Chronic oxidative stress in the RVLM modulates sympathetic control of circulation in pigs

Abstract.

Oxidative stress is a key event in the pathogenesis of several cardiovascular diseases and may be similarly induced by long-term treatment with organic nitrates. We examined the effects of inhibiting extracellular oxidative stress in the rostral ventrolateral medulla (RVLM), the brain stem area which primarily controls sympathetic tone. Superoxide dismutase (SOD, 10 U/µl) was microinjected into the RVLM of anesthetized pigs that were either untreated (control, n=10), treated for 4 weeks with the organic nitrate isosorbidedinitrate (ISDN, 4 mg kg^–1 day^–1, n=6) or ISDN-treated followed by a 2-week recovery period (recovery, n=4). In control animals SOD produced moderate inhibitory effects on baseline sympathetic activity, indicated by decreases in renal sympathetic nerve activity (RSNA), mean arterial blood pressure (MAP), and heart rate (HR) without causing changes in femoral vascular conductance (FC). These effects of SOD were greatly enhanced in ISDN-treated pigs. Following the recovery period, SOD again produced smaller effects in the RVLM but they were, however, still significantly greater than in untreated animals. In contrast, the transmission of sympathoexcitatory reflexes by the RVLM, as evoked by sciatic nerve stimulation, was not affected by SOD injections in either experimental group. Furthermore, the number of NO-synthase-positive neurons in the RVLM region was significantly reduced both in ISDN-treated and the recovery pigs, suggesting that oxidative stress caused sustained changes in NOS activity within the brain stem. These data suggest that excitatory actions of oxidative stress contribute significantly to the generation of baseline sympathetic tone in the RVLM during long-term treatment with organic nitrates. Similar mechanisms could promote sympathetic tone in cardiovascular diseases that are associated with endogenous oxidative stress for longer periods.