H-89 inhibits transient outward and inward rectifier potassium currents in isolated rat ventricular myocytes

Br J Pharmacol. 2006 Aug;148(8):1091-8. doi: 10.1038/sj.bjp.0706810. Epub 2006 Jun 26.


1. Voltage clamp was used to investigate the effects of N-[2-p-bromo-cinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), a potent inhibitor of PKA, on transient outward K(+) current (I(to)) and inward rectifying K(+) current (I(K1)) in rat cardiac muscle. 2. Initial experiments, performed using descending voltage ramps, showed that H-89 inhibited both the outward and inward ramp currents in a concentration-dependent manner at concentrations between 5 and 60 micromol l(-1). A similar degree of inhibition was observed when I(to) and I(K1) were recorded using square wave depolarising and hyperpolarising voltage steps, respectively. 3. The IC(50) was 35.8 micromol l(-1) for I(to) and 27.8 micromol l(-1) for I(K1) compared to 5.4 micromol l(-1) for L-type Ca(2+) current (I(Ca)). The Hill coefficients for I(to), I(K1) and I(Ca) were -1.97, -1.60 and -1.21, respectively. In addition to inhibiting I(to) amplitude, H-89 also accelerated the time to peak and the rate of voltage-dependent inactivation so that the time course of I(to) was abbreviated. 4. Paired-pulse protocols were performed to study the effects of H-89 on steady-state activation and inactivation as well as recovery from voltage-dependent inactivation. H-89 produced a concentration-dependent rightward shift in voltage-dependent activation but had no significant effect on steady-state inactivation. Recovery from voltage-dependent inactivation was delayed, although this was only visible at the highest concentration (60 micromol l(-1)) used. In experiments investigating the effects of elevated cyclic AMP, the beta-adrenergic agonist isoprenaline and the phosphatase inhibitor calyculin A had no major effects on I(to) or I(K1). 6. Data suggest that the effects of H-89 on K(+) currents are more complex than simple inhibition of PKA-mediated phosphorylation.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Heart Ventricles / drug effects*
  • Heart Ventricles / enzymology
  • Heart Ventricles / metabolism
  • In Vitro Techniques
  • Ion Channel Gating / drug effects
  • Isoquinolines / pharmacology*
  • Male
  • Phosphorylation
  • Potassium Channels / drug effects*
  • Potassium Channels / physiology
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Rats, Wistar
  • Sulfonamides / pharmacology*


  • Isoquinolines
  • Potassium Channels
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide