title: Carrier-mediated norepinephrine release and reperfusion arrhythmias induced by protracted ischemia in isolated perfused guinea pig hearts: effect of presynaptic modulation by alpha(2)-adrenoceptor in mild hypothermic ischemia.
abstract: Yohimbine, an alpha(2)-adrenoceptor antagonist, has been reported to protect hypoxic myocardium and inhibit carrier-mediated norepinephrine (NE) release and reperfusion arrhythmias (ventricular fibrillation; VF) in normothermic ischemia. In heart surgery, mild hypothermic (tepid) cardioplegia has been reported to reduce metabolic demand and permit immediate recovery of cardiac function. Therefore, we determined the effect of yohimbine on NE release and reperfusion arrhythmias in isolated perfused guinea pig hearts of tepid temperature (32 degrees C) ischemia model. Stepwise increase of global ischemia period (20, 40, and 60 min) induced a progressive increase of NE release and duration of VF. Neuronal uptake 1 inhibitor desipramine (100 nM) and Na(+)-H(+) exchanger inhibitor 5-N-ethyl-N-isopropyl-amiloride (10 microM) decreased NE and VF in 60-min hypothermic ischemia. This indicated that NE release induced by protracted tepid ischemia was due to carrier-mediated release. Yohimbine (1 microM) markedly reduced NE release and VF (p < 0.01 versus control) and 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine [UK 14,304 (UK); 10 microM], an alpha(2)-adrenoceptor agonist, increased NE release and VF (p < 0.01 versus control). Yohimbine (1 microM) prevented the potentiated effect of UK (10 microM) in hypothermia (p < 0.01 versus UK). Our findings indicate that presynaptic reduction of carrier-mediated NE release seems to be one of the most important factors controlling reperfusion arrhythmias, and alpha(2)-adrenoceptor blockade by yohimbine (1 microM) in tepid ischemia may contribute to effective myocardial protection in terms of NE release and reperfusion arrhythmia.
authors.affiliation: Department of Cardiovascular Surgery, Hokkaido University School of Medicine, N14W5, Kita-Ku, Sapporo 060-8648, Japan. jungeka@med.hokudai.ac.jp
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Oka
authors.forename: Michiaki
authors.initials: M
authors.lastname: Imamura
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Hatta
authors.forename: Ryushi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Isaka
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Murashita
authors.forename: Keishu
authors.initials: K
authors.lastname: Yasuda
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007036:Hypothermia, Induced; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D027981:Symporters / Q000037:antagonists & inhibitors; D013569:Synapses / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017923:Sodium-Hydrogen Exchangers; D027981:Symporters; D015016:Yohimbine; D009638:Norepinephrine