GABA&lt;sub&gt;B&lt;/sub&gt; Receptor Gene Transfer Into the Nucleus Tractus Solitarii Induces Chronic Blood Pressure Elevation in Normotensive Rats

Li, Bo; Liu, Qing; Xuan, Chengluan; Guo, Lirong; Shi, Ruofan; Zhang, Qi; O’Rourke, Stephen T.; Liu, Kexiang; Sun, Chengwen

doi:10.1253/circj.cj-13-0305

Cited by 8 publications

(12 citation statements)

References 26 publications

(51 reference statements)

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“…43 Involvement of the nucleus of the solitary tract (NTS) in the development of hypertension is also reported. 44 In contrast, a mechanism for the shift of the neural arc towards higher input pressure in SHR is less clear. A reduced distensibility of the arterial wall at the baroreceptor regions can change the pressure-diameter relation towards higher input pressure.…”

Section: Discussionmentioning

confidence: 99%

Predominant Role of Neural Arc in Sympathetic Baroreflex Resetting of Spontaneously Hypertensive Rats

Sata

Kawada

Shimizu

et al. 2015

Circ J

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592SATA Y et al. Circulation JournalOfficial Journal of the Japanese Circulation Society http://www. j-circ.or.jp classified as a short-term blood pressure control system, 8 carotid baroreflex activation therapy has succeeded in reducing blood pressure in patients with resistant hypertension for more than 1 year, 9 suggesting a potential role of the arterial baroreflex in the long-term regulation of blood pressure. 10 Considering the multifactorial and complex nature of hypertension, further research is needed to understand how sympathetic nerve activity (SNA) and AP are determined in hypertension. The arterial baroreflex system constitutes a key link between the autonomic nervous system and the cardiovascular system. The reflex arc of baroreflex can be divided into 2 principal arcs: the neural arc from pressure input to SNA, and the peripheral arc from SNA to AP. 11,12 Under normal physiological conditions, because the arterial baroreflex operates as a closedloop feedback control system, it is difficult to separately quantify neural and peripheral arc characteristics.The behavior of a system might be described by dynamic and static characteristics. The dynamic characteristics determine he arterial baroreflex control of arterial pressure (AP) is known to reset to a higher input pressure range in hypertension. 1 To cope with the resetting, carotid baroreflex activation is proposed as a potential treatment of drugresistant hypertension. 2,3 Involvement of both neural and cardiovascular factors has been proposed in the pathophysiology of hypertension. Previous studies have demonstrated that sympathetic outflow from the central nervous system is increased in spontaneously hypertensive rats (SHR). 4,5 Peripheral factors such as cardiac hypertrophy and increased vascular resistance are also considered responsible for high AP in SHR. 6 Abnormality in vascular function is also reported in hypertensive patients. 7 Editorial p 510Device-based neuromodulation therapy has increasingly drawn scientific interest. While the arterial baroreflex has been Background: There is ongoing controversy over whether neural or peripheral factors are the predominant cause of hypertension. The closed-loop negative feedback operation of the arterial baroreflex hampers understanding of how arterial pressure (AP) is determined through the interaction between neural and peripheral factors.

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Section: Discussionmentioning

confidence: 99%

Predominant Role of Neural Arc in Sympathetic Baroreflex Resetting of Spontaneously Hypertensive Rats

Sata

Kawada

Shimizu

et al. 2015

Circ J

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“…This sympathetic overactivation may be the result of placental pathogenic factors (e.g., inflammatory cytokines) acting primarily on brainstem nuclei that govern sympathovagal balance (154–156) of cardiovascular physiology. In other forms of hypertension, the mechanism is disinhibition of the RVLM by upregulating the expression of GABA B receptors in the regions of the nucleus of the solitary tract that receive baroreceptor afferents (Figure 2) (157–163). Whether this mechanism is active in PE is an area ripe for new research.…”

