Background— Prolonged action potentials (APs) and decreased transient outward K⁺ currents (I_to) are consistent findings in hypertrophic myocardium. However, the connection of these changes with cardiac hypertrophy is unknown. The present study investigated the effects of changes in I_to and the associated alterations in AP on myocyte hypertrophy induced by phenylephrine.

Methods and Results— Chronic incubation of cultured neonatal ventricular rat myocytes (NVRMs) with phenylephrine (PE) reduced I_to density and prolonged AP duration, leading to a 2-fold increase in the net Ca²⁺ influx per beat and a 1.4-fold increase in Ca²⁺-transient amplitude. PE treatment of chronically paced (2-Hz) NVRM also induced increases in cell size, protein/DNA ratio, atrial natriuretic factor mRNA expression, as well as β/α myosin mRNA ratio. These hypertrophic changes were associated with a 2.4-fold increase in activation of nuclear factor of activated T-cells (NFAT), indicating increased activity of the Ca²⁺-dependent phosphatase calcineurin. Overexpression of Kv4.2 channels using adenovirus prevented the AP duration prolongation as well as the increases in Ca²⁺ influx and Ca²⁺-transient amplitude induced by PE. Kv4.2 overexpression also prohibited the PE-induced increases in cell size, protein/DNA ratio, atrial natriuretic factor expression, β/α myosin mRNA ratio, and NFAT activation.

Conclusions— Our results demonstrate that PE-mediated hypertrophy in NRVMs seems to require I_to reductions and AP prolongation associated with increased Ca²⁺ influx and Ca²⁺ transients as well as calcineurin activation. The clinical implications of these studies and the possible involvement of other signaling pathways are discussed.