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Role of mitochondrial permeability transition pore (mPTP) in volatile anaesthetic-induced cardioprotection

Projectomschrijving

Hartspierweefsel kan worden beschermd tegen een hartinfarct door het tijdelijk aanbrengen van zuurstofarme omstandigheden of het toedienen van vluchtige verdovingsmiddelen (‘preconditionering’). Het edelgas helium heeft een vergelijkbaar effect. Het mechanisme daarachter is onderzocht met harten van gezonde en van oude ratten en van ratten met diabetes. Helium blijkt invloed te hebben op de calciumkanaaltjes in de mitochondriën (de energiefabriekjes) van de cellen en regelt zo de ademhaling in de mitochondriën. Zowel het effect van helium op de mitochondriën als op de bescherming van het hartweefsel is afhankelijk van de leeftijd (hoe ouder hoe minder groot). Het hart van ratten met diabetes laat zich niet door helium beschermen tegen ischemie (zuurstofloze omstandigheden).

Producten

Titel: Postconditioning by xenon and hypothermia in the rat heart in vivo
Auteur: Schwiebert C, Huhn R, Heinen A, Weber NC, Hollmann MW, Schlack W, Preckel B
Magazine: European Journal of Anaesthesiology
Titel: Helium-induced late preconditioning in the rat heart in vivo
Auteur: Huhn R, Heinen A, Weber NC, Hieber S, Hollmann MW, Schlack W, Preckel B
Magazine: British Journal of Anaesthesia
Titel: Hyperglycaemia blocks sevoflurane-induced postconditioning in the rat heart in vivo: cardioprotection can be restored by blocking the mitochondrial permeability transition pore
Auteur: Huhn R, Heinen A, Weber NC, Hollmann MW, Schlack W, Preckel B
Magazine: British Journal of Anaesthesia
Titel: Cyclosporine A administered during reperfusion fails to restore cardioprotection in prediabetic Zucker obese rats in vivo
Auteur: Huhn R, Heinen A, Hollmann MW, Schlack W, Preckel B, Weber NC
Magazine: Nutrition Metabolism and Cardiovascular Biology
Titel: Helium-induced preconditioning in young and old rat heart - Impact of mitochondrial Ca2+-sensitive potassium channel activation
Auteur: Heinen A & Huhn R, Smeele KMA, Zuurbier CJ, Schlack W, Preckel B, Weber NC, Hollmann MW
Magazine: Anesthesiology
Titel: Helium-induced early preconditioning and postconditioning is abolished in obese Zucker rats in vivo
Auteur: Huhn R, Heinen A, Hauck-Weber NC, Kerindongo RP, Oei GT, Hollmann MW, Schlack W, Preckel B
Magazine: Journal of Pharmacology and Experimental Therapeutics
Titel: Physiological levels of glutamine prevent morphine induced preconditioning in the isolated rat heart
Auteur: Heinen A, Huhn R, Schlack W, Hollmann MW, Preckel B, Fräßdorf J, Weber NC
Magazine: European Journal of Pharmacology
Titel: The Role of Mitochondria in Cardioprotection
Auteur: Heinen A

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Samenvatting van de aanvraag

Brief exposures to a volatile anaesthetic protect the myocardium against the consequences of ischaemia/ reperfusion (I/R) injury; a phenomenon that is known as anaesthetic-induced preconditioning (APC). This protection is manifested not only by decreased infarct size but also by decreased postischaemic myocardial contractile dysfunction (“myocardial stunning”) and less endothelial dysfunction. There is increasing evidence for a role of mitochondria both as “trigger’ and “end-effector” of APC. It was shown that opening of mitochondrial permeability transition pore (mPTP) during I/R is a key step to induce necrosis and/or apoptosis. Our working hypothesis is that APC protects the heart against I/R injury via modulation of the mPTP. Here, we will investigate, if APC protects the myocardium by prevention of mPTP opening. Furthermore, we will investigate, if APC regulates mitochondrial function before ischaemia to prevent mPTP opening during ischaemia and reperfusion. For this purpose we will use a) a isolated perfused heart model to investigate a general role for mPTP in APC, b) isolated mitochondria to investigate the mechanism(s) by which APC affects mitochondrial function to prevent mPTP opening, and c) western blot analysis to investigate the impact of APC on release of apoptogenic Cytochrome C, caspase-3 activation and DNA fragmentation due to mPTP opening. The results of this study will help to understand the underlying mechanisms by which APC protects the heart against ischaemia/reperfusion injury. The following specific questions will be addressed: 1. Role of mPTP in APC: Does APC protect the heart against infarction via modulation of mPTP during I/R in an isolated rat heart model? 2. Mitochondrial mechanisms of APC: What are the underlying mitochondrial mechanisms by which APC prevents mPTP opening?

Onderwerpen

Kenmerken

Projectnummer:
92003450
Looptijd: 100%
Looptijd: 100 %
2007
2009
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. M.W. Hollmann
Verantwoordelijke organisatie:
Amsterdam UMC - locatie AMC