Academisch Medisch Centrum Universiteit van Amsterdam

• Effects of anesthetics on intracellular signaling transduction, especially Local Anesthetic interactions with G protein coupled receptor signaling
• Modulation of NMDA receptor signaling
• Ketamine & Magnesium in pain therapy
• Clinical "alternative" effects of Local Anesthetics, especially modulation of inflammatory and hemostatic responses, effects on gastro-intestinal motility, cognitive function, bronchial hyperreactivity and wound healing

Research Interests:

1. Anesthetics & Intracellular Signaltransduction
Effects of different anesthetics (local anesthetics, volatile anesthetics, ketamine) on G protein-coupled receptor (GPCR) and glutamate (e.g. NMDA receptor) signaling with special emphasis on less known properties (so called “alternative” effects) of local anesthetics (e.g. anti-inflammatory, anti-thrombotic, anti-hyperalgesic, neuroprotective actions) and their underlying mechanisms.

In a translational approach these effects were studied from a very basic level, e.g. anesthetic interactions with specific G protein subunits (in a completely reconstituted system – baculovirus vector expression in Sf9 insect cells), via recombinant expression systems (Xenopus oocytes) and human polymorphonuclear cells to the clinical setting.

Most likely based on their modulatory action on inflammation and coagulation, local anesthetics when applied continuous intravenously in the perioperative period were shown to improve outcome.

Research Group
This work is primarily done at the Departments of Anesthesiology and Pharmacology of the University Heidelberg, Germany (PI: Dr. med. Susanne Herroeder, Dr. med. Marianne Schoenherr, Drs. Grit Kaulitz, Drs. Sibylle Bayer, Drs. Barbara Troester) and in collaboration with the Laboratorium of Experimental Anesthesiology & Intensive Care (EXPANIT Signaling - http://www.expanitsignaling.com) at the University of Munster, Germany. (PI: PD Dr. med. Klaus Hahnenkamp)

2. Pharmacological Cardioprotection

This is one the key aspects of research activities at L.E.I.C.A. Cardioprotective actions of anesthetics (e.g. volatile anesthetics, opiates) are evaluated under various experimental conditions for their effectiveness and mechanisms of action.

3. Pharmacological Modulation of transalveolar Ion transport  

These projects are performed in collaboration with the Departments of Anesthesiology (PI: Dr. med. M. M. Berger) and Sports Medicine (Direktor Prof. Bartsch) at the University of Heidelberg, Germany. The effects of different anesthetics (e.g. ketamine) on transalveolar ion transport and fluid shift in various experimental models is investigated. Detailed mechanisms of action and involvement of epithelial sodium channels (E_Nac) will be determined. Link to: http://www.klinikum.uni-heidelberg.de/Sektion-Klinisch-Experimentelle-Anaesthesiologie.4288.0.html

4. Pathophysiology and Treatment of Cerebral Air Embolism  

Gas embolism, defined as the entry of gas into vascular structures, can occur in many clinical environments as an iatrogenic complication and in diving medicine. In most cases gas embolism is in fact an air embolism, although the medical use of other gases (such as carbon dioxide) can also result in this condition. Air bubbles may reach any organ, but their effect on the cerebral and cardiac circulation is particularly deleterious because these organs are highly vulnerable for hypoxia. In a clinical situation most venous gas emboli occur in patients in whom a central venous catheter has been placed. The greatest risks for arterial gas embolism occur with cardiac surgery with cardiopulmonary bypass, craniotomy performed with the patients in the sitting position, and hip replacement procedures. Hyperbaric oxygen therapy has been advocated as a therapy for gas embolism, whereby the patient breathes 100% oxygen at a pressure above that of the atmosphere at sea level. The increased ambient pressure (decreases the size of the gas bubbles) and the resulting systemic hyperoxia improves oxygenation of hypoxic tissue. Questions have been raised about the effect of HBO therapy in relation to timing of treatment. Most investigators agree, however, that early, rather than late, treatment is most appropriate for air embolism. Unfortunately, data supporting this statement are more anecdotal than scientific. Animal studies reported that lidocaine reduces brain infarct size, preserves cerebral blood flow, reduces cerebral edema and preserves neuro-electrical function. These results in brain-injured animals showed that lidocaine improves cerebral function. In close cooperation with the Diving Medical Center , Royal Netherlands Navy, we study lidocaine as a brain protective drug and the use of hyperbaric oxygen therapy, in particular different time delays before treatment. We use a validated animal model of cerebral air embolism. We employ microsensor technology to measure brain oxygenation and intracranial pressure combined with a microdialysis technique to measure brain glucose and lactate levels.

5. Molecular Mechanisms of neurotoxicity of anesthetics  

Toxic effects of local and general anesthetics were evaluated in different human cell culture models. The apoptotic pathways of different local anesthetics and various general anesthetics (ketamine, midazolam, propofol) were elucidated in neuronal (SHEP) and lymphoma (Jurkat) cells. Llocal anesthetic in clinical concentrations induce apoptosis via the mitochondrial pathway (protected by Bcl 2 overexpression and Caspase 9 deficiency) independently of the death-receptor pathway (FADD and Caspase 8 deficiency).

Research Group
This work is primarily done at the Department of Anesthesiology at the University Hospital Duesseldorf, Germany (Coworkers: Dr. Sebastian Braun, Prof. Dr. Peter Lipfert, Dr. Henning Hermanns, Dr. Robert Werdehausen) in collaboration with the Institute of Molecular Medicine of the University Hospital Duesseldorf (PD Dr. Frank Essmann, Prof. Dr. Klaus Schulze-Osthoff) and the Division of Apoptosis Regulation, German Cancer Research Center (DKFZ), Heidelberg (Dr. Henning Walczak)

International Collaborations:

• Department of Anesthesiology, University of Heidelberg, Germany
• Department of Pharmacology, University of Heidelberg, Germany
• Department of Anesthesiology, University of Dusseldorf, Germany
• Department of Anesthesiology, EXPANIT Signaling, University of Munster, Germany
• Department of Anesthesiology, University of Virginia , Charlottesville, US
• Department of Anesthesiology, University of Colorado (UCHSC), Denver, US

Funding
The work is funded by the German Research Society (DFG), NWO, Society of Cardiovascular Anesthesia (SCA), European Society of Anesthesiologists (ESA), Dutch Ministry of Defense, Medical Faculty of the University of Heidelberg, Germany, Medical Faculty of the Academic Medical Center (AMC), Amsterdam, The Netherlands and Institutional grants.

In the range of cardioprotection we established different experimental models to investigate cardioprotective effects of anesthetics. 1) an in vivo model to study Sevoflurane-induced cardioprotection in hyperglycaemic rats, 2)  an in vitro model to determine the influence of different substrate conditions and preconditioning protocols on morphine-induced cardioprotection in the isolated rat heart and 3) Isolation of mitochondria from rat heart to identify the role of mitochondrial function in cardioprotection. Additionally, we evaluated the role of cardiac hexokinase in cell death. We examined how morphine affects cardiac hexokinase, and its relation to anesthesia, preconditioning, and genetic manipulation. Furthermore in collaboration with Rotterdam (EG Mik) we determined for the first time ever liver mitochondrial oxygen tension in vivo. Clinically, we studied how insulin therapy affects the neurohumoral stress response in cardiac surgery patients. With regard to anesthetics and intracellular signal transduction we were able to show that local anesthetics (LA) inhibit the activation of human NMDA receptors in a concentration dependent manner, independent of the charge of the LA and by an intracellular mechanism most likely mediated via inhibition of proteinkinase C (PKC). This effect may contribute to reduced hyperalgesia and opiate tolerance observed after systemic administration of LA.

Theme: Cardiovascular Diseases