Inhibition of nonexocytotic norepinephrine release by desipramine reduces myocardial infarction size.
During myocardial ischemia, a substantial accumulation of norepinephrine occurs in the ischemic zone due to a local nonexocytotic release of norepinephrine. Norepinephrine release is driven by the neuronal monoamine transporter (NET), which reverses its usual transmembrane transport direction. We investigated whether this local accumulation of norepinephrine contributes to irreversible myocardial injury in an in vivo model of myocardial infarction. Male, anaesthetized Wistar rats were subjected to 30 min coronary occlusion and subsequent 120 min reperfusion. Five minutes prior to coronary occlusion, the NET inhibitor desipramine was administered intravenously. Infarct size (IS) was determined by TTC-staining and was related to the area at risk (AAR). The influence of desipramine on cardiac norepinephrine release was investigated in isolated perfused hearts with 30 min of regional ischemia. Norepinephrine was measured in the effluent from the hearts by HPLC and electrochemical detection. Desipramine (0.1-0.8 mg/kg) dose-dependently reduced infarct size (IS/AAR) from 0.54 to 0.21 and suppressed postischemic norepinephrine release from 245 to 108 pg/mL. In summary, the data indicate that nonexocytotic release of norepinephrine in myocardial ischemia exaggerates acute ischemic damage, because suppression of ischemia-induced release of norepinephrine by the tricyclic antidepressant desipramine effectively reduces infarct size in an in vivo model of myocardial ischemia.
Richardt
Doreen
D
Institut für experimentelle und klinische Pharmakologie und Toxikologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Germany.
Dendorfer
Andreas
A
Tölg
Ralph
R
Dominiak
Peter
P
Richardt
Gert
G
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003331:Coronary Vessels / Q000601:surgery; D003891:Desipramine / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry / Q000379:methods; D066298:In Vitro Techniques; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D018759:Adrenergic Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; D003891:Desipramine; D009638:Norepinephrine