Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity

Abstract

Recent studies have implicated reactive oxygen species (ROS) in the pathogenesis of hypertension and activation of the sympathetic nervous system (SNS). Because nitric oxide (NO) exerts a tonic inhibition of central SNS activity, increased production of ROS could enhance inactivation of NO and result in activation of the SNS. To test the hypothesis that ROS may modulate SNS activity, we infused Tempol (4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl), a superoxide dismutase mimetic, or vehicle either intravenously (250 microg x kg(-1) x min(-1)) or in the lateral ventricle (50 microg x kg body wt(-1) x min(-1)), and we determined the effects on blood pressure (BP), norepinephrine (NE) secretion from the posterior hypothalamus (PH) measured by the microdialysis technique, renal sympathetic nerve activity (RSNA) measured by direct microneurography, the abundance of neuronal NO synthase (nNOS)-mRNA in the PH, paraventricular nuclei (PVN), and locus coeruleus (LC) measured by RT-PCR, and the secretion of nitrate/nitrite (NO(x)) in the dialysate collected from the PH of Sprague-Dawley rats. Tempol reduced BP whether infused intravenously or intracerebroventricularly. Tempol reduced NE secretion from the PH and RSNA when infused intracerebroventricularly but raised NE secretion from the PH and RSNA when infused intravenously. The effects of intravenous Tempol on SNS activity were blunted or abolished by sinoaortic denervation. Tempol increased the abundance of nNOS in the PH, PVN, and LC when infused intracerebroventricularly, but it decreased the abundance of nNOS when infused intravenously. When given intracerebroventricularly, Tempol also reduced the concentration of NO(x) in the dialysate collected from the PH. Pretreatment with N(omega)-nitro-l-arginine methyl ester did not abolish the effects of intracerebral Tempol on BP, heart rate, NE secretion from the PH, and RSNA suggesting that the effects of Tempol on SNS activity may be in part dependent and in part independent of NO. In all, these studies support the notion that ROS may raise BP via activation of the SNS. This activation may be mediated in part by downregulation of nNOS and NO production, in part by mechanisms independent of NO. The discrepancy in results between intracerebroventricular and intravenous infusion of Tempol can be best explained by direct inhibitory actions on SNS activity when given intracerebral. By contrast, Tempol may exert direct vasodilation of the peripheral circulation and reflex activation of the SNS when given intravenously.

Activation of Vascular BK Channel by Tempol in DOCA-Salt Hypertensive Rats

“…Tempol is known to activate inhibitory mechanisms in the central and peripheral nervous systems that decrease sympathetic nerve activity. [7][8][9] Shokoji et al 7 reported that 4-aminopyridine (4-AP) (0.1 mmol/L) blocked reduction of nerve activity by local application of tempol onto renal sympathetic nerves. They concluded that tempol may activate voltage-gated K ϩ (Kv) channels.…”

“…7 The results suggested that changes in K ϩ channel activity might contribute to sympatho-inhibition caused by tempol. Central administration of tempol in normotensive rats reduced sympathetic nerve discharge 8,9 and attenuated sympathetic excitation caused by central angiotensin II administration. 9 Therefore, it is possible that tempol-induced vasodilation in vivo is masked by its sympatho-inhibitory effects.…”

“…Central administration of tempol in normotensive rats reduced sympathetic nerve discharge 8,9 and attenuated sympathetic excitation caused by central angiotensin II administration. 9 Therefore, it is possible that tempol-induced vasodilation in vivo is masked by its sympatho-inhibitory effects. 9 Chronic tempol treatment attenuates blood pressure increases in hypertensive animals, an effect attributed to improvement in endothelium function and/or a reduction of oxidative stress.…”

“…9 Therefore, it is possible that tempol-induced vasodilation in vivo is masked by its sympatho-inhibitory effects. 9 Chronic tempol treatment attenuates blood pressure increases in hypertensive animals, an effect attributed to improvement in endothelium function and/or a reduction of oxidative stress. 10,11 However, data obtained in salt-induced or corticotropin (ACTH)-induced hypertension in rats indicate tempol-induced depressor effects are independent of endothelial function and oxidative stress.…”

Sympathoexcitation by Brain Oxidative Stress Mediates Arterial Pressure Elevation in Salt-Induced Chronic Kidney Disease

“…ICV infusion of antioxidants, including in the present study, elicited a sympathoinhibitory effect, suggesting that oxidative stress directly stimulates central sympathetic nerve activity. 18,19,40 In stroke-prone spontaneously hypertensive rats, the level of ROS was higher in the RVLM, and manganese superoxide dismutase overexpression in the RVLM decreased sympathetic nerve activity. 41 Thus, brain ROS overproduction may induce central activation of the sympathetic nervous system.…”