R. Kaprielian et al., Relationship between K+ channel down-regulation and [Ca2+](i) in rat ventricular myocytes following myocardial infarction, J PHYSL LON, 517(1), 1999, pp. 229-245
1. Cardiac hypertrophy and prolongation of the cardiac action potential are
hallmark features of heart disease. We examined the molecular mechanisms a
nd the functional consequences of this action potential prolongation on cal
cium handling in right ventricular myocytes obtained from rats 8 weeks foll
owing ligation of the left anterior descending coronary artery (post-myocar
dial infarction (MI) myocytes).
2. Compared with myocytes from sham-operated rats (sham myocytes), post-MI
myocytes showed significant reductions in transient outward K+ current (I-t
o) density (sham 19.7 +/- 1.1 pA pF(-1) versus post-MI 11.0 +/- 1.3 pA pF(-
1); means +/- S.E.M), inward rectifier K+ current, density (sham -13.7 +/-
0.6 pA pF(-1) versus post-MI -10.3 +/- 0.9 pA pF(-1)) and resting membrane
potential (sham -84.4 +/- 1.3 mV versus post-MI -74.1 +/- 2.6 mV). Depresse
d I-to amplitude correlated with significant reductions in Kv4.2 and Kv4.3
mRNA and Kv4.2 protein levels. Kv1.4 mRNA and protein levels were increased
and coincided with the appearance of a slow component of recovery from ina
ctivation for I-to.
3. In current-clamp recordings, post-MI myocytes showed a significant incre
ase in [Ca2+](i) transient amplitude compared with sham myocytes. Using vol
tage-clamp depolarizations, no intrinsic differences in Ca+ handling by the
sarcoplasmic reticulum or in L-type Ca2+ channel density (I-Ca,I-L) were d
etected between the groups.
4. Stimulation of post-MI myocytes with an action potential derived from a
sham myocyte reduced the [Ca2+] transient amplitude to the sham level and v
ice versa.
5. The net Ca2+ influx per beat via I-Ca,I-L was increased about 2-fold in
myocytes stimulated with post-MI action potentials compared with sham actio
n potentials.
6. Our findings demonstrate that reductions in K+ channel expression in pos
t-MI myocytes prolong action potential duration resulting in elevated Ca2influx and [Ca2+](i) transients.