Mechanisms underlying delayed afterdepolarizations in hypertrophied left ventricular myocytes of rats

Abstract

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.