Circulation, Vol 90, 2213-2224, Copyright © 1994 by American Heart Association
S Koumi, CE Arentzen, CL Backer and JA Wasserstrom
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 (IKI) and the muscarinic K+ channel
[IK(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, IK1 channel conductance and gating characteristics
were the same in HF and donor atria. When ACh was included in the pipette
solution, IK(ACh) was activated in both groups. Single-channel slope
conductance of IK(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 IK1 and IK(ACh) channel densities were less in HF.
Channel open probability of IK(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 mumol/L in HF and 0.03 mumol/L in
donors. In excised inside-out patches, IK(ACh) from HF required higher
concentrations of GTP and GTP gamma S to activate the channel compared with
donors. These results suggest a reduced IK(ACh) channel sensitivity to M2
cholinergic receptor-linked G protein (Gi) 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 IK1 and IK(ACh) channel density and
reduced IK(ACh) channel sensitivity to Gi-mediated channel activation in
HF.
ARTICLES
Alterations in muscarinic K+ channel response to acetylcholine and to G protein-mediated activation in atrial myocytes isolated from failing human hearts
Department of Medicine (Reingold ECG Center), Northwestern University School of Medicine, Chicago, IL 60611.
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