title: Mitochondrial pores modulate the protective effect of acetylcholine on ventricular myocytes during ischemia/reperfusion injury.
abstract: In this study, we investigated the cardioprotective effect of acetylcholine (ACh) via modulation of mitochondrial permeability transition pore (MPTP) opening through the mitochondrial ATP-sensitive potassium channel (mitoK(ATP) channel). In isolated ventricular myocytes from male Sprague-Dawley rats, 0.1 micromol/L ACh was administered for 6 min, before 30 min of simulated ischemia and 30 min of reperfusion (I/R). A mitoK(ATP) inhibitor (5-hydroxydecanoate, 5-HD) and an MPTP opener (atractyloside, Atr) were used to analyze the underlying mechanisms. Myocyte contractile function, myocyte viability, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) and mitochondrial membrane potential were assayed. During reperfusion, the amplitudes of contraction, +/-dL/dt(max), and end-diastolic length of myocytes were decreased, which were markedly improved by pretreatment with ACh. However, such effects of ACh were reversed by 100 micromol/L 5-HD for 20 min before ischemia, or 20 micromol/L Atr for 20 min at the beginning of reperfusion. Pretreatment with ACh markedly reduced I/R-induced cell death, LDH release, ROS signals and mitochondrial membrane potential dissipation, all of which were reversed by 5-HD or Atr. In conclusion, ACh may protect ventricular myocytes from I/R injury by inhibiting MPTP opening and stabilizing the mitochondrial membrane potential through activating the mitoK(ATP) channel.
authors.affiliation: Department of Physiology, Zhejiang Medical College, Hangzhou, China.
authors.forename: Guo-Quan
authors.initials: GQ
authors.lastname: Sun
authors.forename: Jue
authors.initials: J
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Zhi-Guo
authors.initials: ZG
authors.lastname: Ye
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D018678:Cholinergic Agents / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D018678:Cholinergic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D015221:Potassium Channels; D017382:Reactive Oxygen Species; C117780:mitochondrial K(ATP) channel; D007770:L-Lactate Dehydrogenase; D000109:Acetylcholine