β-Adrenergic modulation of the inwardly rectifying potassium channel in isolated human ventricular myocytes alteration in channel response to β-Adrenergic stimulation in failing human hearts

Shin Ichi Koumi*, Carl L. Backer, Carl E. Arentzen, Ryoichi Sato

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

The β-adrenergic modulation of the inwardly-rectifying K+ channel (IK1) was examined in isolated human ventricular myocytes using patch-clamp techniques. Isoproterenol (ISO) reversibly depolarized the resting membrane potential and prolonged the action potential duration. Under the whole-cell Cl--free condition, ISO applied via the bath solution reversibly inhibited macroscopic IK1. The reversal potential of the ISO-sensitive current was shifted by ∼ 60 mV per 10-fold change in the external K+ concentration and was sensitive to Ba2+. The ISO-induced inhibition of IK1 was mimicked by forskolin and dibutyryl cAMP, and was prevented by including a cAMP-dependent protein kinase (PKA) inhibitor (PKI) in the pipette solution. In single-channel recordings from cell-attached patches, bath applied ISO could suppress IK1 channels by decreasing open state probability. Bath application of the purified catalytic subunit of PKA to inside-out patches also inhibited IK1 and the inhibition could be antagonized by alkaline phosphatase. When β-adrenergic modulation of IK1 was compared between ventricular myocytes isolated from the failing and the nonfailing heart, channel response to ISO and PKA was significantly reduced in myocytes from the failing heart. Although ISO inhibited IK1 in a concentration-dependent fashion in both groups, a half-maximal concentration was greater in failing (0.12 μM) than in nonfailing hearts (0.023 μM). These results suggest that IK1 in human ventricular myocytes can be inhibited by a PKA-mediated phosphorylation and the modulation is significantly reduced in ventricular myocytes from the failing heart compared to the nonfailing heart.

Original languageEnglish (US)
Pages (from-to)2870-2881
Number of pages12
JournalJournal of Clinical Investigation
Volume96
Issue number6
DOIs
StatePublished - Dec 1995

Keywords

  • β receptor
  • Human ventricular myocytes
  • Inwardly rectifying K channel
  • Isoproterenol
  • Phosphorylation

ASJC Scopus subject areas

  • Medicine(all)

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