ALTERATIONS IN MUSCARINIC K-PROTEIN-MEDIATED ACTIVATION IN ATRIAL MYOCYTES ISOLATED FROM FAILING HUMAN HEARTS( CHANNEL RESPONSE TO ACETYLCHOLINE AND TO G)

Background A variety of previous studies have demonstrated reduced dia stolic potential and electrical activity in atrial specimens from pati ents with heart disease. Although K+ channels play a major role in det ermining resting membrane potential and repolarization of the action p otential, little is known about the effects of preexisting heart disea se on human atrial K+ channel activity. Methods and Results We charact erized the inwardly rectifying K+ channel (I-Kl) and the muscarinic K channel [I-K(ACh)] in atrial myocytes isolated from patients with hea rt failure (HF) and compared electrophysiological characteristics with those from donors (control) by the patch-clamp technique. Resting mem brane potentials of isolated atrial myocytes from HF were more depolar ized (-51.1+/-9.7 mV, mean+/-SD, n=30 patients) than those from donors (-73.01+/-7.2 mV, n=4 patients, P<.001). The action potential duratio n in HF was longer than that in donors. Although acetylcholine (ACh) s hortened the action potential, reduced the overshoot, and hyperpolariz ed the atrial cell membrane in HF, these effects were attenuated compa red with those observed in donors. The whole-cell membrane current slo pe conductance in HF was small, the reversal potential was more positi ve, and the sensitivity to ACh was less compared with donors. In singl e-channel recordings from cell-attached patches, I-K1 channel conducta nce and gating characteristics were the same in HF and donor atria. Wh en ACh was included in the pipette solution, I-K(ACl) 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 life time was 1.3+/-0.3 milliseconds (n=24) in HF and 1.5+/-0.4 millisecond s (n=4) in donors. These values were virtually identical in the two gr oups (not significantly different, NS), although both single I-K1 and I-K(ACh) channel densities were less in HF. Channel open probability o f 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 activati on was 0.11 mu mol/L in HF and 0.03 mu mol/L in donors. In excised ins ide-out patches, I-K(ACh) from HF required higher concentrations of GT P and GTP gamma S to activate the channel compared with donors. These results suggest a reduced I-K(ACh) channel sensitivity to M(2) choline rgic receptor-linked G protein (G(i)) in HF compared with donors. Conc lusions Atrial myocytes isolated from failing human hearts exhibited a lower resting membrane potential and reduced sensitivity to ACh compa red with donor atria. Whole-cell and single-channel measurements sugge st that these alterations are caused by reduced I-K(ACh) and I-K(ACh) channel density and reduced IK(ACh) channel sensitivity to G(i)-mediat ed channel activation in HF.