Blood pressure lowering efficacy of potassium-sparing diuretics (that block the epithelial sodium channel) for primary hypertension

Heran, Balraj S; Chen, Jenny MH; Wang, Josh J.; Wright, James M

doi:10.1002/14651858.cd008167.pub2

Cited by 14 publications

(12 citation statements)

References 14 publications

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“…Furthermore, the currently available EpNaC blockers do not have a substantial effect on reduction of systemic blood pressure, at least in the currently used dosing regimens. 17 An exception to this overall analysis is provided by the salulatory responses to amiloride in adolescents with Liddle syndrome, who presumably have not developed the long-term vascular changes associated with chronic hypertension, although this effect may represent a primary renal effect rather than an effect on the vascular endothelium in Liddle syndrome and is clearly predicated on control of dietary salt intake. 9,13 EnNaC may present a specific target for therapeutic intervention if its inhibition can be functionally separated from EpNaC, and thus avoiding or at least minimizing impairment of renal and intestinal K + secretion.…”

Section: Warnock Vascular Tone and Ennac 953mentioning

confidence: 99%

The Amiloride-Sensitive Endothelial Sodium Channel and Vascular Tone

Warnock

2013

Hypertension

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Further work to precisely define the subunit structures and assembly, the possibility of alternative transcription start sites or splicing, and even other subunits 12 need to be fully explored. As an example, in the original clinical phenotype of the autosomal dominant gain-of-function condition by Liddle et al, 13 there was a striking effect of increased dietary sodium intake (and presumably increased urinary sodium concentration) to reduce the effectiveness of sodium channel blockade observed with triamterene. In contrast, EnNaC activity as described in the current report by Jeggle and colleagues was fully inhibited by amiloride in the presence of normal extracellular sodium concentrations of 140 mmol/L. A recent report by Kleyman and colleagues describes a novel point mutation in the γ ENaC subunit (γL511Q) that increases amiloride-sensitive currents and largely eliminates the Na + self-inhibition response, which reflects downregulation of ENaC open probability by higher extracellular Na + concentrations. This sort of downregulation would be appropriate for the amiloride-sensitive EpNaC in the distal nephron but would not be relevant for EnNaC in the systemic circulation that is continuously bathed in relative higher extracellular Na + concentrations. Hence, sequence variations in the γ ENaC subunit at the single nulceotide level could have important conseqences for understanding the regulation of EnNaC activity.It is well recognized that renin-angiotension-aldosterone system blockade is an important avenue for treating chronic kidney disease and reducing mortality in cardiovascular disease. Major efforts have demonstrated the clinical benefit of using mineralocorticoid receptor antagonism in cardiovascular disease, with novel new approaches coming to the fore.14 Unfortunately, the cardioprotective effects associated with mineralocorticoid receptor blockade nearly 15 years ago 15 are not readily available to patients with moderate-tosevere chronic kidney disease who can develop dose-limiting hyperkalemia in the setting of aggressive renin-angiotensionaldosterone system blockade, such as described in the recent ALTITUDE Trial. 16 Previous consideration has been given to trying to separate the effects of Na-channel blockers like amiloride or triamterene from the parallel decreases in K + secretion that invariably accompany EpNaC blockade. Furthermore, the currently available EpNaC blockers do not have a substantial effect on reduction of systemic blood pressure, at least in the currently used dosing regimens. 17 An exception to this overall analysis is provided by the salulatory responses to amiloride in adolescents with Liddle syndrome, who presumably have not developed the long-term vascular changes associated with chronic hypertension, although this effect may represent a primary renal effect rather than an effect on the vascular endothelium in Liddle syndrome and is clearly predicated on control of dietary salt intake. 9,13EnNaC may present a specific target for therapeutic intervention if its inhibition ca...

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Section: Warnock Vascular Tone and Ennac 953mentioning

confidence: 99%

The Amiloride-Sensitive Endothelial Sodium Channel and Vascular Tone

Warnock

2013

Hypertension

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“…Amiloride has but a modest antihypertensive effect when given as monotherapy. Its BP-lowering effect can be considerably enhanced when coadministered with a thiazide diuretic [ 45 ]. Unlike HCTZ, amiloride appears not to have a negative effect on glucose homeostasis [ 46 ].…”

Section: Amiloridementioning

confidence: 99%

Diuretics for the Treatment of Hypertension

Sica

2015

Pathophysiology and Pharmacotherapy of Cardiovascular Disease

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Diuretics are agents commonly used in diseases characterized by excess extracellular fl uid, including chronic kidney disease, nephrotic syndrome, cirrhosis, and heart failure. Diuretics are also commonly used either as monotherapy or in combination with other antihypertensive agents in the management of hypertension. Multiple diuretic classes, including thiazide-type diuretics, loop diuretics, and potassium-sparing diuretics, are used to treat patients with these diseases. An understanding of what determines a patient's response to a diuretic is a prerequisite to the correct use of these drugs. The response of patients with these diseases to diuretics, which is related to the dose, is best described by a sigmoid curve whose contour can become distorted by any of the several sodium-retaining states that are directly or indirectly associated with renal disease. The pharmacodynamic effect of diuretics as used in the treatment of hypertension involves both a volume removal element and more long-term vasodilation. Diuretic actions are of considerable importance to patients who have renal disease, as their effective use assists in extracellular fl uid volume control, reducing excretion of protein in urine and lessening the risk of developing hyperkalemia. Diuretic-related adverse events that involve the uric acid, sodium, and potassium axes are not uncommon; therefore, the clinician must be vigilant in looking for biochemical disturbances. As a result of diuretic-related adverse events, clinicians must be resourceful in the dose amount and frequency of dosing.

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“…Four studies with amiloride and 2 studies with triamterene have evaluated the dose-related blood pressure efficacy of these drugs when added, as a second antihypertensive agent, to hydrochlorothiazide or chlorthalidone (Heran et al, 2010).…”

Section: Epithelial Sodium Channel Blockersmentioning

confidence: 99%