DOCA-Salt Hypertension: an Update

Basting, Tyler M.; Lazartigues, Eric

doi:10.1007/s11906-017-0731-4

Cited by 124 publications

(130 citation statements)

References 77 publications

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“…These connections contribute to the pronounced increase of sympathetic nerve activity in hypertension (Guyenet, ; Ye et al . ; Basting & Lazartigues, ).…”

Section: Discussionmentioning

confidence: 99%

Glutamatergic neurons of the paraventricular nucleus are critical contributors to the development of neurogenic hypertension

Basting

Mukerjee

et al. 2018

The Journal of Physiology

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Neuro-cardiovascular dysregulation leads to increased sympathetic activity and neurogenic hypertension. The paraventricular nucleus (PVN) of the hypothalamus is a key hub for blood pressure (BP) control, producing or relaying the increased sympathetic tone in hypertension. We hypothesize that increased central sympathetic drive is caused by chronic over-excitation of glutamatergic PVN neurons. We tested how stimulation or lesioning of excitatory PVN neurons in conscious mice affects BP, baroreflex and sympathetic activity. Glutamatergic PVN neurons were unilaterally transduced with channelrhodopsin-2 using an adeno-associated virus (CamKII-ChR2-eYFP-AAV2) in wildtype mice (n = 7) to assess the impact of acute stimulation of excitatory PVN neurons selectively on resting BP in conscious mice. Stimulation of the PVN glutamatergic population resulted in an immediate frequency-dependent (2, 10 and 20 Hz) increase in BP from baseline by ∼9 mmHg at 20 Hz stimulation (P < 0.001). Additionally, in vGlut2-cre mice glutamatergic neurons of the PVN were bilaterally lesioned utilizing a cre-dependent caspase (AAV2-flex-taCASP3-TEVp). Resting BP and urinary noradrenaline (norepinephrine) levels were then recorded in conscious mice before and after DOCA-salt hypertension. Partial lesions of glutamatergic neurons of the PVN (39.3%, P < 0.05) resulted in an attenuated rise in BP following DOCA-salt treatment (P < 0.05 at 7 day time point, n = 8). Noradrenaline levels as an index of sympathetic activity between the lesion and wildtype groups showed a significant reduction after DOCA-salt treatment in the lesioned animals (P < 0.05). These experiments suggest that stimulation of PVN glutamatergic neurons is sufficient to cause autonomic dysfunction and drive the increase in BP.

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“…These connections contribute to the pronounced increase of sympathetic nerve activity in hypertension (Guyenet, ; Ye et al . ; Basting & Lazartigues, ).…”

Section: Discussionmentioning

confidence: 99%

Glutamatergic neurons of the paraventricular nucleus are critical contributors to the development of neurogenic hypertension

Basting

Mukerjee

et al. 2018

The Journal of Physiology

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“…Deoxycorticosterone acetate‐salt rats show hypertension resulting from hypervolaemia induced by hyperaldosteronism and high salt intake followed by increasing renal reabsorption of water and sodium . In this study, the pressor responses to PNS in the isolated mesenteric vascular bed with the intestinal tract in DOCA‐salt rats were significantly lower than those in sham rats.…”

Section: Discussionmentioning

confidence: 51%

“…When DOCA‐treated rats are given NaCl‐containing water, they display volume‐dependent hypertension (DOCA‐salt rat) . The DOCA‐salt rat has been used as a model of hypertension since the 1970s . The Dahl S rat, a genetic model of hypertension, is well known for its rapid elevation in blood pressure when placed on a high‐sodium diet (4%–8% NaCl) .…”

Section: Introductionmentioning

confidence: 99%

Differences in the response to periarterial nerve stimulation or exogenous noradrenaline infusion in the mesenteric vascular bed with the intestinal tract harvested from commonly used rat models of hypertension

