Effects of protein kinase inhibitors on canine Purkinje fibre pacemaker depolarization and the pacemaker current i(f)

J Physiol. 1991;440:367-84. doi: 10.1113/jphysiol.1991.sp018713.


1. The effects of the protein kinase inhibitors H-7 and H-8 were investigated on diastolic depolarization of the action potential with microelectrodes and on the pacemaker current if with the two-microelectrode voltage clamp in canine cardiac Purkinje fibres. 2. Both 200 microM-H-7 and 100 microM-H-8 had no significant effect on the slope of diastolic depolarization but eliminated the actions of isoprenaline (1 microM). 3. We examined the actions of H-7 and H-8 on if in the presence and absence of isoprenaline. H-7 (200 microM) shifted the pacemaker current if in the negative direction on the voltage axis, whereas 100 microM-H-8 had no significant effect by itself. Both 200 microM-H-7 and 100 microM-H-8 can reverse or prevent the actions of isoprenaline (1-5 microM) on if. 4. We applied activators of the cyclic AMP cascade down-stream to the beta-receptor, to further evaluate where H-7 and H-8 might be exerting their effects. When exposing Purkinje fibres to an adenylyl cyclase activator (forskolin, 10-50 microM), a phosphodiesterase inhibitor (IBMX, 100 microM) and a permeable cyclic AMP analogue (8-chlorophenylthio-cyclic AMP, 200 microM-1 mM), the amplitude of if was increased. H-7 and H-8 at 100-200 microM eliminated each of these actions. 5. These results suggest that a phosphorylation process is involved in the modulation of the pacemaker current, if, in Purkinje fibres. The different actions of H-7 and H-8 on basal if suggest the hypothesis that other protein kinases, possibly protein kinase C, might also be involved in regulating basal phosphorylation of if in Purkinje fibres.

Publication types

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

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Action Potentials / drug effects
  • Animals
  • Colforsin / pharmacology
  • Dogs
  • Electrophysiology
  • In Vitro Techniques
  • Ion Channel Gating / physiology*
  • Isoproterenol / antagonists & inhibitors
  • Isoquinolines / pharmacology
  • Phosphorylation
  • Piperazines / pharmacology
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase Inhibitors
  • Protein Kinases / physiology*
  • Purkinje Fibers / physiology*


  • Isoquinolines
  • Piperazines
  • Protein Kinase Inhibitors
  • Colforsin
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide
  • Protein Kinases
  • Protein Kinase C
  • Isoproterenol