Renal Denervation Therapy for Hypertension

Thukkani, Arun K.; Bhatt, Deepak L.

doi:10.1161/circulationaha.113.004660

Cited by 21 publications

(16 citation statements)

References 33 publications

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“…1 Ablating renal sympathetic nerves is an old approach to resistant hypertension that has recently regained favor, owing to technical advances, which make it easier and safer. In many animal and human studies, this approach has reduced arterial pressure substantially; 12 yet a rigorous and large clinical trial recently could not confirm that renal denervation is superior to standard care. Thus, even though renal denervation reduces blood pressure in models of hypertension, its role in clinical medicine remains to be established.…”

Section: Discussionmentioning

confidence: 99%

“…12 Substantial effects of renal nerve ablation on arterial pressure have been observed in many studies, using a variety of experimental models; 1 early success in clinical trials, 13 led to wide adoption of the technique in Europe, and high anticipation for Food and Drug Administration approval in the U.S. The recent announcement that the SYMPLICITY HTN-3 trial 14 did not reach its primary efficacy endpoint, when compared with sham treatment, was disappointing, but it suggests that maximal medical treatment of humans, as achieved in this trial, may interrupt many of the pathways activated by renal nerves.…”

Section: Introductionmentioning

confidence: 99%

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Sympathetic Stimulation of Thiazide-Sensitive Sodium Chloride Cotransport in the Generation of Salt-Sensitive Hypertension

et al. 2014

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Excessive renal efferent sympathetic nerve activity contributes to hypertension in many circumstances. While both hemodynamic and tubular effects likely participate, most evidence supports a major role for α-adrenergic receptors in mediating the direct epithelial stimulation of sodium retention. Recently, it was reported, however, that norepinephrine activates the thiazide-sensitive transporter, NCC, by stimulating β-adrenergic receptors. Here, we confirmed this effect and developed an acute adrenergic stimulation model to study the signaling cascade. The results show that norepinephrine increases the abundance of phosphorylated NCC rapidly (161% increase), an effect largely dependent on β-adrenergic receptors. This effect is not mediated by activation of angiotensin II receptors. We used immunodissected mouse distal convoluted tubule (DCT) to show that DCT cells are especially enriched for β1-adrenergic receptors, and that the effects of adrenergic stimulation can occur ex vivo (79% increase), suggesting they are direct. As two protein kinases, Ste20p-related Proline Alanine-rich kinase (SPAK) and Oxidative stress responsive 1 (OxSR1), phosphorylate and activate NCC, we examined their roles in norepinephrine effects. Surprisingly, norepinephrine did not affect SPAK abundance or its localization in the DCT; instead, we observed a striking activation of OxSR1. We confirmed that SPAK is not required for NCC activation, using SPAK knockout mice. Together, the data provide strong support for a signaling system involving β1- receptors in the DCT that activates NCC, at least in part via OxSR1. The results have implications regarding device- and drug-based treatment of hypertension.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sympathetic Stimulation of Thiazide-Sensitive Sodium Chloride Cotransport in the Generation of Salt-Sensitive Hypertension

et al. 2014

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“…However, the early studies were insufficient to prove the efficacy of renal artery denervation. 2 Larger, confirmatory studies were still necessary. Thus, approval in many parts of the world to perform the procedure outside clinical trials was premature.…”

Section: Early Results Of Renal Artery Denervation and The Birth Of Smentioning

confidence: 99%

Future prospects for renal artery denervation

Bhatt

2016

Journal of the American Society of Hypertension

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“…Ever since, it has been assumed that the underlying mechanism of the BP effects of oxygen supplementation in CKD patients is mediated by a decrease in sympathetic outflow leading to a reduction in systemic vascular resistance (Thukkani and Bhatt, 2013). However, so far this has never been substantiated.…”

Section: Introductionmentioning

confidence: 99%

Blood Pressure Increase during Oxygen Supplementation in Chronic Kidney Disease Patients Is Mediated by Vasoconstriction Independent of Baroreflex Function

et al. 2017

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Renal hypoxia is thought to be an important pathophysiological factor in the progression of chronic kidney disease (CKD) and the associated hypertension. In a previous study among CKD patients, supplementation with 100% oxygen reduced sympathetic nerve activity (SNA) and lowered blood pressure (BP). We aimed to assess the underlying haemodynamic modulation and hypothesized a decreased systemic vascular resistance (SVR). To that end, 19 CKD patients were studied during 15-min intervals of increasing partial oxygen pressure (ppO2) from room air (0.21 ATA) to 1.0 ATA and further up to 2.4 ATA, while continuously measuring finger arterial blood pressure (Finapres). Off-line, we derived indexes of SVR, cardiac output (CO) and baroreflex sensitivity from the continuous BP recordings (Modelflow). During oxygen supplementation, systolic, and diastolic BP both increased dose-dependently from 128 ± 24 and 72 ± 19 mmHg respectively at baseline to 141 ± 23 (p < 0.001) and 80 ± 21 mmHg (p < 0.001) at 1.0 ATA oxygen. Comparing baseline and 1.0 ATA oxygen, SVR increased from 1440 ± 546 to 1745 ± 710 dyn·s/cm5 (p = 0.009), heart rate decreased from 60 ± 8 to 58 ± 6 bpm (p < 0.001) and CO from 5.0 ± 1.3 to 4.6 ± 1.1 L/min (p = 0.02). Baroreflex sensitivity remained unchanged (13 ± 13 to 15 ± 12 ms/mmHg). These blood pressure effects were absent in a negative control group of eight young healthy subjects. We conclude that oxygen supplementation in CKD patients causes a non-baroreflex mediated increased in SVR and blood pressure.

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Renal Denervation Therapy for Hypertension

Cited by 21 publications

References 33 publications

Sympathetic Stimulation of Thiazide-Sensitive Sodium Chloride Cotransport in the Generation of Salt-Sensitive Hypertension

Sympathetic Stimulation of Thiazide-Sensitive Sodium Chloride Cotransport in the Generation of Salt-Sensitive Hypertension

Future prospects for renal artery denervation

Blood Pressure Increase during Oxygen Supplementation in Chronic Kidney Disease Patients Is Mediated by Vasoconstriction Independent of Baroreflex Function

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