The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia
Neuroprotective strategies after cardiopulmonary resuscitation are currently the focus of experimental and clinical research. Levosimendan has been proposed as a promising drug candidate because of its cardioprotective properties, improved haemodynamic effects in vivo and reduced traumatic brain injury in vitro. The effects of levosimendan on brain metabolism during and after ischaemia/hypoxia are unknown.
Transient cerebral ischaemia/hypoxia was induced in 30 male Wistar rats by bilateral common carotid artery clamping for 15 min and concomitant ventilation with 6% O2 during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 μg kg-1 levosimendan followed by a continuous infusion of 0.2 μg kg-1 min-1. The changes in the energy-related metabolites lactate, the lactate/pyruvate ratio, glucose and glutamate were monitored by microdialysis. In addition, the effects on global haemodynamics, cerebral perfusion and autoregulation, oedema and expression of proinflammatory genes in the neocortex were assessed.
Levosimendan reduced blood pressure during initial reperfusion (72 ± 14 vs. 109 ± 2 mmHg, p = 0.03) and delayed flow maximum by 5 minutes (p = 0.002). Whereas no effects on time course of lactate, glucose, pyruvate and glutamate concentrations in the dialysate could be observed, the lactate/pyruvate ratio during initial reperfusion (144 ± 31 vs. 77 ± 8, p = 0.017) and the glutamate release during 90 minutes of reperfusion (75 ± 19 vs. 24 ± 28 μmol·L-1) were higher in the levosimendan group. The increased expression of IL-6, IL-1ß TNFα and ICAM-1, extend of cerebral edema and cerebral autoregulation was not influenced by levosimendan.
Although levosimendan has neuroprotective actions in vitro and on the spinal cord in vivo and has been shown to cross the blood–brain barrier, the present results showed that levosimendan did not reduce the initial neuronal injury after transient ischaemia/hypoxia.
- Fukuda S, Warner DS: Cerebral protection. Br J Anaesth 2007, 99:10–17. CrossRef
- Valtysson J, Persson L, Hillered L: Extracellular ischaemia markers in repeated global ischaemia and secondary hypoxaemia monitored by microdialysis in rat brain. Acta Neurochir (Wien) 1998, 140:387–395. CrossRef
- Zoremba N, Homola A, Rossaint R, Sykova E: Brain metabolism and extracellular space diffusion parameters during and after transient global hypoxia in the rat cortex. Exp Neurol 2007, 203:34–41. CrossRef
- Sanders RD, Manning HJ, Robertson NJ, Ma D, Edwards AD, Hagberg H, Maze M: Preconditioning and postinsult therapies for perinatal hypoxic-ischemic injury at term. Anesthesiology 2010, 113:233–249. CrossRef
- Zhao Z, Corvera JS, Halkos ME, Kerendi F, Wang N, Guyton RA, Vinten-Johansen J: Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 2003, 285:H579-H588.
- Zhao Z:Vinten-Johansen J: Postconditioning: reduction of reperfusion-induced injury. Cardiovasc Res 2006, 70:200–211. CrossRef
- Saver JL: Time is brain–quantified. Stroke 2006, 37:263–266. CrossRef
- Bernard S: Hypothermia after cardiac arrest: expanding the therapeutic scope. Crit Care Med 2009, 37:S227-S233. CrossRef
- Hausenloy DJ, Yellon DM: The therapeutic potential of ischemic conditioning: an update. Nat Rev Cardiol 2011,8(11):619–629. CrossRef
- Gao X, Ren C, Zhao H: Protective effects of ischemic postconditioning compared with gradual reperfusion or preconditioning. J Neurosci Res 2008, 86:2505–2511. CrossRef
- Kersten JR, Montgomery MW, Pagel PS, Warltier DC: Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels. Anesth Analg 2000, 90:5–11. CrossRef
- Hein M, Roehl AB, Baumert JH, Scherer K, Steendijk P, Rossaint R: Anti-ischemic effects of inotropic agents in experimental right ventricular infarction. Acta Anaesthesiol Scand 2009, 53:941–948. CrossRef
- Katircioglu SF, Seren M, Parlar AI, Turan NN, Manavbasi Y, Aydog G, Cicekcioglu F, Tutun U, Ulus AT: Levosimendan effect on spinal cord ischemia-reperfusion injury following aortic clamping. J Card Surg 2008, 23:44–48. CrossRef
- Lafci B, Yasa H, Ilhan G, Ortac R, Yilik L, Kestelli M, Goktogan T, Gurbuz A: Protection of the spinal cord from ischemia: comparative effects of levosimendan and iloprost. Eur Surg Res 2008, 41:1–7. CrossRef
- Roehl AB, Hein M, Loetscher PD, Rossaint J, Weiss J, Rossaint R, Coburn M: Neuroprotective properties of Levosimendan in an in vitro model of traumatic brain injury. BMC Neurol 2010, 10:97. CrossRef
