Abstract 5344: Exogenous Angiotensin II Increases Intracellular Cl− Concentrations and Incidence of Afterdepolarization in Mouse Ventricular Myocytes
Activation of AT1 receptors plays a critical role in ischemia and reperfusion-induced injury and AT1 receptor blockade may be a promising strategy for preventing ischemic injury including arrhythmias. However, the detailed mechanism involved is still unclear. To explore whether Ang II induces any change in action potentials, including early and delayed afterdepolarization (EAD and DAD) or not, effects of exogenous angiotensin II (Ang II) on action potentials were investigated with glass-microelectrode techniques in 26 ventricular papillary muscles obtained from 13 animals. Ang II dose-dependently increased the incidence and amplitude of afterdepolarization, including EAD and DAD (Fig. A⇓), and evoked trigger activities. Furthermore, measurement of the intracellular Cl− concentration ([Cl−]i) was performed in single ventricular myocytes incubated with 5 mM N-(6-methoyquinolyl)acetoxyacetyl-ester (MQAE) with an image processor system. Ang II increases the [Cl−]i from 20.6±4.8 mM (n=5) in the control to 51.4±7.9 mM (n=4) in the Ang II group (P<0.05, Fig. B). Both Ang II-induced increases in the afterdepolarization and in the [Cl−]i were inhibited by an angiotensin II receptor blocker, telmisartan, in a dose-dependent manner. In a model of ischemia and reperfusion established in C57BL6J mice by high-placed ligation of left anterior descending coronary artery, telmisartan also suppressed the incidence of lethal arrhythmias and the animal mortality. Our data suggest that the Ang II-induced afterdepolarization and changes of intracellular Cl−-homeostasis are important in the development of lethal arrhythmias during cardiac diseases.