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      Dysregulation of the Excitatory Renal Reflex in the Sympathetic Activation of Spontaneously Hypertensive Rat

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          Abstract

          Excessive sympathetic activation plays crucial roles in the pathogenesis of hypertension. Chemical stimulation of renal afferents increases the sympathetic activity and blood pressure in normal rats. This study investigated the excitatory renal reflex (ERR) in the development of hypertension in the spontaneously hypertensive rat (SHR). Experiments were performed in the Wistar-Kyoto rat (WKY) and SHR aged at 4, 12, and 24 weeks under anesthesia. Renal infusion of capsaicin was used to stimulate renal afferents, and thus, to induce ERR. The ERR was evaluated by the changes in the contralateral renal sympathetic nerve activity and mean arterial pressure. At the age of 4 weeks, the early stage with a slight or moderate hypertension, the ERR was more enhanced in SHR compared with WKY. The pressor response was greater than the sympathetic activation response in the SHR. At the age of 12 weeks, the development stage with severe hypertension, there was no significant difference in the ERR between the WKY and SHR. At the age of 24 weeks, the later stage of hypertension with long-term several hypertensions, the ERR was more attenuated in the SHR compared with the WKY. On the other hand, the pressor response to sympathetic activation due to the ERR was smaller at the age of 12 and 24 weeks than those at the age of 4 weeks. These results indicate that ERR is enhanced in the early stage of hypertension, and attenuated in the later stage of hypertension in the SHR. Abnormal ERR is involved in the sympathetic activation and the development of hypertension.

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          Most cited references42

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          The sympathetic nervous system alterations in human hypertension.

          Several articles have dealt with the importance and mechanisms of the sympathetic nervous system alterations in experimental animal models of hypertension. This review addresses the role of the sympathetic nervous system in the pathophysiology and therapy of human hypertension. We first discuss the strengths and limitations of various techniques for assessing the sympathetic nervous system in humans, with a focus on heart rate, plasma norepinephrine, microneurographic recording of sympathetic nerve traffic, and measurements of radiolabeled norepinephrine spillover. We then examine the evidence supporting the importance of neuroadrenergic factors as promoters and amplifiers of human hypertension. We expand on the role of the sympathetic nervous system in 2 increasingly common forms of secondary hypertension, namely hypertension associated with obesity and with renal disease. With this background, we examine interventions of sympathetic deactivation as a mode of antihypertensive treatment. Particular emphasis is given to the background and results of recent therapeutic approaches based on carotid baroreceptor stimulation and radiofrequency ablation of the renal nerves.
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            NLRP3 inflammasome activation contributes to VSMC phenotypic transformation and proliferation in hypertension

            Inflammation is involved in pathogenesis of hypertension. NLRP3 inflammasome activation is a powerful mediator of inflammatory response via caspase-1 activation. The present study was designed to determine the roles and mechanisms of NLRP3 inflammasome in phenotypic modulation and proliferation of vascular smooth muscle cells (VSMCs) in hypertension. Experiments were conducted in spontaneously hypertensive rats (SHR) and primary aortic VSMCs. NLRP3 inflammasome activation was observed in the media of aorta in SHR and in the VSMCs from SHR. Knockdown of NLRP3 inhibited inflammasome activation, VSMC phenotypic transformation and proliferation in SHR-derived VSMCs. Increased NFκB activation, histone acetylation and histone acetyltransferase expression were observed in SHR-derived VSMCs and in media of aorta in SHR. Chromatin immunoprecipitation analysis revealed the increased histone acetylation, p65-NFκB and Pol II occupancy at the NLRP3 promoter in vivo and in vitro. Inhibition of NFκB with BAY11-7082 or inhibition of histone acetyltransferase with curcumin prevented the NLRP3 inflammasome activation, VSMC phenotype switching and proliferation in VSMCs from SHR. Moreover, curcumin repressed NFκB activation. Silencing of NLRP3 gene ameliorated hypertension, vascular remodeling, NLRP3 inflammasome activation and phenotype switching in the aorta of SHR. These results indicate that NLRP3 inflammasome activation response to histone acetylation and NFκB activation contributes to VSMC phenotype switching and proliferation and vascular remodeling in hypertension.
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              Evidence for a critical role of the sympathetic nervous system in hypertension.

              Autonomic cardiovascular control is impaired in hypertension, leading to a reduction in the parasympathetic tone and to an increase in the sympathetic influences to the heart and peripheral vessels. The sympathetic dysfunction depends on a variety of reflex and nonreflex mechanisms and participates at development and progression of the essential hypertensive state. This has been shown to be the case for borderline hypertension, for moderate and severe high blood pressure, and for resistant hypertension as well. In addition, the adrenergic overdrive participates at the pathophysiology of the complex cardiometabolic alterations, known as "end-organ damage," detectable in the clinical course of hypertensive disease. In the present article, we will review the main features of the adrenergic abnormalities characterizing essential hypertension, the mechanisms potentially involved in this neural abnormality, and its consequences as well. We will also discuss the most recent information achieved in the field and the areas worthy of future investigations.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                03 June 2021
                2021
                : 12
                : 673950
                Affiliations
                [1] 1Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center of Translational Medicine for Cardiovascular Disease, Department of Physiology, Nanjing Medical University , Nanjing, China
                [2] 2Department of Pathophysiology, Nanjing Medical University , Nanjing, China
                [3] 3Department of Physiology and Pathophysiology, Cardiovascular Research Center, Xi’an Jiaotong University School of Medicine , Xi’an, China
                Author notes

                Edited by: Lilei Yu, Renmin Hospital of Wuhan University, China

                Reviewed by: Jasenka Zubcevic, University of Florida, United States; Hanjun Wang, University of Nebraska Medical Center, United States; Jie Qi, Xi’an Jiaotong University, China

                This article was submitted to Autonomic Neuroscience, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2021.673950
                8209386
                924790a3-bb03-44ae-a687-4603729bdd5e
                Copyright © 2021 Ye, Zheng, Wang, Wang, Chen, Li, Kang and Zhu.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 February 2021
                : 08 April 2021
                Page count
                Figures: 5, Tables: 1, Equations: 0, References: 42, Pages: 9, Words: 0
                Categories
                Physiology
                Original Research

                Anatomy & Physiology
                renal reflex,hypertension,sympathetic activity,blood pressure,kidney
                Anatomy & Physiology
                renal reflex, hypertension, sympathetic activity, blood pressure, kidney

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