Amiloride lowers blood pressure and attenuates urine plasminogen activation in patients with treatment–resistant hypertension

Oxlund, Christina Stolzenburg; Buhl, Kristian Bergholt; Jacobsen, I.A.; Hansen, Maj; Gram, Jeppe; Henriksen, Jan Erik; Schousboe, Karoline; Tarnow, Lise; Jensen, Boye L.

doi:10.1016/j.jash.2014.09.019

Cited by 45 publications

(63 citation statements)

References 27 publications

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“…Alternatively, very-low-dose amiloride could have prevented proteinuria via its ENaC-independent effects on urokinase-type plasminogen activator, which are known to reduce proteinuria (Zhang et al, 2012). However, amiloride doses known to attenuate plasminogen activation also reduce blood pressure (Oxlund et al, 2014). Therefore, whether very-low-dose amiloride improved proteinuria via effects on renal vascular function and structure, or via its effects on plasminogen activation remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Amiloride Improves Endothelial Function and Reduces Vascular Stiffness in Female Mice Fed a Western Diet

et al. 2017

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Obese premenopausal women lose their sex related cardiovascular disease protection and develop greater arterial stiffening than age matched men. In female mice, we have shown that consumption of a Western diet (WD), high in fat and refined sugars, is associated with endothelial dysfunction and vascular stiffening, which occur via activation of mineralocorticoid receptors and associated increases in epithelial Na+ channel (ENaC) activity on endothelial cells (EnNaC). Herein our aim was to determine the effect that reducing EnNaC activity with a very-low-dose of amiloride would have on decreasing endothelial and arterial stiffness in young female mice consuming a WD. To this end, we fed female mice either a WD or control diet and treated them with or without a very-low-dose of the ENaC-inhibitor amiloride (1 mg/kg/day) in the drinking water for 20 weeks beginning at 4 weeks of age. Mice consuming a WD were heavier and had greater percent body fat, proteinuria, and aortic stiffness as assessed by pulse-wave velocity than those fed control diet. Treatment with amiloride did not affect body weight, body composition, blood pressure, urinary sodium excretion, or insulin sensitivity, but significantly reduced the development of endothelial and aortic stiffness, aortic fibrosis, aortic oxidative stress, and mesenteric resistance artery EnNaC abundance and proteinuria in WD-fed mice. Amiloride also improved endothelial-dependent vasodilatory responses in the resistance arteries of WD-fed mice. These results indicate that a very-low-dose of amiloride, not affecting blood pressure, is sufficient to improve endothelial function and reduce aortic stiffness in female mice fed a WD, and suggest that EnNaC-inhibition may be sufficient to ameliorate the pathological vascular stiffening effects of WD-induced obesity in females.

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Section: Discussionmentioning

confidence: 99%

Amiloride Improves Endothelial Function and Reduces Vascular Stiffness in Female Mice Fed a Western Diet

et al. 2017

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“…Thus, at least in some patients with HA, ENaC blockade with low‐dose amiloride‐based therapy is highly effective in controlling BP control and in protecting against macro‐ and microvascular disease over 18 years (90 patient‐years) and adverse cardiovascular, cerebrovascular, and renal events over 20 years (100 patient‐years) of follow‐up. Given the typical admonition that patients with HA experience more end‐organ damage and adverse cardiovascular events, present results are noteworthy but how much of the observed benefits are attributable to excellent BP control and how much to other mechanisms cannot be determined. However, amiloride is highly specific for ENaC and does not appear to affect aldosterone secretion, which remained high throughout.…”

Section: Discussionmentioning

confidence: 88%

“…At a cellular level, the primary effect of aldosterone and other mineralocorticoids is stimulation of mineralocorticoid receptors (MR). A major function of the MR is to regulate the availability of ion channels, especially epithelial sodium channels (ENaC), in cell membranes . Recent studies suggest that ENaC originally found in renal tubular cells also exists in the brain and in other tissues and cell lines including mouse vascular endothelium and fibroblasts, so direct and indirect hemodynamic and volume regulatory effects of ENaC are plausible.…”

