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

It is known that the elevated sympathetic tone plays an important role in the pathogenesis of hypertension and progression of organ damage. Inhibition of the enhanced sympathetic activity has been considered as an antihypertensive strategy. Our previous studies have shown that the cardiac sympathetic afferent reflex(CSAR) is enhanced in two-kidney one-clip (2K1C) rats and the enhanced CSAR partially contributes to the sympathetic activation and hypertension. This positive feedback mechanism of the CSAR may be deleterious to the organism over the long term in hypertension. The enhanced reflex then contributes to the increase in sympathetic outflow. We previously reported that the abnormal action of Angâ…¡and AT1 receptor in the paraventricular nucleus (PVN) played an important part in the enhanced CSAR. Endogenous H2O2 in the PVN mediated the CSAR evoked by epicardial application of bradykinin (BK) in normal rats, and was involved in tonic control of sympathetic activity and arterial pressure. On the other hand, the enhanced CSAR and RSNA responses as well as pressor response caused by exogenous Angâ…¡in the PVN were mediated by H2O2 in the PVN. However, it is not known whether H2O2 mediate CSAR and the effects of Angâ…¡on CSAR or not in 2K1C rats. In the present study, we investigated whether endogenous H2O2 in the PVN mediated the CSAR and the enhanced CSAR response caused by exogenous Angâ…¡in the PVN in 2K1C rats. Furthermore, the roles of the endogenous H2O2 in regulating sympathetic activity and arterial pressure in 2K1C rats were determined.The study was carried out on the anesthetized 2K1C rats and sham rats with sinoaortic denervation and cervical vagotomy. The coordinates for PVN were determined in a stereotaxic instrument according to the Paxinos and Watson rat atlas. 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 renal sympathetic nerve activity (RSNA) to epicardial application of bradykinin (BK) in rats. The primary findings were as follows:1. Effects of endogenous H2O2 in the PVN on the CSAR in 2K1C rats Bilateral microinjection of polyethylene glycol-catalase (PEG-CAT, an analogue of endogenous catalase) into the PVN abolished the CSAR evoked by epicardial application of BK in 2K1C rats. Aminotriazole (a catalase inhibitor, ATZ) enhanced the CSAR in 2K1C rats.2. Effects of endogenous H2O2 in the PVN on sympathetic activity and arterial pressure in 2K1C rats Microinjection of PEG-CAT into the PVN decreased baseline RSNA and MAP in 2K1C rats. ATZ caused increases in RSNA and MAP in 2K1C rats.3. Effects of endogenous H2O2 in the PVN on the enhanced CSAR induced by Angâ…¡in 2K1C rats Microinjection of Angâ…¡into the PVN enhanced CSAR significantly in 2K1C rats. Pretreatment with PEG-CAT into the PVN abolished the effect of Angâ…¡on the CSAR in 2K1C rats. However, ATZ, a catalase inhibitor, failed to further enhance the effects of Angâ…¡on CSAR in 2K1C rats.4. Effects of endogenous H2O2 in the PVN on the Angâ…¡-induced RSNA and MAP change in 2K1C ratsMicroinjection of the Angâ…¡into the PVN significantly increased the RSNA and MAP in 2K1C rats. PEG-CAT abolished the effects of Angâ…¡on the RSNA and MAP compared with saline in 2K1C rats. However, ATZ did not further enhance the effects of Angâ…¡on the RSNA and MAP in 2K1C rats.5.Effects of different dose of PEG-CAT on baseline CSAR, RSNA, and MAP in 2K1C rats PEG-CAT dose-dependently inhibited the CSAR, and decreased the baseline RSNA and MAP in 2K1C rats.6. Effects of different dose of PEG-CAT on the CSAR, RSNA, and MAP responses to Angâ…¡in 2K1C ratsPEG-CAT dose-dependently inhibited the CSAR, RSNA, and MAP responses to Angâ…¡in 2K1C rats.In conclusion, endogenous H2O2 in the PVN mediated the CSAR evoked by epicardial application of BK in 2K1C rats, and was involved in tonic control of sympathetic activity and arterial pressure in 2K1C rats. On the other hand, the enhanced CSAR and RSNA responses as well as pressor response caused by exogenous Angâ…¡in the PVN were mediated by H2O2 in the PVN in 2K1C rats.