- Honisch A, Theuring N, Ebner B, Wagner C, Strasser RH, Weinbrenner C: Postconditioning with levosimendan reduces the infarct size involving the PI3K pathway and KATP-channel activation but is independent of PDE-III inhibition. Basic Res Cardiol 2010, 105:155–167. CrossRef
- Das B, Sarkar C: Pharmacological preconditioning by levosimendan is mediated by inducible nitric oxide synthase and mitochondrial KATP channel activation in the in vivo anesthetized rabbit heart model. Vascul Pharmacol 2007, 47:248–256. CrossRef
- Kopustinskiene DM, Pollesello P, Saris NE: Levosimendan is a mitochondrial K(ATP) channel opener. Eur J Pharmacol 2001, 428:311–314. CrossRef
- Mayanagi K, Gaspar T, Katakam PV, Busija DW: Systemic administration of diazoxide induces delayed preconditioning against transient focal cerebral ischemia in rats. Brain Res 2007, 1168:106–111. CrossRef
- Bantel C, Maze M, Trapp S: Neuronal preconditioning by inhalational anesthetics: evidence for the role of plasmalemmal adenosine triphosphate-sensitive potassium channels. Anesthesiology 2009, 110:986–995. CrossRef
- Guide for the care and use of laboratory animals: Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council. 8th edition. Washington, DC: National Academy Press; 2011.
- Zoremba N, Homola A, Slais K, Vorisek I, Rossaint R, Lehmenkuhler A, Sykova E: Extracellular diffusion parameters in the rat somatosensory cortex during recovery from transient global ischemia/hypoxia. J Cereb Blood Flow Metab 2008,28(10):1665–1673. CrossRef
- Dethloff TJ, Knudsen GM, Larsen FS: Cerebral blood flow autoregulation in experimental liver failure. J Cereb Blood Flow Metab 2008, 28:916–926. CrossRef
- Ungerstedt U: Microdialysis–principles and applications for studies in animals and man. J Intern Med 1991, 230:365–373. CrossRef
- Blaustein MP, Lederer WJ: Sodium/calcium exchange: its physiological implications. Physiol Rev 1999, 79:763–854.
- Kulik A, Trapp S, Ballanyi K: Ischemia but not anoxia evokes vesicular and Ca(2+)-independent glutamate release in the dorsal vagal complex in vitro . J Neurophysiol 2000, 83:2905–2915.
- Kunimatsu T, Asai S, Kanematsu K, Zhao H, Kohno T, Misaki T, Ishikawa K: Transient in vivo membrane depolarization and glutamate release before anoxic depolarization in rat striatum. Brain Res 1999, 831:273–282. CrossRef
- Lasarzik I, Noppens RR, Wolf T, Bauer H, Luh C, Werner C, Engelhard K, Thal SC: Dose-Dependent Influence of Sevoflurane Anesthesia on Neuronal Survival and Cognitive Outcome After Transient Forebrain Ischemia in Sprague–Dawley Rats. Neurocrit Care 2011,15(3):577–584. CrossRef
- Iqbal S, Baziany A, Gordon S, Wright S, Hussain M, Miyashita H, Shuaib A, Hasan Rajput A: Neuroprotective effect of tiagabine in transient forebrain global ischemia: an in vivo microdialysis, behavioral, and histological study. Brain Res 2002, 946:162–170. CrossRef
- Nakayama R, Yano T, Ushijima K, Abe E, Terasaki H: Effects of dantrolene on extracellular glutamate concentration and neuronal death in the rat hippocampal CA1 region subjected to transient ischemia. Anesthesiology 2002, 96:705–710. CrossRef
- Choi SK, Lee G, Choi S, Kim YJ, Park H, Park BJ: Neuroprotective effects by nimodipine treatment in the experimental global ischemic rat model: real time estimation of glutamate. J Korean Neurosurg Soc 2011, 49:1–7. CrossRef
- Kang SW, Choi S, Park E, Chae S, Choi S, Jin Joo H, Lee G, Park H: Neuroprotective effects of magnesium-sulfate on ischemic injury mediated by modulating the release of glutamate and reduced of hyperreperfusion. Brain Res 2011, 1371:121–128. CrossRef
- Domoki F, Perciaccante JV, Veltkamp R, Bari F, Busija DW: Mitochondrial potassium channel opener diazoxide preserves neuronal-vascular function after cerebral ischemia in newborn pigs. Stroke 1999, 30:2713–8–2718–9. discussion CrossRef
- Robin E, Simerabet M, Hassoun SM, Adamczyk S, Tavernier B, Vallet B, Bordet R, Lebuffe G: Postconditioning in focal cerebral ischemia: role of the mitochondrial ATP-dependent potassium channel. Brain Res 2011, 1375:137–146. CrossRef
- Yamada K, Ji JJ, Yuan H, Miki T, Sato S, Horimoto N, Shimizu T, Seino S, Inagaki N: Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure. Science 2001, 292:1543–1546. CrossRef
- Grover GJ, Newburger J, Sleph PG, Dzwonczyk S, Taylor SC, Ahmed SZ, Atwal KS: Cardioprotective effects of the potassium channel opener cromakalim: stereoselectivity and effects on myocardial adenine nucleotides. J Pharmacol Exp Ther 1991, 257:156–162.
