title: Potassium channel openers are uncoupling protonophores: implication in cardioprotection.
abstract: Excessive build-up of mitochondrial protonic potential is harmful to cellular homeostasis, and modulation of inner membrane permeability a proposed countermeasure. Here, we demonstrate that structurally distinct potassium channel openers, diazoxide and pinacidil, facilitated transmembrane proton translocation generating H(+)-selective current through planar phospholipid membrane. Both openers depolarized mitochondria, activated state 4 respiration and reduced oxidative phosphorylation, recapitulating the signature of mitochondrial uncoupling. This effect was maintained in K(+)-free conditions and shared with the prototypic protonophore 2,4-dinitrophenol. Diazoxide, pinacidil and 2,4-dinitrophenol, but not 2,4-dinitrotoluene lacking protonophoric properties, preserved functional recovery of ischemic heart. The identified protonophoric property of potassium channel openers, thus, implicates a previously unrecognized component in their mechanism of cardioprotection.
authors.affiliation: Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Guggenheim 7, Rochester, MN 55905, USA.
authors.forename: Ekhson L
authors.initials: EL
authors.lastname: Holmuhamedov
authors.forename: Arshad
authors.initials: A
authors.lastname: Jahangir
authors.forename: Andrew
authors.initials: A
authors.lastname: Oberlin
authors.forename: Alexander
authors.initials: A
authors.lastname: Komarov
authors.forename: Marco
authors.initials: M
authors.lastname: Colombini
authors.forename: Andre
authors.initials: A
authors.lastname: Terzic
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003981:Diazoxide / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000502:physiology; D010085:Oxidative Phosphorylation; D020110:Pinacidil / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists*; D051381:Rats; D014475:Uncoupling Agents / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D015221:Potassium Channels; D014475:Uncoupling Agents; D020110:Pinacidil; D003981:Diazoxide