Central Inhibition of Tumor Necrosis Factor Alpha Reduces Hypertension by Attenuating Oxidative Stress in the Rostral Ventrolateral Medulla in Renovascular Hypertensive Rats

Abstract

Inflammation in the central nervous system is being considered a key player linked to neurogenic hypertension. Using combined in vivo and in vitro approaches, we investigated the effects of central inhibition of TNF-α on blood pressure, sympathetic tone, baroreflex sensitivity, and oxidative stress in the rostral ventrolateral medulla (RVLM) of rats with 2-kidney-1-clip (2K1C) renovascular hypertension. Continuous infusion of pentoxifylline, a TNF-α inhibitor, into the lateral ventricle of the brain for 14 consecutive days reduced blood pressure and improved baroreflex sensitivity in renovascular hypertensive rats. Furthermore, central TNF-α inhibition reduced sympathetic modulation and blunted the increased superoxide accumulation in the RVLM of 2K1C rats. Our findings suggest that TNF-α play an important role in the maintenance of sympathetic vasomotor tone and increased oxidative stress in the RVLM during renovascular hypertension.

The Renin-Angiotensin System in the Central Nervous System and Its Role in Blood Pressure Regulation

“…Indeed, upregulation of the brain ADAM17 was associated with elevated TNF-α implicating that attenuation of TNF-α-related mechanisms could be mediating part of the phenotype observed in mice lacking hypothalamic ADAM17. Numerous reports suggest elevation of TNF-α and activation of inflammatory cells (microglia) within certain brain regions triggers hypertensive responses [97][98][99]. Therefore, future studies are expected to clarify whether TNF-α plays a regulatory role in ACE2 activity and other RAS components.…”

SARS-CoV-2 and Hypertension: Evidence Supporting Invasion into the Brain Via Baroreflex Circuitry and the Role of Imbalanced Renin-Angiotensin-Aldosterone-System

“…In addition, it has been recorded that oxidative stress in areas such as CVO, hypothalamus, and brainstem can trigger cardiovascular problems. 86 , 88 Hypertension caused by ANG-II elevates the level of ROS, but hypertension induced by norepinephrine does not infer this parameter, indicating a characteristic effect of ANG-II. 86 , 88 …”

“… 86 , 88 Hypertension caused by ANG-II elevates the level of ROS, but hypertension induced by norepinephrine does not infer this parameter, indicating a characteristic effect of ANG-II. 86 , 88 …”

“…The activation of leukocytes, in turn, causes vascular inflammation and renal and vascular hypertension. 70 , 87 , 88 The stimulation of defense cells weakens the BBB, facilitating the entry of T cells and ANG-II circulating in the CNS and increasing neurological damage. 25 , 30 , 31 , 68 , 89 …”

“… 87 , 88 The increased inflammatory status induced by ANG-II within the PVN and the RVLM have been associated with a vasomotor sympathetic tone, which contributes to hypertension. 87 , 88 Effects of the production of these cytokines and the alterations in immune pathways affect kidneys and the heart, contributing to the fibrosis response of peripheral structures and the development of CVDs. The increase in peripheral cytokines can even exert effects in central areas, such as SFO, because it does not have BBB 20 and lead to the development of hypertension, suggesting that, even if neuroinvasion does not occur, peripheral effects of SARS-CoV-2 infection, as the increase in the arrival of ANG-II and cytokines, can trigger the hypertensive response via central mechanisms, which implies the possibility of direct or indirect action of this virus in the pressure control structures.…”