Electrophysiologic Perturbations and Arrhythmogenic Activity Caused by Activation of the Fas Receptor in Murine Ventricular Myocytes: Role of the Inositol Trisphosphate Pathway

Ionic Basis of Fas Receptor Effects on Ventricular Myocytes.Introduction: Experimental evidence suggests a major role for Fas receptor activation in a wide range of myocardial pathologies. Because clinical situations, which are likely to be associated with Fas activation, are accompanied by a variety of ventricular arrhythmias, the major goal of this study was to investigate the ionic mechanisms responsible for these phenomena. Methods and Results: To delineate the origin of Fas‐mediated electrophysiologic perturbations, the transient outward K + current I to and the L‐type Ca 2+ current I Ca,L were studied in murine ventricular myocytes treated with the Fas‐activating monoclonal antibody Jo2. Jo2 decreased I to ( 4.36 ± 1.2 pA/pF vs 17.48 ± 2.36 pA/pF in control, V M =+50 mV; P < 0.001 ) and increased I Ca,L ( − 13.17 ± 1.38 pA/pF vs − 3.94 ± 0.78 pA/pF in control, V M = 0 mV; P < 0.001 ). Pretreatment of ventricular myocytes with ryanodine or thapsigargin prevented the electrophysiologic effects of Jo2, suggesting that [ Ca 2+ ] i elevation is important for Fas‐mediated action. In agreement with our previous studies demonstrating dependence of Fas‐based myocyte dysfunction on an intact inositol trisphosphate (1,4,5‐IP 3 ) pathway, the effects of Jo2 on I to and I Ca,L were prevented by the phospholipase C (generates 1,4,5‐IP 3 ) blocker U73122, and by xestospongin C (tested with I to ), a specific blocker of IP 3 ‐operated sarcoplasmic reticulum Ca 2+ release channels. Furthermore, intracellular perfusion with 1,4,5‐IP 3 , but not with 1,3,4‐IP 3 , caused electrophysiologic effects resembling those of Jo2. Conclusion: Decreased I to and increased I Ca,L underlie Fas‐induced action potential alterations and arrhythmias in murine ventricular myocytes, effects that appear to be mediated by 1,4,5‐IP 3 ‐induced intracellular calcium release.