Rapid component I(Kr) of cardiac delayed rectifier potassium currents in guinea-pig is inhibited by alpha(1)-adrenoreceptor activation via protein kinase A and protein kinase C-dependent pathways

Eur J Pharmacol. 2009 Apr 17;608(1-3):1-6. doi: 10.1016/j.ejphar.2009.02.017. Epub 2009 Feb 20.

Abstract

Ventricular tachyarrhythmias are often precipitated by physical or emotional stress, indicating a link between increased adrenergic stimulation and cardiac ion channel activity. Human ether-a-go-go related gene (hERG) potassium channels conduct the rapid component of delayed rectifier potassium current, I(kr), a crucial component for action potential repolarization. To evaluate the correlation between increased alpha(1)-adrenergic activity and the rapid component of cardiac I(kr), whole-cell patch-clamp recording was performed in isolated guinea-pig ventricular myocytes. Stimulation of alpha(1)-adrenoceptors using phenylephrine (0.1 nM-100 microM) reduced I(kr) current in a dose-dependent manner at 37 degrees C. Phenylephrine (0.1 microM) reduced I(kr) current to 66.83+/-3.16%. Chelerythrine (1 microM), a specific inhibitor of protein kinase C (PKC) completely inhibited the changes in I(kr) trigged by 0.1 microM phenylephrine. KT5720 (2.5 microM), a specific inhibitor of protein kinase A (PKA) partially inhibited the current decrease induced by 0.1 microM phenylephrine. Both chelerythrine and KT5720 drastically reduced the phenylephrine-induced effects, indicating possible involvement of PKC and PKA in the alpha(1)-adrenergic inhibition of I(kr). Our data suggest a link between I(kr) and the alpha(1)-adrenoceptor, involving activation of PKC and PKA in arrhythmogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzophenanthridines / pharmacology
  • Carbazoles / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Dose-Response Relationship, Drug
  • Electrophysiology
  • Enzyme Inhibitors / pharmacology
  • Guinea Pigs
  • Heart Ventricles / cytology
  • Kinetics
  • Myocytes, Cardiac / metabolism*
  • Patch-Clamp Techniques
  • Phenylephrine / pharmacology
  • Potassium / metabolism
  • Potassium Channels, Inwardly Rectifying / antagonists & inhibitors
  • Potassium Channels, Inwardly Rectifying / metabolism*
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism*
  • Pyrroles / pharmacology
  • Receptors, Adrenergic, alpha-1 / metabolism*

Substances

  • Benzophenanthridines
  • Carbazoles
  • Enzyme Inhibitors
  • Potassium Channels, Inwardly Rectifying
  • Pyrroles
  • Receptors, Adrenergic, alpha-1
  • Phenylephrine
  • KT 5720
  • chelerythrine
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Potassium