- Antila S, Huuskonen H, Nevalainen T, Kanerva H, Vanninen P, Lehtonen L: Site dependent bioavailability and metabolism of levosimendan in dogs. Eur J Pharm Sci 1999, 9:85–91. CrossRef
- Abo-Ramadan U, Durukan A, Pitkonen M, Marinkovic I, Tatlisumak E, Pedrono E, Soinne L, Strbian D, Tatlisumak T: Post-ischemic leakiness of the blood–brain barrier: a quantitative and systematic assessment by Patlak plots. Exp Neurol 2009, 219:328–333. CrossRef
- Koizumi H, Fujisawa H, Suehiro E, Shirao S, Suzuki M: Neuroprotective effects of ebselen following forebrain ischemia: involvement of glutamate and nitric oxide. Neurol Med Chir (Tokyo) 2011, 51:337–343. CrossRef
- Munakata H, Okada K, Hasegawa T, Hino Y, Kano H, Matsumori M, Okita Y: Controlled low-flow reperfusion after warm brain ischemia reduces reperfusion injury in canine model. Perfusion 2010, 25:159–168. CrossRef
- Bravo MC, Lopez P, Cabanas F, Perez-Rodriguez J, Perez-Fernandez E, Quero J, Pellicer A: Acute effects of levosimendan on cerebral and systemic perfusion and oxygenation in newborns: an observational study. Neonatology 2011, 99:217–223. CrossRef
- Cengiz SL, Erdi MF, Tosun M, Atalik E, Avunduk MC, Sonmez FC, Mehmetoglu I, Baysefer A: Beneficial effects of levosimendan on cerebral vasospasm induced by subarachnoid haemorrhage: an experimental study. Brain Inj 2010, 24:877–885. CrossRef
- Lenzser G, Kis B, Bari F, Busija DW: Diazoxide preconditioning attenuates global cerebral ischemia-induced blood–brain barrier permeability. Brain Res 2005, 1051:72–80. CrossRef
- Zhu H, Luo W, Wang H: Iptakalim protects against hypoxic brain injury through multiple pathways associated with ATP-sensitive potassium channels. Neuroscience 2008, 157:884–894. CrossRef
- Denes A, Ferenczi S, Kovacs KJ: Systemic inflammatory challenges compromise survival after experimental stroke via augmenting brain inflammation, blood- brain barrier damage and brain oedema independently of infarct size. J Neuroinflammation 2011, 8:164. CrossRef
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/12/81/prepub
- The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
- Online Date
- August 2012
- Online ISSN
- BioMed Central
- Additional Links
- Cerebral ischaemia
- Author Affiliations
- 1. Department of Anaesthesiology, RWTH Aachen University Hospital, Pauwelstrasse 30, Aachen, D-52074, Germany
- 2. Department of Neuroanatomy, RWTH Aachen, Wendlingweg 2, Aachen, 52072, Germany
- 3. Department of Neurology, RWTH Aachen University Hospital, Pauwelstrasse 30, Aachen, 52074, Germany
- 4. MLHB, Medical Laboratory Bremen, Haferwende 12, Bremen, 28357, Germany
- 5. Department of Experimental Animal Science, RWTH Aachen University Hospital, Pauwelstrasse 30, Aachen, 52074, Germany