Abstract 11114: Inositol Triphosphate Receptor Function is Enhanced in the Infarcted Rodent Heart
Myocardial infarction (MI) is accompanied by modifications of the electrical and Ca2+ cycling properties of surviving myocytes. Based on this premise, we raised the possibility that these functional changes are mediated partly by Ca2+ mobilization via activation of inositol triphosphate receptors (IP3Rs). Therefore, the objective of this study was to determine whether IP3Rs are upregulated in mouse myocytes after infarction and whether this cellular response results in alterations of the action potential (AP), Ca2+ transient and propensity to arrhythmia. First, we documented that IP3R-Ca2+ mobilization in normal myocytes prolonged AP, increased Ca2+ transients and contractility, and promoted early afterdepolarization (EADs) and extra-systolic Ca2+ release. Based on these observations, LV myocytes were obtained from infarcted mouse hearts ~2 weeks after coronary artery ligation and compared to control cells. MI led to a 1.4-fold increase in IP3R expression in surviving myocytes, measured by Western blotting. With respect to control cells, viable myocytes from infarcted hearts displayed Ca2+ transients with larger amplitude and APs with prolonged repolarization times. Additionally, extra-systolic Ca2+ release was enhanced at baseline and following stimulation of IP3Rs with endothelin-1 and ATP. Importantly, IP3R blockade or inhibition of IP3 production in myocytes from infarcted hearts significantly shortened the AP, decreased the Ca2+ transient amplitude and reduced the number of episodes of EADs and extra-systolic Ca2+ release. To evaluate these phenomena at the organ level, a Langendorff perfused heart preparation was employed. Infarcted hearts presented a 1.6-fold increase in repolarization time of the monophasic AP at 50%, in respect to control. Moreover, in non-infarcted hearts, IP3R activation was required to induce arrhythmic events and triggered activity. In infarcted hearts, however, these alterations were present at baseline. Inhibition of IP3R function blunted these electrical abnormalities. In conclusions, myocardial infarction results in an increased expression and function of IP3Rs leading to prolongation of the AP, enhanced Ca2+ transient and contractility together with greater propensity to arrhythmia.
- © 2011 by American Heart Association, Inc.