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

  • Wang S
  • Xu D
  • Cai J
 et al. 
  • 11

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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.

Author-supplied keywords

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

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Authors

  • S Wang

  • D J Xu

  • J B Cai

  • Y Z Huang

  • J G Zou

  • K J Cao

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