Document Detail

Nonexocytotic noradrenaline release and ventricular fibrillation in ischemic rat hearts.
MedLine Citation:
PMID:  8751077     Owner:  NLM     Status:  MEDLINE    
In myocardial ischemia, nonexocytotic noradrenaline release has been identified as underlying mechanism of ischemia-evoked noradrenaline release. Nonexocytotic noradrenaline release can be suppressed by inhibitors of the neuronal noradrenaline carrier (uptake), such as desipramine. Utilizing this pharmacological intervention the role of local noradrenaline release in the genesis of ischemia-induced ventricular arrhythmias was studied. Regional ischemia was induced in rat isolated perfused hearts by ligature of the left anterior descending coronary artery, and the venous effluent obtained during the first 2 min of reperfusion was used to measure the release of endogenous noradrenaline by high-performance liquid chromatography methods. Coronary occlusion caused ventricular fibrillation in a well reproducible manner with an incidence of 70 to 80% during a 30 min observation period. Blockage of uptake1 by desipramine decreased the occurrence of ischemia-induced ventricular fibrillation to 60% (0.01 mumol/l) or 20% (0.1 mumol/l), and ventricular fibrillation was completely suppressed by 1 mumol/l desipramine. Likewise, desipramine (0.01-1 mumol/l) concentration-dependently reduced endogenous noradrenaline release during 30 min of regional myocardial ischemia. Nisoxetine, a structurally unrelated inhibitor of uptake1, also suppressed ischemia-evoked ventricular fibrillation. In contrast to its antifibrillatory effect during regional myocardial ischemia, desipramine precipitated arrhythmias when ventricular fibrillation was induced by perfusing normoxic hearts with exogenous noradrenaline. Combination of desipramine (0.1 mumol/l) with exogenous noradrenaline (0.01 to 1 mumol/l) increased the incidence of ventricular fibrillation compared to noradrenaline perfusion alone. Under these conditions, uptake1-blockade is known to increase the extracellular concentration of the perfused noradrenaline. Finally, in the isolated, spontaneously beating papillary muscle of the left rat heart, desipramine (0.1 and 1.0 mumol/l) had no effect on the upstroke velocity of action potentials, the action potential duration and the effective refractory period. In conclusion, the findings demonstrate that nonexocytotic noradrenaline release is an important mediator of ischemia-induced ventricular fibrillation in isolated hearts of the rat. It is also documented that uptake1 inhibitors such as desipramine reveal their effects on ventricular fibrillation secondary to their action on transmembrane noradrenaline transport.
T Kurz; B Offner; J Schreieck; G Richardt; R Tölg; A Schömig
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Naunyn-Schmiedeberg's archives of pharmacology     Volume:  352     ISSN:  0028-1298     ISO Abbreviation:  Naunyn Schmiedebergs Arch. Pharmacol.     Publication Date:  1995 Nov 
Date Detail:
Created Date:  1996-09-24     Completed Date:  1996-09-24     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0326264     Medline TA:  Naunyn Schmiedebergs Arch Pharmacol     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  491-6     Citation Subset:  IM    
Medizinische Klinik der Technischen Universität München, Klinikum rechts der Isar, Germany.
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MeSH Terms
Adrenergic Uptake Inhibitors / pharmacology
Anti-Arrhythmia Agents / pharmacology
Carrier Proteins / antagonists & inhibitors,  metabolism
Desipramine / pharmacology
Fluoxetine / analogs & derivatives,  pharmacology
Myocardial Ischemia / metabolism*,  physiopathology
Norepinephrine / metabolism*
Rats, Wistar
Ventricular Fibrillation / metabolism*
Reg. No./Substance:
0/Adrenergic Uptake Inhibitors; 0/Anti-Arrhythmia Agents; 0/Carrier Proteins; 50-47-5/Desipramine; 51-41-2/Norepinephrine; 54910-89-3/Fluoxetine; 57226-61-6/nisoxetine

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