The actions of mdivi-1, an inhibitor of mitochondrial fission, on rapidly activating delayed-rectifier K⁺ current and membrane potential in HL-1 murine atrial cardiomyocytes

Eur J Pharmacol. 2012 May 15;683(1-3):1-9. doi: 10.1016/j.ejphar.2012.02.012. Epub 2012 Feb 21.


Mdivi-1 is an inhibitor of dynamin related protein 1- (drp1)-mediated mitochondrial fission. However, the mechanisms through which this compound interacts directly with ion currents in heart cells remain unknown. In this study, its effects on ion currents and membrane potential in murine HL-1 cardiomyocytes were investigated. In whole-cell recordings, the addition of mdivi-1 decreased the amplitude of tail current (I(tail)) for the rapidly activating delayed-rectifier K⁺ current (I(Kr)) in a concentration-dependent manner with an IC₅₀ value at 11.6 μM, a value that resembles the inhibition requirement for mitochondrial division. It shifted the activation curve of I(tail) to depolarized voltages with no change in the gating charge. However, mdivi-1 did not alter the rate of recovery from current inactivation. In cell-attached configuration, mdivi-1 inside the pipette suppressed the activity of acetylcholine-activated K⁺ channels without modifying the single-channel conductance. Mdivi-1 (30 μM) slightly depressed the peak amplitude of Na⁺ current with no change in the overall current-voltage relationship. Under current-clamp recordings, addition of mdivi-1 resulted in prolongation for the duration of action potentials (APs) and to increase the firing of spontaneous APs in HL-1 cells. Similarly, in pituitary GH₃ cells, mdivi-1 was effective in directly suppressing the amplitude of ether-à-go-go-related gene-mediated K⁺ current. Therefore, the lengthening of AP duration and increased firing of APs caused by mdivi-1 can be primarily explained by its inhibition of these K⁺ channels enriched in heart cells. The observed effects of mdivi-1 on ion currents were direct and not associated with its inhibition of mitochondrial division.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / antagonists & inhibitors
  • Acetylcholine / metabolism
  • Animals
  • Cell Line
  • Cell Physiological Phenomena / drug effects*
  • Delayed Rectifier Potassium Channels / antagonists & inhibitors
  • Delayed Rectifier Potassium Channels / metabolism
  • Dynamins / antagonists & inhibitors
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Heart Atria / drug effects*
  • Heart Atria / metabolism
  • Membrane Potential, Mitochondrial / drug effects*
  • Mice
  • Mitochondria, Heart / drug effects*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Osmolar Concentration
  • Patch-Clamp Techniques
  • Pituitary Gland / drug effects
  • Pituitary Gland / metabolism
  • Potassium Channel Blockers / pharmacology*
  • Quinazolinones / pharmacology*
  • RNA Interference
  • RNA, Small Interfering
  • Rats


  • 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
  • Delayed Rectifier Potassium Channels
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Potassium Channel Blockers
  • Quinazolinones
  • RNA, Small Interfering
  • Dnm1l protein, mouse
  • Dynamins
  • Acetylcholine