Superoxide Mediates Depressive Effects Induced by Hydrogen Sulfide in Rostral Ventrolateral Medulla of Spontaneously Hypertensive Rats

Abstract

Hydrogen sulfide (H2S) plays a crucial role in the regulation of blood pressure and oxidative stress. In the present study, we tested the hypothesis that H2S exerts its cardiovascular effects by reducing oxidative stress via inhibition of NADPH oxidase activity in the rostral ventrolateral medulla (RVLM). We examined cell distributions of cystathionine-β-synthase (CBS) and effects of H2S on reactive oxygen species (ROS) and mean arterial blood pressure (MAP) in spontaneously hypertensive rats (SHRs). We found that CBS was expressed in neurons of the RVLM, and the expression was lower in SHRs than in Wistar-Kyoto rats. Microinjection of NaHS (H2S donor), S-adenosyl-l-methionine (SAM, a CBS agonist), or Apocynin (NADPH oxidase inhibitor) into the RVLM reduced the ROS level, NADPH oxidase activity, and MAP, whereas microinjection of hydroxylamine hydrochloride (HA, a CBS inhibitor) increased MAP. Furthermore, intracerebroventricular infusion of NaHS inhibited phosphorylation of p47phox, a key step of NADPH oxidase activation. Since decreasing ROS level in the RVLM reduces MAP and heart rate and increasing H2S reduces ROS production, we conclude that H2S exerts an antihypertensive effect via suppressing ROS production. H2S, as an antioxidant, may be a potential target for cardiovascular diseases.

Hydrogen Sulfide Regulates the [Ca2+]i Level in the Primary Medullary Neurons

“…It has been reported that H 2 S in the RVLM inhibits sympathetic vasomotor tone through opening K ATP channels [29, 30]. We have shown that H 2 S in RVLM suppressed the blood pressure in SHRs [14]. The signaling mechanisms in the CNS of the antihypertensive effect of H 2 S have not been elucidated.…”

“…H 2 S is mainly produced endogenously by CBS and MST in the CNS [4, 5] and CBS is mainly expressed in the hippocampus and cerebellum, as well as the cerebral cortex and brain stem [8]. Our previous study has shown that CBS immunoreactivity was found in the rostral ventrolateral medulla (RVLM) neurons in vivo and the level of CBS proteins in the RVLM was lower in SHRs than in WKY rats [14]. In this study, our results showed that more than 80% of cultured medullary neurons were glutamate positive neurons, and CBS and MST were, respectively, expressed in these neurons in vitro, while the expression of CSE was negative in these primarily cultured medullary neurons.…”

“…It was also found that H 2 S decreased blood pressure in various models of hypertension [11–14]. H 2 S treatment reduced blood pressure and oxidative stress in angiotensin II induced hypertensive mice [15] and in spontaneously hypertensive rats (SHRs) [14]. These findings indicate that H 2 S, as an important neuromodulator, produces antineuroinflammatory, antioxidant, and antiapoptotic effects in neurons and glial cells.…”

“…NaHS attenuated the inflammation induced by LPS in microglia via inhibiting of p38-MAPK [10], suggesting the implication of H 2 S in the neuroprotection or treatment of cerebral ischemia and neuroinflammatory diseases. It was also found that H 2 S decreased blood pressure in various models of hypertension [11–14]. H 2 S treatment reduced blood pressure and oxidative stress in angiotensin II induced hypertensive mice [15] and in spontaneously hypertensive rats (SHRs) [14].…”

“…We recently reported that H 2 S exerts its cardiovascular effects by decreasing oxidative stress via inhibition of NADPH oxidase activity in the rostral ventrolateral medulla (RVLM) of SHRs [14]. RVLM, where sympathetic premotor neurons are located, is connected with other cardiovascular nuclei in the CNS, functioning to regulate the cardiovascular effects by regulating sympathetic nerve activity [23–25].…”