SOD1 gene transfer into paraventricular nucleus attenuates hypertension and sympathetic activity in spontaneously hypertensive rats

Abstract

Excessive sympathetic activity contributes to the initiation and progression of hypertension. Reactive oxygen species in the paraventricular nucleus (PVN) is involved in sympathetic overdrive and hypertension. The present study was designed to investigate whether superoxide dismutase 1 (SOD1) overexpression in the PVN attenuated sympathetic activation and hypertension. Adenoviral vectors containing human SOD1 or null adenoviral vectors were microinjected into the PVN of Wistar rats and spontaneously hypertensive rats (SHR). Significant depressor effects were observed from weeks 1 to 4 after SOD1 gene transfer in SHR. Acute experiments were carried out at the end of the 3rd week. In the PVN, superoxide anion and angiotensin II levels were increased while SOD1 activity and protein expression were decreased in SHR, which were attenuated by SOD1 overexpression in the PVN. However, SOD1 overexpression had no significant effect on the SOD2 activity in the PVN. The blood pressure response to ganglionic blockade, cardiac sympathetic nerve activity, and cardiac sympathetic afferent reflex (CSAR) were enhanced, and the plasma norepinephrine level was increased in SHR, which were prevented by SOD1 gene transfer in the PVN. Furthermore, SOD1 overexpression decreased the ratio of left ventricular weight to body weight, cross-sectional areas of myocardial cells, media thickness, and the media/lumen ratio of small arteries in the heart in SHR. These results indicate that SOD1 overexpression in the PVN reduces arterial blood pressure, attenuates excessive sympathetic activity and CSAR, and improves myocardial and vascular remodeling in SHR.

Hexamethonium attenuates sympathetic activity and blood pressure in spontaneously hypertensive rats

“…Hexamethonium is a ganglionic blocker (10,11) and reduces blood pressure in SHR and Wistar rats (8). In the present study, the intravenous injection of four doses (0.2, 1.0, 5.0 or 25.0 mg/kg body weight) of hexamethonium was demonstrated to significantly reduce the RSNA, MAP and HR in the Wistar rats and the SHRs.…”

“…The MAP response to ganglionic blockade has been used to evaluate basal sympathetic nerve activity in conscious rats (8). In the present study, the four doses of hexamethonium investigated were demonstrated to significantly reduce the RSNA, MAP and HR in the Wistar rats and the SHRs.…”

“…Several methods have been used to evaluate sympathetic activity including the cardiac sympathetic afferent reflex (7), the adipose afferent reflex (4), plasma norepinephrine levels (8) and blood pressure response to ganglionic blockade (9).…”

Superoxide Anions in Paraventricular Nucleus Modulate Adipose Afferent Reflex and Sympathetic Activity in Rats

“…NAD(P)H oxidase in the PVN contributes to elevated sympathetic activity and the hypertensivogenic actions induced by mineralocorticoid excess [35]. We found that superoxide dismutase 1 (SOD1) gene transfer into the PVN attenuates sympathetic activity and hypertension in spontaneously hypertensive rats [38], and improves post-infarct myocardial remodeling and ventricular function in chronic heart failure rats [12]. The first aim of the present study was designed to determine whether superoxide anions in the PVN are involved in modulating the AAR.…”

Hypothalamic and inflammatory basis of hypertension

“…However, enhanced nitric oxide signaling reduces blood pressure, decreases SNS activity, and shows anti-hypertensive effect via adrenomedullin receptors (162). Anti-oxidative treatments, such as overexpression of superoxide dismutase 1 (SOD1), or bilateral infusion of the radical scavenger tempol into the PVN inhibit ROS-driven SNS activation and hypertension (163). Regarding the mechanisms involved, inflammation is likely involved in the mitochondrial dysfunction (164).…”