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Protecting the ischemic heart : pharmacological protection against myocardial ischemia in rats in vivo and in vitro

Butz, Silvia. Protecting the ischemic heart : pharmacological protection against myocardial ischemia in rats in vivo and in vitro. 2004, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_6831

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Abstract

Today in Switzerland approximately 40% of all deaths are due to cardiovascular diseases. More than half of these are due to ischemic heart disease. Among the fatal consequences of ischemic heart disease are life-threatening arrhythmias and myocardial infarction. This thesis contains two studies focusing on pharmacological protection against the consequences of myocardial ischemia. The first study focuses on reperfusion arrhythmias and the second study focuses on reducing myocardial infarction size. The first study is based on the finding, that the angiotensin II receptor type(AT1) blocker losartan might be associated with a lower mortality than that found with the angiotensin converting enzyme (ACE) inhibitor captopril in elderly heart failure patients. This difference appeared to arise largely from a decrease of sudden death in losartantreated patients. As ventricular tachyarrhythmias, particularly ventricular fibrillation (VF), contribute largely to sudden death, losartan has been suggested to be antiarrhytmic. Therefore, the goal of the present study was to assess acute antiarrhythmic effects of losartan and enalaprilat in hypertrophied rat hearts during low-flow ischemia/reperfusion. In dose-finding experiments in non-hypertrophied isolated perfused hearts, we performed dose-response curves of losartan (1 nM tomM) and enalaprilat (1 nM tomM) studying monophasic action potential duration at 90% repolarisation (MAPD90%) and ventricular fibrillation (VF) threshold. Subsequently, we determined the effects of losartan and enalaprilat in therapeutically relevant concentrations on ventricular tachyarrhythmias induced by low-flow ischemia/reperfusion in hearts demonstrating left ventricular (LV) hypertrophy 70 days after aortic banding. We found that neither drug significantly affected MAPD90% or VF threshold in non-hypertrophied hearts. Similarly in hypertrophied hearts, neither drug significantly affected the incidence or the duration of ventricular tachyarrhythmias (ventricular tachycardia and VF) during low-flow ischemia. However,µM losartan significantly reduced the duration of ventricular tachyarrhythmias during reperfusion. In conclusion, neither losartan nor enalaprilat is acutely antiarrhythmic in hypertrophied rat hearts during low-flow ischemia. During reperfusion, however, losartan but not enalaprilat exerts acute antiarrhythmic effects. The second study focuses on nuclear factor kappa-B (NF-kB), an ubiquitous transcription
factor, that is involved in immune, inflammatory, and stress responses. Accordingly NFkB
might play an important role in myocardial ischemia-reperfusion injury. Dimethyl
fumarate (DMF), an orally available small molecule drug for psoriasis patients, has been
shown to inhibit TNFa-induced nuclear entry of NF-kB in endothelial cells in vitro.
Therefore we postulated that DMF might also affect NF-kB in cardiomyocytes in vivo
and thus reduce myocardial infarction following ischemia and reperfusion. Male
Sprague-Dawley rats undergoing left coronary artery occlusion for 45 min received either
DMF (10 mg/kg b.w.) or vehicle 90 min before ischemia as well as immediately before
ischemia. The positive control group received the vehicle plus ischemic preconditioning
(2 x 5 min ischemia, each followed by 5 min of reperfusion). After 120 min of
reperfusion, the hearts were stained with phthalocyanine blue dye (area at risk) and
2,3,5-triphenyltetrazolium chloride (infarct area). Heart rate and QTC interval were
determined on the recorded ECG. Additionally, acute hemodynamic and
electrophysiologic effects of DMF were determined in dose-response curves in isolated
perfused rat hearts. We found that myocardial infarct size was significantly smaller in rats
that had received DMF or ischemic preconditioning than in control rats. Neither heart rate
nor QTC interval differed between DMF-treated and untreated animals. Dose-response
experiments (0.1 μM to 1000 μM) in isolated perfused rat hearts excluded acute
hemodynamic (coronary flow and left ventricular pressure) or electrophysiologic effects
(action potential duration) as a mechanism for the antinecrotic effects of DMF. In
conclusion, this study in rats in vivo demonstrates that DMF reduces myocardial infarct
size after ischemia and reperfusion. The molecular mechanisms for this effect of DMF on
myocardial infarct size are presently not clear.
Advisors:Eberle, Alex N.
Committee Members:Hofbauer, Karl G. and Zaugg, Christian Ernst
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Endocrinology (Eberle)
UniBasel Contributors:Eberle, Alex N. and Hofbauer, Karl G.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:6831
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:76
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:50
Deposited On:13 Feb 2009 15:28

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