title: BKCa channel activation increases cardiac contractile recovery following hypothermic ischemia/reperfusion.
abstract: Mitochondrial Ca(2+)-activated large-conductance K(+) (BKCa) channels are thought to provide protection during ischemic insults in the heart. Rottlerin (mallotoxin) has been implicated as a potent BKCa activator. The purpose of this study was twofold: 1) to investigate the efficacy of BKCa channel activation as a cardioprotective strategy during ischemic cardioplegic arrest and reperfusion (CP/R) and 2) to assess the specificity of rottlerin for BKCa channels. Wild-type (WT) and BKCa knockout (KO) mice were subjected to an isolated heart model of ischemic CP/R. A mechanism of rottlerin-induced cardioprotection was also investigated using H9c2 cells subjected to in vitro CP/reoxygenation and assessed for mitochondrial membrane potential and reactive oxygen species (ROS) production. CP/R decreased left ventricular developed pressure, positive and negative first derivatives of left ventricular pressure, and coronary flow (CF) in WT mice. Rottlerin dose dependently increased the recovery of left ventricular function and CF to near baseline levels. BKCa KO hearts treated with or without 500 nM rottlerin were similar to WT CP hearts. H9c2 cells subjected to in vitro CP/R displayed reduced mitochondrial membrane potential and increased ROS generation, both of which were significantly normalized by rottlerin. We conclude that activation of BKCa channels rescues ischemic damage associated with CP/R, likely via effects on improved mitochondrial membrane potential and reduced ROS generation.
authors.affiliation: Cardiovascular Research Center and Department of Surgery, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Brenda
authors.initials: B
authors.lastname: Cordeiro
authors.affiliation: Cardiovascular Research Center and Department of Surgery, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Terentyev
authors.affiliation: Cardiovascular Research Center and Department of Surgery, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island richard_clements@brown.edu.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D050792:Circulatory Arrest, Deep Hypothermia Induced; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D016277:Ventricular Function, Left
chemical_list: D000098:Acetophenones; D001578:Benzopyrans; D051036:Large-Conductance Calcium-Activated Potassium Channels; D017382:Reactive Oxygen Species; C085746:rottlerin
keywords: ischemia; mitochondria; potassium channel; reactive oxygen species; reperfusion