Section: Introductionmentioning

confidence: 99%

“…Nongenetic forms of HA are often treated surgically but chronic oral MR antagonism, generally with spironolactone, has also been used successfully to lower BP and maintain serum potassium . A potentially useful but often forgotten drug is amiloride, a specific ENaC inhibitor . Persistent BP‐lowering effects of amiloride have been reported in short‐term studies in low‐renin hypertension and HA, but there have been no long‐term or outcome trials with this agent.…”

Section: Introductionmentioning

confidence: 99%

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Maintenance of long‐term blood pressure control and vascular health by low‐dose amiloride‐based therapy in hyperaldosteronism

Izzo

Hong

Hussain

et al. 2019

J of Clinical Hypertension

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Whether aldosterone itself contributes directly to macro‐ or microcirculatory disease in man or to adverse cardiovascular outcomes is not fully known. We report our long‐term single‐practice experience in an unusual group of five patients with chronic hyperaldosteronism (HA, including three with glucocorticoid‐remediable aldosteronism, GRA) treated with low‐dose amiloride (a specific epithelial sodium channel [ENaC] blocker) 5‐10 (mean 7) mg daily for 14‐28 (mean 20) years. Except for one GRA diagnosed in infancy, all had severe resistant hypertension. In each case, BP was normalized within 1‐4 weeks after starting amiloride and office BP’s remained well controlled throughout the next two decades. 24‐hour ambulatory BP monitoring with pulse wave analysis (cardiac output, vascular resistance, augmentation index, reflection magnitude), regional pulse wave velocities, pulse stiffening ratio, ankle‐brachial index, serum creatinine, estimated glomerular filtration rate, and spot urinary albumin:creatinine ratio were measured after a mean of 18 years; all of these indicators were essentially normal. Over two additional years of observation (100 patient‐years total), no cardiovascular or renal event occurred. We conclude that long‐term ENaC blockade with amiloride can normalize BP and protect macro‐ and microvascular function in patients with HA. This suggests that either (a) putative vasculopathic effects of aldosterone are mediated via ENaC or (b) aldosterone may not play a direct role in age‐dependent vasculopathic changes in humans independent of blood pressure. These findings, coupled with our literature review in both animal and human results, underscore the need for additional studies.

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“…Urokinase activity was detectable in macroalbuminuric urine, with a tendency toward reduction in activity after amiloride treatment. 227 …”

Section: Chronic Periodontitismentioning

confidence: 99%

Detection of inflammatory biomarkers in saliva and urine: Potential in diagnosis, prevention, and treatment for chronic diseases

Prasad

Tyagi

Aggarwal

2016

Exp Biol Med (Maywood)

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Inflammation is a part of the complex biological response of inflammatory cells to harmful stimuli, such as pathogens, irritants, or damaged cells. This inflammation has been linked to several chronic diseases including cancer, atherosclerosis, rheumatoid arthritis, and multiple sclerosis. Major biomarkers of inflammation include tumor necrosis factor, interleukins (IL)-1, IL-6, IL-8, chemokines, cyclooxygenase, 5-lipooxygenase, and C-reactive protein, all of which are regulated by the transcription factor nuclear factor-kappaB. Although examining inflammatory biomarkers in blood is a standard practice, its identification in saliva and/or urine is more convenient and non-invasive. In this review, we aim to (1) discuss the detection of these inflammatory biomarkers in urine and saliva; (2) advantages of using salivary and urinary inflammatory biomarkers over blood, while also weighing on the challenges and/or limitations of their use; (3) examine their role(s) in connection with diagnosis, prevention, treatment, and drug development for several chronic diseases with inflammatory consequences, including cancer; and (4) explore the use of innovative salivary and urine based biosensor strategies that may permit the testing of biomarkers quickly, reliably, and cost-effectively, in a decentralized setting.

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Amiloride lowers blood pressure and attenuates urine plasminogen activation in patients with treatment–resistant hypertension

Cited by 45 publications

References 27 publications

Amiloride Improves Endothelial Function and Reduces Vascular Stiffness in Female Mice Fed a Western Diet

Amiloride Improves Endothelial Function and Reduces Vascular Stiffness in Female Mice Fed a Western Diet

Maintenance of long‐term blood pressure control and vascular health by low‐dose amiloride‐based therapy in hyperaldosteronism

Detection of inflammatory biomarkers in saliva and urine: Potential in diagnosis, prevention, and treatment for chronic diseases

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