Dietary salt blunts vasodilation by stimulating epithelial sodium channels in endothelial cells from salt‐sensitive Dahl rats

Wang, Zi-Rui; Liu, Huibin; Sun, Yingying; Hu, Qingqing; Li, Yuxia; Zheng, Wei; Yu, Changjiang; Li, Xinyuan; Wu, Ming‐Ming; Song, Bo; Mu, Jianjun; Yuan, Zuyi; Zhang, Zhi-Ren; Ma, Heping

doi:10.1111/bph.13817

Cited by 25 publications

(56 citation statements)

References 55 publications

(73 reference statements)

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“…| 5 of 12 single cultured endothelial cells 7 was observed only under the unusual condition of elevated extracellular [Na + ] combined with elevated aldosterone (0.45 mmol/L). 19 More recent data with benzamil application showed no effect on baseline NO formation in line with the present observations but inhibited acetyl-choline-induced NO release in stark WT mice with eNOS inhibition (L-NAME infusion, 30 mg/kg/day for three days) (n = 9), three doses (5, 50, 500 μg/kg) of amiloride were administered intravenously at 10-minute interval, starting with an initial vehicle bolus injection. Ten minutes after the last dose, blood was collected from the arterial line.…”

Section: Discussionsupporting

confidence: 92%

“…In humans, only renal arteries exhibited faintly α and β ENaC products while no subunits were expressed in mammary arteries and cultured endothelial cells with highly significant amplification of endothelial markers. Previous data showed αβγENaC protein and mRNA in rodent cultured vascular smooth muscle cells 36 and endothelial cells 19 although others have reported absence of detectable αβγENaC from arterioles of the rat. 37 Likewise, αENaC transcripts are present in cultured human endothelial cells 2,3 but the current study could not reproduce this in human aortic endothelial cells.…”

Section: Discussionmentioning

confidence: 90%

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The acute blood pressure‐lowering effect of amiloride is independent of endothelial ENaC and eNOS in humans and mice

et al. 2018

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Aims:The epithelial sodium channel (ENaC) is expressed in cultured endothelial cells and inhibitory coupling to eNOS activity has been proposed. The present study tested the hypothesis that ENaC blockers increase systemic NO-products and lower blood pressure in patients and mice, depending on eNOS. Methods: NO-products and cGMP were measured in diabetes patient urine and plasma samples before and after amiloride treatment (20-40 mg for two days, plasma n = 22, urine n = 12 and 5-10 mg for eight weeks, plasma n = 52, urine n = 55). Indwelling catheters were implanted in the femoral artery and vein in mice for continuous arterial blood pressure and heart rate recordings and infusion. Results: Treatment with amiloride for two days increased plasma and urine NOproducts, while plasma cGMP decreased and urinary cGMP was unchanged in patient samples. Eight weeks of treatment with amiloride did not alter NO-products and cGMP. In mice, amiloride boli of 5, 50, and 500 µg/kg lowered heart rate and arterial blood pressure significantly and acutely. Benzamil had no effect on pressure and raised heart rate. In hypertensive eNOS −/− and L-NAME-treated mice, amiloride lowered blood pressure significantly. L-NAME infusion significantly decreased NO-products in plasma; amiloride and eNOS-deletion had no effect. An acetylcholine bolus resulted in acute blood pressure drop that was attenuated in eNOS −/− and L-NAME mice. ENaC subunit expressions were not detected consistently in human and mouse arteries and endothelial cells. Conclusion: Amiloride has an acute hypotensive action not dependent on ENaC and eNOS and likely related to the heart.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 90%

The acute blood pressure‐lowering effect of amiloride is independent of endothelial ENaC and eNOS in humans and mice

et al. 2018

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“…Our recent studies demonstrated that elevated ENaC activity accounts for the reduced EDR by decreasing NO levels in endothelial cells from salt‐sensitive rats fed a high‐salt (HS) diet, and that blockade of ENaC by amiloride increased both phosphorylated eNOS and NO and, therefore, prevented the HS diet‐induced loss of vasorelaxation and endothelial dysfunction (Wang et al ). Others have also shown that inhibition of ENaC increases NOS phosphorylation and NO production in small‐diameter rat mesenteric arteries (Perez et al , ).…”

Section: Discussionmentioning

confidence: 99%

Oxidized low‐density lipoprotein stimulates epithelial sodium channels in endothelial cells of mouse thoracic aorta

Chen

Wang

et al. 2017

British J Pharmacology

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“…The epithelial sodium channels (ENaC) play important parts in the regulation of total body Na + homeostasis and salt-sensitive hypertension (Peng et al, 2017;Wang et al, 2018). It is assembled from homologous gene products, mainly encoding α, β, and γ subunits (Canessa et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Lovastatin attenuates hypertension induced by renal tubule‐specific knockout of ATP‐binding cassette transporter A1, by inhibiting epithelial sodium channels

Chen

et al. 2019

British J Pharmacology

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Background and Purpose We have shown that cholesterol is synthesized in the principal cells of renal cortical collecting ducts (CCD) and stimulates the epithelial sodium channels (ENaC). Here we have determined whether lovastatin, a cholesterol synthesis inhibitor, can antagonize the hypertension induced by activated ENaC, following deletion of the cholesterol transporter (ATP‐binding cassette transporter A1; ABCA1). Experimental Approach We selectively deleted ABCA1 in the principal cells of mouse CCD and used the cell‐attached patch‐clamp technique to record ENaC activity. Western blot and immunofluorescence staining were used to evaluate protein expression levels. Systolic BP was measured with the tail‐cuff method. Key Results Specific deletion of ABCA1 elevated BP and ENaC single‐channel activity in the principal cells of CCD in mice. These effects were antagonized by lovastatin. ABCA1 deletion elevated intracellular cholesterol levels, which was accompanied by elevated ROS, increased expression of serum/glucocorticoid regulated kinase 1 (Sgk1), phosphorylated neural precursor cell‐expressed developmentally down‐regulated protein 4‐2 (Nedd4‐2) and furin, along with shorten the primary cilium, and reduced ATP levels in urine. Conclusions and Implications These data suggest that specific deletion of ABCA1 in principal cells increases BP by stimulating ENaC channels via a cholesterol‐dependent pathway which induces several secondary responses associated with oxidative stress, activated Sgk1/Nedd4‐2, increased furin expression, and reduced cilium‐mediated release of ATP. As ABCA1 can be blocked by cyclosporine A, these results suggest further investigation of the possible use of statins to treat CsA‐induced hypertension.

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Dietary salt blunts vasodilation by stimulating epithelial sodium channels in endothelial cells from salt‐sensitive Dahl rats

Abstract: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Cited by 25 publications

References 55 publications

The acute blood pressure‐lowering effect of amiloride is independent of endothelial ENaC and eNOS in humans and mice

The acute blood pressure‐lowering effect of amiloride is independent of endothelial ENaC and eNOS in humans and mice

Oxidized low‐density lipoprotein stimulates epithelial sodium channels in endothelial cells of mouse thoracic aorta

Lovastatin attenuates hypertension induced by renal tubule‐specific knockout of ATP‐binding cassette transporter A1, by inhibiting epithelial sodium channels

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