Mechanisms underlying delayed afterdepolarizations in hypertrophied left ventricular myocytes of rats

Cardiac hypertrophy was induced in rats by daily injection of isoproterenol (5 mg/kg ip) for 7 days. Membrane voltage and currents were recorded using the whole cell patch-clamp technique in left ventricular myocytes from control and hypertrophied hearts. Ryanodine-sensitive delayed afterdepolarizations (DADs) and transient inward current (I(ti)) appeared in hypertrophied cells more often and were of larger amplitude than in control cells. DADs and I(ti) are carried principally by Na/Ca exchange with smaller contributions from a nonselective cation channel and from a Cl- channel. The latter is expressed only in hypertrophied myocytes. In hypertrophy, the density of caffeine-induced Na/Ca exchange current (I(Na/Ca)) was increased by 26%, sarcoplasmic reticulum (SR) Ca2+ content as assessed from the integral of I(Na/Ca) was increased by 30%, the density of Na-pump current (I(pump)) was reduced by 40%, and the intracellular Na+ content, measured by Na+-selective microelectrodes was increased by 55%. The results indicate that DADs and I(ti) are generated by spontaneous Ca2+ release from an overloaded SR caused by a downregulated Na pump and an upregulated Na/Ca exchange. These findings may explain the propensity for arrhythmias seen in this model of hypertrophy.