Reducing the ATP sensitivity of the sarcolemmal ATP-sensitive K + (KATP) channel is predicted to lead to active channels in normal metabolic conditions and hence cause shortened ventricular action potentials and reduced myocardial inotropy. We generated transgenic (TG) mice that express an ATP-insensitive KATP channel mutant [Kir6.2(ΔN2-30,K185Q)] under transcriptional control of the α-myosin heavy chain promoter. Strikingly, myocyte contraction amplitude was increased in TG myocytes (15.68 ± 1.15% vs. 10.96 ± 1.49%), even though KATP channels in TG myocytes are very insensitive to inhibitory ATP. Under normal metabolic conditions, steady-state outward K + currents measured under whole cell voltage clamp were elevated in TG myocytes, consistent with threshold KATP activation, but neither the monophasic action potential measured in isolated hearts nor transmembrane action potential measured in right ventricular muscle preparations were shortened at physiological pacing cycles. Taken together, these results suggest that there is a compensatory remodeling of excitation-contraction coupling in TG myocytes. Whereas there were no obvious differences in other K+ conductances, peak L-type Ca2+ current (ICa) density (-16.42 ± 2.37 pA/pF) in the TG was increased compared with the wild type (-8.43 ± 1.01 pA/pF). Isoproterenol approximately doubled both ICa and contraction amplitude in wild-type myocytes but failed to induce a significant increase in TG myocytes. Baseline and isoproterenol-stimulated cAMP concentrations were not different in wild-type and TG hearts, suggesting that the enhancement of ICa in the latter does not result from elevated cAMP. Collectively, the data demonstrate that a compensatory increase in ICa counteracts a mild activation of ATP-insensitive KATP channels to maintain the action potential duration and elevate the inotropic state of TG hearts.
|Journal||American Journal of Physiology - Heart and Circulatory Physiology|
|Issue number||4 55-4|
|State||Published - 2004|
- ATP-sensitive K channels
- Action potential