig. 4
Fig. 4
Image Tools
Fig. 5
Fig. 5
Image Tools

Comparison of the mitochondrial viability index showed significant differences between the CsA group and the control group (76.9% ± 6.8% vs. 51.4% ± 5.6%, P < 0.01) (Fig. 6). Mitochondrial viability index results confirmed better mitochondrial preservation in the CsA group (Fig. 6), and the values correlated with tissue oxygen levels (PtO2) (r = 0.85) and mitochondrial CytOx (r = 0.92).

Fig. 6
Fig. 6
Image Tools

Muscle ischemia followed by reperfusion resulted in tissue edema as indicated by a significantly increased wet-to-dry weight ratio (control group: 5.6 ± 0.5 vs. nonischemic control: 3.26 ± 0.2, P < 0.01) (Fig. 7). After ischemia and 2-h reperfusion, the CsA group developed decreased edema with significantly different wet-to-dry weight ratio compared with the control group (P < 0.05) (Fig. 7).

Fig. 7
Fig. 7
Image Tools

Light microscopy confirmed better morphological preservation in the CsA group (Fig. 8) and revealed marked morphological changes, necrosis, and edema in the muscle specimen of the control group animals.

Fig. 8
Fig. 8
Image Tools
Back to Top | Article Outline

DISCUSSION

After ischemia-reperfusion, recovery of tissue oxygenation and cellular/mitochondrial oxygen metabolism are key determinants for oxidative processes to generate HEP (PCr, ATP) and determine tissue vitality (1–4). In this study, the tissue PtO2 levels were significantly higher after I/R in the CsA group in comparison to controls (Fig. 2). The tissue oxygen and mitochondrial CytOx data are consistent with the findings in the mitochondrial viability index and tissue edema. Pretreatment with a single CsA bolus markedly improved microvascular tissue oxygenation and intracellular/mitochondrial oxidative processes in line with the recovery of HEP (PCr and ATP levels).

Oxidative ATP synthesis is a function of three factors: mitochondrial morphology and function, oxygen supply, and the metabolism. We found that tissue reoxygenation is significantly improved in the CsA group compared with control group and may result from excessive oxygen demand or inadequate microvascular tissue perfusion during reperfusion (Fig. 2). It has been reported that significant vasoconstriction and vasospasm in arterioles (particularly in the terminal arterioles) occur after I/R (8, 18, 19). Cellular oxygen delivery in the postischemic tissue could be further compromised by alterations to oxygen diffusion (due to changes in arteriole diameter, interstitial edema formation, perivascular edema, capillary recruitment, and endothelial swelling), which can critically decrease the oxygen diffusion distance and reduce oxygen flux, determined by the rate of mitochondrial respiration (5). The effects of I/R on tissue PtO2 have been documented in experimental and clinical settings (5, 8, 9, 20–22). We obtained tissue PtO2 values during baseline that are comparable to in vivo mitochondrial oxygen tension values reported as ∼30 to 40 mmHg (22).

The measurement of mitochondrial CytOx using optimized NIR spectroscopy provides in situ measurement of mitochondrial oxidative capacity (24, 25). The time course of CytOx response during I/R in the control group was significantly different from that with CsA pretreatment (Fig. 3). These findings favor the protective effects of CsA and related alterations of MPT on mitochondrial function by conditioned suppression during ischemia and accelerated recovery during reperfusion-reoxygenation (26–30). Mitochondrial swelling is a well-documented ultrastructural change occurring after I/R and may be the response for uncoupling or inhibition of oxidative phosphorylation (31, 32). A subcritical decreased intracellular energy state promotes necrosis (5, 7, 28). Cyclosporine pretreatment blocks MPT pore opening and may prevent the energy-depleting effects of I/R injury with preservation of oxidative phosphorylation and ATP synthesis (12–17, 26–30, 33). Inhibition of MPT preserves the hydrogen ion gradient required for oxidative phosphorylation and ATP synthesis and mitochondrial morphology and function (12–17, 26–30, 33). Furthermore, increased ATP availability may also improve cellular calcium handling and mitochondrial performance (26, 28).

Protective effects on mitochondria and tissue including were observed in experimental investigations with different CsA doses (11–17, 28, 33). The reported dose of CsA in a previous rabbit myocardial I/R study was 25 mg/kg (16) and 50 mg/kg in a brain damage model (12). We used the single higher-dose bolus to achieve maximal load on the ischemic tissue with an effective dose of CsA.

Cyclosporine as a strong immunosuppressive drug is widely used clinically, and its adverse effects are well known (34, 35). Extensive research concerning the long-time use of CsA in organ transplantation revealed some adverse effects, which may include hypertension, reduction of kidney and liver function, paresthesia, tremor, gum hypertrophy or bleeding gums, increased risk of bacterial, and fungal or viral infections (34, 35). There are very few experiences about the adverse effects in the single-dose CsA treatment (11–17, 28, 33). Further investigations are needed to determine the optimal timing of application, routes (systemic or local administration), dose regimen, and common adverse effects.