Gamoh

Shiba

DiPette

et al. 2019

Clin Exp Pharma Physio

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Summary Many hypertensive animal models have been developed and used to elucidate the pathophysiology of hypertension and to develop antihypertensive drugs. Among them, the spontaneous hypertensive rat (SHR), deoxycorticosterone acetate (DOCA)‐treated and high salt intake rat (DOCA‐salt), and high sodium‐fed Dahl salt‐sensitive rat (HS) models are commonly used. Multiple studies have been conducted, however, elevation in blood pressure in these models due to the reactivity of adrenergic vasoconstriction has not been well characterized in a centralized experiment. In this study, the pressor responses to periarterial nerve stimulation (PNS) or exogenous noradrenaline (NA) infusion were measured in the isolated mesenteric vascular bed with the intestinal tract to investigate the reactivity of mesenteric adrenergic vasoconstriction. The systemic arterial blood pressure of the hypertensive rat models was uniformly elevated compared with their respective controls. However, the changes in perfusion pressure in the mesenteric vascular bed in response to PNS and exogenous NA infusion were quite different depending on the model. The pressor responses to PNS in SHRs and Dahl S HS rats were significantly higher, and those in DOCA‐salt rats were significantly lower than those in the controls. The pressor responses to exogenous NA infusion in SHRs were significantly higher, and those in Dahl S HS rats were significantly lower than those in their respective controls. No difference was observed in the pressor responses to the exogenous NA between the DOCA‐salt and sham groups. These results demonstrate that the reactivity of adrenergic vasoconstriction is different for each type of experimental hypertensive model rat.

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“…Previous studies from our lab and others showed that DOCA-salt hypertension, a model of neurogenic hypertension, is associated with autonomic dysfunction and elevated sympathetic activation. 4, 21 Autonomic function was identical at baseline between sham-treated WT and B1RKO mice (Figure 2C–E). DOCA-salt administration resulted in significant increases in both cardiac (increased bradycardia to propranolol, −145 ±21 beats/minutes, P<0.01 vs. sham) and vascular (decreased MAP to chlorisondamine, −88 ±7 mmHg, P<0.01 vs. sham) sympathetic drive, as well as reduction of vagal tone (reduced tachycardia to atropine, +111 ±8 beats/minute, P<0.01 vs. sham) in WT mice, which were normalized in B1RKO mice (−72 ±13 beats/minutes, −59 ±3 mmHg, and +165 ±6 beats/minute, respectively, P<0.01 vs. WT+DOCA).…”

Section: Resultsmentioning

confidence: 86%

“…Since DOCA-salt hypertension is mainly driven by an alteration in central mechanisms regulating BP, 21 we further investigated the importance of kinin B1R in BP control, using a brain targeted pharmacological approach. Chronic icv infusion of R715, a B1R specific antagonist, attenuated the development of DOCA-salt hypertension.…”

Section: Discussionmentioning

confidence: 99%

Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms

Sriramula

Lazartigues

2017

Hypertension

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Hypertension is associated with increased activity of the kallikrein-kinin system. Kinin B1 receptor (B1R) activation leads to vasoconstriction and inflammation. Despite evidence supporting a role for the B1R in blood pressure (BP) regulation, the mechanisms by which B1R could alter autonomic function and participate in the pathogenesis of hypertension remain unidentified. We sought to explore whether B1R-mediated inflammation contribute to hypertension and investigate the molecular mechanisms involved. In this study, we tested the hypothesis that activation of B1R in the brain is involved in the pathogenesis of hypertension, using the DOCA-salt model of neurogenic hypertension in wild-type (WT) and B1R knockout mice (B1RKO). DOCA-salt treatment in WT mice led to significant increases in B1R mRNA and protein levels and bradykinin levels, enhanced gene expression of carboxypeptidase N supporting an increase in the B1R ligand, associated with enhanced BP, inflammation, sympatho-excitation, autonomic dysfunction and impaired baroreflex sensitivity, while these changes were blunted or prevented in B1RKO mice. B1R stimulation was further shown to involve activation of the ASK1-JNK-ERK1/2 and NF-kB pathways in the brain. To dismiss potential developmental alterations in KO mice, we further used B1R blockade selectively in the brain of WT mice. Supporting the central origin of this mechanism, intracerebroventricular infusion of a specific B1R antagonist, attenuated the DOCA-salt-induced increase in BP in WT mice. Our data provide the first evidence of a central role for B1R-mediated inflammatory pathways in the pathogenesis of DOCA-salt hypertension, and offer novel insights into possible B1R-targeteted therapies for the treatment of neurogenic hypertension.

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DOCA-Salt Hypertension: an Update

Cited by 124 publications

References 77 publications

Glutamatergic neurons of the paraventricular nucleus are critical contributors to the development of neurogenic hypertension

Glutamatergic neurons of the paraventricular nucleus are critical contributors to the development of neurogenic hypertension

Differences in the response to periarterial nerve stimulation or exogenous noradrenaline infusion in the mesenteric vascular bed with the intestinal tract harvested from commonly used rat models of hypertension

Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms

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