Endogenous Hydrogen Peroxide In Paraventricular Nucleus Mediating Cardiac Sympathetic Afferent Reflex In Rats

Cardiac sympathetic afferent reflex (CSAR) is enhanced in chronic heartfailure (CHF) state, which at least partially contributes to theover-excitation of sympathetic nervous system. The degree ofsympathetic excitation is prognostic for survival in this disease. Wepreviously reported that the abnormal action of Angâ…¡and AT₁ receptorin the paraventricular nucleus (PVN) played an important part in theenhanced CSAR in CHF, and reactive oxygen species (ROS) especiallysuperoxide anions in the PVN mediated CSAR and the effects of Angâ…¡on CSAR. It is known that superoxide anions are quickly converted tohydrogen peroxide (H₂O₂) by superoxide dismutase (SOD). H₂O₂ is acell-permeant and relative stable ROS, and has been found as animportant cellular signaling agent in the brain and peripheral tissues.However, it is not known whether H₂O₂ mediate CSAR and the effects ofAngâ…¡on CSAR or not. In the present study, we investigated whetherendogenous H₂O₂ in the PVN mediated the CSAR and the enhancedCSAR response caused by exogenous Angâ…¡in the PVN. Furthermore,the roles of the endogenous H₂O₂ in regulating sympathetic activity andarterial pressure were determined. The study was carried out on the anesthetized rats with sinoaorticdenervation and cervical vagotomy. The coordinates for PVN weredetermined in a stereotaxic instrument according to the Paxinos andWatson rat alas. All the drugs are bilaterally microinjected into PVN.Renal sympathetic nerve activity (RSNA) and mean arterial pressure(MAP) were recorded. The CSAR was evaluated by the response of renalsympathetic nerve activity (RSNA) to epicardial application ofbradykinin (BK) in rats. The primary findings were as follows:1. Effects of endogenous H₂O₂ in the PVN on CSARBilateral microinjection of polyethylene glycol-catalase (PEG-CAT,an analogue of endogenous catalase), polyethylene glycol-superoxidedismutase (PEG-SOD, an analogue of endogenous superoxide dismutase)or PEG-CAT+PEG-SOD into the PVN abolished the CSAR evoked byepicardial application of BK. Aminotriazole (a catalase inhibitor, ATZ)alone enhanced the CSAR. But pretreatment with PEG-SOD reversed theeffects of ATZ on the CSAR.2. Effects of endogenous H₂O₂ in the PVN on sympathetic activityand arterial pressureMicroinjection of PEG-CAT, PEG-SOD or PEG-SOD+PEG-CATinto the PVN decreased baseline RSNA and MAP. ATZ caused increasesin RSNA and MAP. However, pretreatment with PEG-SOD failed toabolish the effects of ATZ on RSNA and MAP. 3. Effects of endogenous H₂O₂ in the PVN on the enhanced CSARinduced by Angâ…¡Microinjection of Angâ…¡into the PVN enhanced CSARsignificantly. Pretreatment with PEG-CAT, PEG-SOD, PEG-SOD+PEG-CAT, or PEG-SOD+ATZ into the PVN abolished the effect of Angâ…¡on the CSAR. However, ATZ, a catalase inhibitor, failed to furtherenhance the effects of Angâ…¡on CSAR.4. Effects of endogenous H₂O₂ in the PVN on the Angâ…¡-inducedRSNA and MAP changeMicroinjection of the Angâ…¡into the PVN significantly increasedthe RSNA and MAP. PEG-CAT, PEG-SOD, PEG-SOD+PEG-CAT, orPEG-SOD+ATZ abolished the effects of Angâ…¡on the RSNA and MAPcompared with saline. However, ATZ alone did not further enhance theeffects of Angâ…¡on the RSNA and MAP.5. Effects of different dose of PEG-CAT on baseline CSAR, RSNA,and MAPPEG-CAT dose-dependently inhibited the CSAR, and decreased thebaseline RSNA and MAP.6. Effects of different dose of PEG-CAT on the CSAR, RSNA, andMAP responses to Angâ…¡PEG-CAT dose-dependently inhibited the CSAR, RSNA, and MAPresponses to Angâ…¡. In conclusion, endogenous H₂O₂ in the PVN mediated the CSARevoked by epicardial application of BK in rats, and was involved in toniccontrol of sympathetic activity and arterial pressure. On the other hand,the enhanced CSAR and RSNA responses as well as pressor responsecaused by exogenous Angâ…¡in the PVN were mediated by H₂O₂ in thePVN.