We can only speculate about the significance of the results of this study and their practical clinical implications. Restoration of blood flow and reoxygenation of the tissue are the main steps to prevent or slow down ischemic injury processes. However, reperfusion can cause further impairment and may exacerbate ischemia-related injury, especially in longer periods of transient ischemia. Under certain circumstances, however, ischemia and reperfusion probably cause persistent tissue injury. The possibility of a pharmacological preprocedural and/or periprocedural protective intervention to attenuate the effects of I/R may be beneficial in different medical fields (transplantation, cardiac and vascular surgery, invasive cardiology, invasive neurology, neurosurgery, reconstructive surgery, vascular medicine, intensive care medicine, trauma) and is supported by recent investigations, particularly in the treatment of myocardial ischemia-reperfusion (6, 13, 14, 16, 36).

The results from this study support our hypothesis that single bolus CsA pretreatment prevents alterations and improves tissue oxygenation and mitochondrial oxidation in skeletal muscle I/R.

Back to Top | Article Outline
ABBREVIATIONS

CsA — cyclosporine

CytOx — cytochrome oxidase redox

I/R — ischemia and reperfusion-reoxygenation

LD — latissimus dorsi

HEP — high-energy phosphates

Pto2 — oxygen tension

PCr — phosphocreatine

ATP — adenosine triphosphate

MPT — mitochondrial permeability transition

NIR — near-infrared

Back to Top | Article Outline

REFERENCES

1. Blaisdell FW: The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg 10 (6): 620–630, 2002.

2. Anaya-Prado R, Toledo-Pereyra LH, Lentsch AB, Ward PA: Ischemia/reperfusion injury. J Surg Res 105 (2): 248–258, 2002.

3. Lundberg J, Elander A, Rakotonirainy O, Zetterlund T, Fogdestam I, Soussi B: Energy metabolism during microsurgical transfer of human skeletal muscle assessed by high-pressure liquid chromatography and by 31P-nuclear magnetic resonance. Scand J Plast Reconstr Surg Hand Surg 36 (3): 141–148, 2002.

4. Wang WZ, Baynosa RC, Zamboni WA: Update on ischemia-reperfusion injury for the plastic surgeon. Plast Reconstr Surg 128 (6): 685e–692e, 2011.

5. Harder Y, Amon M, Georgi M, Banic A, Erni D, Menger MD: Evolution of a “falx lunatica” in demarcation of critically ischemic myocutaneous tissue. Am J Physiol Heart Circ Physiol 288 (3): H1224–H1232, 2005.

6. Wang WZ, Baynosa RC, Zamboni WA: Therapeutic interventions against reperfusion injury in skeletal muscle. J Surg Res 171 (1): 175–182, 2011.

7. Carmo-Araújo EM, Dal-Pai-Silva M, Dal-Pai V, Cecchini R, Anjos Ferreira AL: Ischaemia and reperfusion effects on skeletal muscle tissue: morphological and histochemical studies. Int J Exp Pathol 88 (3): 147–154, 2007.

8. Troitzsch D, Vogt S, Abdul-Khaliq H, Moosdorf R: Muscle tissue oxygen tension and oxidative metabolism during ischemia and reperfusion. J Surg Res 128 (1): 9–14, 2005.

9. Troitzsch D, Moosdorf R, Vogt S: Importance of real-time tissue oximetry: relationship to muscle oxygenation and tissue viability. J Surg Res 169 (1): 156–161, 2011.

10. Mowlavi A, Neumeister MW, Wilhelmi BJ, Song YH, Suchy H, Russell RC: Local hypothermia during early reperfusion protects skeletal muscle from ischemia-reperfusion injury. Plast Reconstr Surg 111 (1): 242–250, 2003.

11. Askar I, Bozkurt M: Protective effects of immunosuppressants and steroids against ischemia-reperfusion injury in cremaster muscle flap at microcirculatory level. Microsurgery 22 (8): 361–366, 2002.

12. Friberg H, Ferrand-Drake M, Bengtsson F, Halestrap AP, Wieloch T: Cyclosporin A, but not FK 506, protects mitochondria and neurons against hypoglycaemic damage and implicates the mitochondrial permeability transition in cell death. J Neurosci 18 (14): 5151–5159, 1998.

13. Gomez L, Li B, Mewton N, Sanchez I, Piot C, Elbaz M, Ovize M: Inhibition of mitochondrial permeability transition pore opening: translation to patients. Cardiovasc Res 83 (2): 226–233, 2009.

14. 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 135 (1): 123–130, 2008.

