Antioxidant tempol reverses autonomic dysregulation and neurogenic hypertension in acid-sensing ion channel 2 deficient mice

Abstract

Acid-Sensing Ion Channel 2 (ASIC2) has been implicated in mechanosensation. We reported previously that ASIC2 is highly expressed in aortic baroreceptor neurons and contributes to baroreceptor mechanotransduction; and that ASIC2 deficient mice exhibit decreased baroreflex sensitivity (BRS), sympathovagal imbalance and neurogenic hypertension. Oxidative stress is widely considered an important contributor to hypertension. The major goal of this study was to determine if treatment of ASIC2^−/− mice with the antioxidant tempol attenuates baroreflex/autonomic dysfunction and hypertension. Blood pressure (BP), heart rate (HR) and locomotor activity were measured by telemetry in conscious, control C57BL/6 and ASIC2^−/− male mice, before and after administration of tempol in drinking water (1 mM) for two weeks. Cardiac sympathetic tone, mean arterial BP and BP variability were higher, and cardiac vagal tone and BRS were lower in ASIC2^−/− mice, compared with controls (P < 0.05). Oxidative stress measured by mRNA expression of NADPH oxidase subunits (Nox2, Nox4, p22phox) and dihydroethidium (DHE) fluorescence was increased significantly (P < 0.05) in ASIC2^−/− mice in a tissue-specific manner (sympathetic and nodose ganglia > > brain stem > > skeletal muscle, with no change in aorta). Treatment with tempol strongly attenuated DHE fluorescence and restored autonomic regulation and BP to control levels in ASIC2^−/− mice, while not affecting these phenotypes in control mice. We conclude: (1) oxidative stress in ASIC2^−/− mice is prominent in the autonomic nervous system but not present in aorta; and (2) the antioxidant tempol reverses decreased BRS, sympathovagal imbalance and hypertension in ASIC2^−/− mice; effects that are associated with decreased oxidative stress.