Relationship between K+ channel down-regulation and [Ca2+](i) in rat ventricular myocytes following myocardial infarction

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.