Abstract 15941: Converging Pathways of Activation of a Cl- Conductance in Nodose Ganglion Neurons: Implication for Ischemic Preconditioning of Vagal Afferents
Reactive oxygen and chloride (Cl-) channels are necessary for the protective influence of ischemic preconditioning in cardiomyocytes (Draz et al 1999; Otani 2011). We recently reported that vagal afferent neurons isolated from nodose ganglia exhibit a prolonged low pHo-conditioned Cl- current (25±5 pA/pF, n=60) similar to the one carried by the Swell-Activated Channel (SAC) during hypoosmolarity. In this study we define the activation pathways of this Cl- conductance. Brief exposure to either low extracellular (EC) pH or hypoosmolarity activates the current through NADPH oxidase (NOX)-dependent production of ROS (dihydroethidine fluorescence). Since NOX activation requires intracellular (IC) alkalinity, we hypothesized that low EC pH induces an increase in IC pH. We found that IC pH measured by pH-sensitive fluorescence dye 2’-7’-bis(carboxyethyl)-5(6)-carboxyfluorescein decreased transiently by 0.13±0.01 pH units and then increased by 0.29±0.05 units to an IC pH of 7.54±0.05 following the brief exposure to EC low pH. Blocking proton efflux with the proton channel blocker Zn2+ and the Na+/H+ exchange blocker amiloride inhibited the pH-conditioned current (from 23.4±6.5 to 3.6±1.1. pA/pF, n=8, p<0.05) whereas the response of the hypoosmolarity-induced SAC remained intact at 25.9±6.3 in control and 28.6±4.5 pA/pF with Zn2+ and amiloride (n=6-7, p>0.05). Since Angiotensin-II AT1 receptors may also be mechanosensitive, we tested the effect of losartan on the hyposmolarity-induced SAC current and found it significantly reduced from 37.3±4.6 to 15.8±2.5 pA/pF (p<0.01, n=6) whereas the pHo-conditioned current was not affected (24.6±4.0 vs. 20.4±7.7 pA/pF (p>0.05, n=4).
Conclusions and Clinical Implications: Activation of NOX in vagal afferent neurons either by low pH or mechanically through activation of AT1 receptors induces a Cl- conductance which may be protective during ischemic preconditioning of vagal afferents
- © 2013 by American Heart Association, Inc.