Section: The Autonomic Regulation Of Cardiovascular Physiological Adamentioning

confidence: 99%

“…Pharmacologic studies in spontaneously hypertensive rats (SHRs) (162, 208–210), and hypertensive Sprague-Dawley rats induced with a one-kidney figure-8 renal wrap (163, 195, 198, 201, 211) have demonstrated that the enhanced expression and activation of GABA B Rs in the regions of the NTS that receive and integrate BR afferent inputs results in hypertension. Additionally, transfer of the GABA B R gene into the NTS of normotensive rats resulted in rapid onset of hypertension, increased heart rate, and increased plasma norepinephrine levels, all of which remained elevated for the duration of the 14-day study (157). This GABA B R-mediated pressor response is potentiated by the actions of AngII on NTS neurons (161).…”

Section: Diverse Models Of Hypertension Demonstrate Electrophysiologimentioning

confidence: 99%

Preeclampsia and the brain: neural control of cardiovascular changes during pregnancy and neurological outcomes of preeclampsia

2016

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Preeclampsia (PE) is a form of gestational hypertension that complicates ~ 5 percent of pregnancies worldwide. Over 70 percent of the fatal cases of PE are attributed to cerebral edema, intracranial hemorrhage, and eclampsia. The etiology of PE originates from abnormal remodeling of the maternal spiral arteries, creating an ischemic placenta that releases factors that drive the pathophysiology. An initial neurological outcome of PE is the absence of the autonomically regulated cardiovascular adaptations to pregnancy. PE patients exhibit sympathetic overactivation, in comparison to both normotensive pregnant and hypertensive non-pregnant females. Moreover, PE diminishes baroreceptor reflex sensitivity (BRS) beyond that observed in healthy pregnancy. The absence of the cardiovascular adaptations to pregnancy, combined with sympathovagal imbalance and a blunted BRS leads to life-threatening neurological outcomes. Behaviorally, the increased incidences of maternal depression, anxiety, and post-traumatic stress disorder (PTSD) in PE are correlated to low fetal birth weight, intrauterine growth restriction (IUGR) and premature birth. This review addresses these neurological consequences of PE that present in the gravid female both during and after the index pregnancy.

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“…Through its role in interpreting interoceptive inputs from the entire body and translating that into autonomic function via the parasympathetic and sympathetic outflows, it forms an attractive target for manipulation. Past studies have shown that manipulations affecting the NTS alone are sufficient to ameliorate hypertension in the SHR model 3,[30][31][32][33] . Many of the pharmacological interventions that show clinical efficacy in lowering blood pressure in hypertensive patients work at many different sites of action in parallel, even if the presumed mechanism of action is narrowly defined.…”

Section: Discussionmentioning

confidence: 99%

Treating the Network: Targeted inhibition of two specific microRNAs in the brainstem prevents the development of hypertension

Gorky

DeCicco

Achanta

et al. 2020

Preprint

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We here test the concept that disease states may result not from a single cause but from small changes in a network that are collectively significant. We recently showed that development of hypertension (HTN) in the spontaneously hypertensive rat (SHR) model of human essential hypertension is accompanied by changes in microRNA expression levels in the brainstem tracking the development of HTN 1,2 . This led to the hypothesis that preventing the change in microRNA levels could prevent the development of HTN. We propose that hypertension emerges from a network that has been pushed out of a normotensive equilibrium into a compensatory, pathological state. We show that small perturbations in the gene regulatory networks in the brainstem by selectively blocking two microRNAs highlighted in our previous results, miR-135a and miR-376a, is sufficient to prevent development of hypertension in the SHR model. This effect appears driven by only modest changes in the expression of rate-limiting genes, many of which are targets of these miRNAs, suggesting that the combination of genes that are targeted in the network is responsible for the effect. The demonstration that hypertension is an emergent property of an underlying regulatory network suggests that a new treatment paradigm altogether is needed.

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GABA<sub>B</sub> Receptor Gene Transfer Into the Nucleus Tractus Solitarii Induces Chronic Blood Pressure Elevation in Normotensive Rats

Cited by 8 publications

References 26 publications

Predominant Role of Neural Arc in Sympathetic Baroreflex Resetting of Spontaneously Hypertensive Rats

Predominant Role of Neural Arc in Sympathetic Baroreflex Resetting of Spontaneously Hypertensive Rats

Preeclampsia and the brain: neural control of cardiovascular changes during pregnancy and neurological outcomes of preeclampsia

Treating the Network: Targeted inhibition of two specific microRNAs in the brainstem prevents the development of hypertension

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