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 afterde-polarizations (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.