15. Halestrap AP, Connern CP, Griffiths EJ, Kerr PM: Cyclosporine A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury. Mol Cell Biochem 174 (1–2): 167–172, 1997.

16. Leshnower BG, Kanemoto S, Matsubara M, Sakamoto H, Hinmon R, Gorman JH 3rd, Gorman RC: Cyclosporine preserves mitochondrial morphology after myocardial ischemia/reperfusion independent of calcineurin inhibition. Ann Thorac Surg 86 (4): 1286–1292, 2008.

17. Mowlavi A, Ghavami A, Song YH, Neumeister M: Limited use of cyclosporin A in skeletal muscle ischemia-reperfusion injury. Ann Plast Surg 46 (4): 426–430, 2001.

18. Wang WZ, Anderson GL, Firrell JC: Arteriole constriction following ischemia in denervated skeletal muscle. J Reconstr Microsurg 11 (2): 99–106, 1995.

19. Olivas TP, Saylor TF, Wong HP, Stephenson LL, Zamboni WA: Timing of microcirculatory injury from ischemia reperfusion. Plast Reconstr Surg 107 (3): 785–788, 2001.

20. Bonde C, Holstein-Rathlou NH, Elberg J: Evaluation of tissue oxygen measurements for flap monitoring in an animal model. J Reconstr Microsurg 24 (6): 391–396, 2008.

21. Schrey AR, Kinnunen IAJ, Grénman RA, Minn HRI, Aitasalo KMJ: Monitoring microvascular free flaps with tissue oxygen measurement and PET. Eur Arch Otorhinolarynol 265 (Suppl 1): S105–S113, 2008.

22. Hjortdal VE, Hauge E, Hansen ES: Differential effects of venous stasis and arterial insufficiency on tissue oxygenation in myocutaneous island flaps: an experimental study in pigs. Plast Reconstr Surg 89 (3): 521–529, 1992.

23. Mik EG, Johannes T, Zuurbier CJ, Heinen A, Houben-Weerts JH, Balestra GM, Stap J, Beek JF, Ince C: In vivo mitochondrial oxygen tension measured by a delayed fluorescence lifetime technique. Biophys J 95 (8): 3977–3990, 2008.

24. Cooper CE, Springett R: Measurement of cytochrome oxidase and mitochondrial energetics by near-infrared spectroscopy. Philos Trans R Soc Lond B Biol Sci 352 (1354): 669–676, 1997.

25. Wilson DF, Erecinska M: Effect of oxygen concentration on cellular metabolism. Chest 88 (Suppl 4): 229S–232S, 1985.

26. Halestrap AP: Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans 34 (Pt 2): 232–237, 2006.

27. Kim JS, He L, Lemasters JJ: Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochim Biophys Res Commun 304 (3): 463–470, 2003.

28. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y: Cyclophilin D–dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434 (7033): 652–658, 2005.

29. Halestrap AP: The regulation of the matrix volume of mammalian mitochondria in vivo and in vitro and its role in the control of mitochondrial metabolism. Biochim Biophys Acta 973 (3): 355–382, 1989.

30. Zoratti M, Szabo I: The mitochondrial permeability transition. Biochim Biophys Acta 1241 (2): 139–176, 1995.

31. Boustany NN, Drezek R, Thakor NV: Calcium-induced alterations in mitochondrial morphology quantified in situ with optical scatter imaging. Biophys J 83 (3): 1691–1700, 2002.

32. Safiulina D, Veksler V, Zharkovsky A, Kaasik A: Loss of mitochondrial membrane potential is associated with increase in mitochondrial volume: physiological role in neurones. J Cell Physiol 206 (2): 347–353, 2005.

33. Vaseva AV, Marchenko ND, Ji K, Tsirka SE, Holzmann S, Moll UM: P53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149 (7): 1536–1548, 2012.

34. Kahan BD: Cyclosporine. N Engl J Med 321 (25): 1725–1738, 1989.

35. Fahr A: Cyclosporin clinical pharmacokinetics. Clin Pharmacokinet 24 (6): 472–495, 1993.

36. Gill RS, Bigam DL, Cheung PY: The role of cyclosporine in the treatment of myocardial reperfusion injury. Shock 37 (4): 341–347, 2012.

Cited By:

This article has been cited 1 time(s).

Shock
What’s New in Shock? February 2013
Moldawer, LL
Shock, 39(2): 117-120.
10.1097/SHK.0b013e318283f6a9
PDF (2831) | CrossRef
Back to Top | Article Outline
Keywords:

Latissimus dorsi muscle; mitochondrial oxidation; oxygen tension; cyclosporine; ischemia-reperfusion; near-infrared spectroscopy; rabbits

©2013The Shock Society

Follow Us

Login

Article Tools

Images

Share

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.