Alterations in muscarinic K+ channel response to acetylcholine and to G protein-mediated activation in atrial myocytes isolated from failing human hearts

Shin Ichi Koumi, Carl E. Arentzen, Carl L. Backer, J. Andrew Wasserstrom*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Background: A variety of previous studies have demonstrated reduced diastolic potential and electrical activity in atrial specimens from patients with heart disease. Although K+ channels play a major role in determining resting membrane potential and repolarization of the action potential, little is known about the effects of preexisting heart disease on human atrial K+ channel activity. Methods and Results: We characterized the inwardly rectifying K+ channel (I(KI)) and the muscarinic K+ channel [I(K(ACh))] in atrial myocytes isolated from patients with heart failure (HF) and compared electrophysiological characteristics with those from donors (control) by the patch-clamp technique. Resting membrane potentials of isolated atrial myocytes from HF were more depolarized (-51.1±9.7 mV, mean±SD, n = 30 patients) than those from donors (-73.0±7.2 mV, n = 4, patients, P<.001). The action potential duration in HF was longer than that in donors. Although acetylcholine (ACh) shortened the action potential, reduced the overshoot, and hyperpolarized the atrial cell membrane in HF, these effects were attenuated compared with those observed in donors. The whole-cell membrane current slope conductance in HF was small, the reversal potential was more positive, and the sensitivity to ACh was less compared with donors. In single channel recordings from cell-attached patches, I(KI) channel conductance and gating characteristics were the same in HF and donor atria. When ACh was included in the pipette solution, I(K(ACh)) was activated in both groups. Single-channel slope conductance of I(K(ACh)) averaged 42±3 pS (n = 28) in HF and 44±2 pS (n = 4) in donors, and mean open lifetime was 1.3±0.3 milliseconds (n = 24) in HF and 1.5±0.4 milliseconds (n = 4) in donors. These values were virtually identical in the two groups (not significantly different, NS), although both single I(KI) and I(K(ACh)) channel densities were less in HF. Channel open probability of I(K(ACh)) was also less in HF (4.0±1.2%, n = 24) than in donors (6.8±1.1%, n = 3, P<.01). The concentration of ACh at half-maximal activation was 0.11 μmol/L in HF and 0.03 μmol/L in donors. In excised inside-out patches, I(K(ACh)) from HF required higher concentrations of GTP and GTPγS to activate the channel compared with donors. These results suggest a reduced I(K(ACh)) channel sensitivity to M2 cholinergic receptor-linked G protein (G(i)) in HF compared with donors. Conclusions: Atrial myocytes isolated from failing human hearts exhibited a lower resting membrane potential and reduced sensitivity to ACh compared with donor atria. Whole-cell and single-channel measurements suggest that these alterations are caused by reduced I(KI) and I(K(ACh)) channel density and reduced I(K(ACh)) channel sensitivity to G(i)- mediated channel activation in HF.

Original languageEnglish (US)
Pages (from-to)2213-2224
Number of pages12
JournalCirculation
Volume90
Issue number5
DOIs
StatePublished - Nov 1994

Keywords

  • potassium
  • potentials
  • proteins

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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