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1 Department of Anatomy & Physiology, Environmental & Hyperbaric Cell Biology Facility, Wright State University School of Medicine, Dayton, OH, USA
2 Department of Anatomy & Physiology, Environmental & Hyperbaric Cell Biology Facility, Wright State University School of Medicine, Dayton, OH, USA; Department of Community Health, Wright State University School of Medicine, Dayton, OH, USA
* To whom correspondence should be addressed. E-mail: jay.dean{at}wright.edu.
Putative chemoreceptors in the SC are sensitive to hypercapnia and oxidative stress. Here we test the hypothesis that oxidative stress stimulates SC neurons by a mechanism independent of pHi. pHi was measured using ratiometric fluorescence imaging microscopy, utilizing the pH-sensitive fluorescent dye BCECF or, during whole cell recordings using pyranine, in SC neurons in brainstem slices from rat pups (P1-P15). Oxidative stress decreased pHi in 270 of 436 (62%) SC neurons tested. Chloramine-T (CT), N-chlorosuccinimide (NCS), dihydroxyfumaric acid (DHF) and hydrogen peroxide (H2O2) decreased pHi by 0.19 ± 0.007, 0.20 ± 0.015, 0.15 ± 0.013, and 0.08 ± 0.003, respectively. Hypercapnia decreased pHi by 0.26 ± 0.006 pH unit (N=95). The combination of hypercapnia and CT or NCS had an additive effect on pHi, causing a 0.42 ± 0.03 (N=21) pH unit acidification. CT slowed pHi recovery mediated by NHE from NH4Cl induced acidification by 53% (N=20) in CO2/HCO3--buffered medium and by 58% (N=10) in HEPES-buffered medium. CT increased firing rate in 14 of 16 SC neurons and there was no difference in the firing rate response to CT with or without a corresponding change in pHi. These results indicate that oxidative stress: i) decreases pHi in some SC neurons; ii) together with hypercapnia have an additive effect on pHi; iii) partially inhibits NHE; and iv) directly effect excitability of CO2/H+-chemosensitive SC neurons independent of pHi changes. These findings suggest that oxidative stress acidifies SC neurons in part by inhibiting NHE and this acidification may contribute ultimately to respiratory control dysfunction.
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