Hypertension Caused by Angiotensin II Infusion Involves Increased Superoxide Production in the Central Nervous System

Abstract

Abstract-Hypertension caused by angiotensin II (Ang II) infusion is associated with oxidative stress in the peripheral vasculature and kidney. The role of redox mechanisms in the central nervous system (CNS), a tissue known to be pivotal in Ang II-dependent hypertension, has not been investigated. ) over a 2-week period in mice caused a gradually developing hypertension that was correlated with marked elevations in O 2 ⅐Ϫ production specifically in the subfornical organ (SFO), a brain region lying outside the blood-brain barrier and known to be a primary sensor for blood-borne Ang II. Adenoviral-mediated delivery of cytoplasmically targeted superoxide dismutase (SOD) selectively to this site prevented the hypertension and the increased O 2 ⅐Ϫ production, whereas gene transfer of SOD targeted to the extracellular matrix had no effect. These data suggest that increased intracellular O 2 ⅐Ϫ production in the SFO is critical in the development of Ang II-induced hypertension. Key Words: reactive oxygen species Ⅲ brain Ⅲ subfornical organ Ⅲ neurons Ⅲ blood pressure V arious forms of hypertension are characterized by an elevation in angiotensin II (Ang II) levels. 1,2 Abundant evidence now suggests that a key mechanism by which Ang II influences blood pressure is via its ability to produce reactive oxygen species (ROS). A decade ago, Griendling et al first discovered that Ang II activates the vascular smooth muscle NAD(P)H oxidase, an important cellular source of ROS. 3 Subsequently, it was shown that hypertension caused by Ang II infusion, but not norepinephrine infusion, increased vascular superoxide (O 2 ⅐Ϫ ) production in vivo 4 and that treatment with liposome-encapsulated superoxide dismutase (SOD) was effective in preventing this form of hypertension. 5 More recent studies demonstrating that genetic disabling of the NADPH oxidase complex attenuates Ang II-induced increases in vascular O 2 ⅐Ϫ production and hypertension further implicates ROS, particularly O 2 ⅐Ϫ

Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats

“…Nevertheless, our observation that site-specific application of tempol to RVLM blunted the increase in GRP78 and p-elF2α expression in RVLM induced by IC infusion of Ang II lends support to a permissive role of ROS in inducing ER stress in RVLM during hypertension. It is well established that oxidative stress in the nucleus tractus solitarii, paraventricular nucleus of the hypothalamus, and circumventricular subfornical organ contributes to neurogenic hypertension, [52][53][54] and our preliminary results showed that ER stress was detected in nucleus tractus solitarii and paraventricular nucleus during hypertension. Whether ER stress in key brain nuclei subserving blood pressure regulation may serve as a common denominator for oxidative stressassociated neurogenic hypertension is beyond the scope of the current study and warrants further investigation.…”

Oxidative stress exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation in rats with hypertension induced by angiotensin II

“…ANG II is suggested to elevate sympathetic nerve activity through its influence on central cardiovascular pathways, which contributes to the development of hypertension (2,28). Moreover, this peptide has been reported to activate NADPH oxidases in the central nervous system (57). In the present study, it is likely that functions of central cardiovascular pathways in the reflex arc are also mediated by ANG II, thereby contributing to the exaggerated exercise pressor reflex responses in ANGII450 rats.…”

“…ANG II, an effector molecule of the RAAS, plays an important role in developing and maintaining hypertension by constricting vessels via its action on smooth muscle cells (5,14). Moreover, this peptide has been known to activate NADPH oxidases, thereby triggering the production of superoxide and other reactive oxygen species (ROS) in various tissues, including skeletal muscle (13,41,51,55,57). The development of oxidative stress has also been implicated in the pathogenesis of hypertension (26,55).…”

Sympathoinhibition caused by orally administered telmisartan through inhibition of the AT1 receptor in the rostral ventrolateral medulla of hypertensive rats

“…5,6 We demonstrated that oxidative stress in the brain causes hypertension through sympathoexcitation. 11,[15][16][17]34,35 We also demonstrated that AT 1 R-inducced oxidative stress in the RVLM causes SNS activation in hypertensive rats. 11,14,15 Direct inhibition of the AT 1 R in the RVLM inhibits SNS activation in hypertensive rats.…”