Background: Cardiac angina is the hallmark of myocardial ischemia, but the role of the cardiac sensory nerve has received relatively little attention. Recently, both acid-sensing ion channel 3 (ASIC3) and capsaicin receptor (TRPV1) have been suggested as important mediators in sensing myocardial ischemia. However, studies comparing the physiological roles of ASIC3 and TRPV1 in the neuronal-cardiac sensing circuits in vivo are lacking. Methods and Results: Isoproterenol (1.5mg/kg, intraperitoneally) was used to induce transient myocardial ischemia in Asic3+/+ and Asic3-/-mice and a radio-telemetry system was used for electrocardiography with mice in a conscious state. Isoproterenol-induced myocardial ischemia was first demonstrated with ST-segment depression and further confirmed by hypoxia-mediated chemical reactions in cardiac tissue. Mice lacking Asic3 showed prolonged duration of ST-segment depression compared with Asic3+/+ mice (44.3±3.1 vs. 31.7±2.9min; P<0.05). Although ischemia was transient, severe cardiac fibrosis was found in Asic3 -/- but not in Asic3+/+ mice littermates. In contrast, isoproterenol-injected Trpv1+/+ and Trpv1 -/- mice showed no difference in duration of ST-segment depression and, surprisingly, deletion of Trpv1 did not aggravate cardiac fibrosis. Conclusions: An isoproterenol-induced myocardial ischemia model mimicking clinical conditions of early cardiac angina was used to demonstrate that ASIC3 but not TRPV1 plays a protective role in sensing myocardial ischemia.
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