Potassium channel openers are uncoupling protonophores: implication in cardioprotection

FEBS Lett. 2004 Jun 18;568(1-3):167-70. doi: 10.1016/j.febslet.2004.05.031.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cardiotonic Agents / pharmacology*
  • Diazoxide / pharmacology
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / physiology
  • Oxidative Phosphorylation
  • Pinacidil / pharmacology
  • Potassium Channels / agonists*
  • Rats
  • Uncoupling Agents / pharmacology*


  • Cardiotonic Agents
  • Potassium Channels
  • Uncoupling Agents
  • Pinacidil
  • Diazoxide