Amiloride, a Specific Drug for Hypertension in Black People With T594M Variant?

Baker, Emma H.; Duggal, Ajay; Dong, Yanbin; Ireson, Nicola J.; Wood, Monique; Markandu, Nirmala D.; MacGregor, Graham A.

doi:10.1161/01.hyp.0000022570.02119.75

Cited by 89 publications

(55 citation statements)

References 14 publications

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“…Therefore, our data call into question the notion advanced by a previous study in which amiloride monotherapy appeared to have a particularly dramatic BP-lowering effect in black hypertensives with the T594M allele. 8 The confirmation of the null hypothesis in our study may be related to several important methodological factors, including: (1) measurement of BP with ambulatory monitoring rather than office measurements; (2) a lower average level of pretreatment BP in our study, which avoids exaggeration of BP response; and, most importantly, (3) inclusion of a control group of black participants lacking the T594M allele. It is possible that a small gene effect was obscured by the number of T594M-positive subjects studied, and we did not assess response to dynamic challenges, such as a high-salt diet.…”

Section: Pharmacogenetic Studysupporting

confidence: 50%

“…3 In a study of 14 T594M heterozygotes with mild-to-moderate hypertension, amiloride monotherapy was as effective in controlling BP as usual empiric combination therapy with 2 or 3 standard antihypertensive agents. 8 However, the conclusions from that study must be considered preliminary, because no control group of black hypertensives lacking the T594M allele was studied for comparison.…”

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confidence: 99%

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Epithelial Sodium Channel Allele T594M Is Not Associated With Blood Pressure or Blood Pressure Response to Amiloride

et al. 2006

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Abstract-The T594M allele of the epithelial sodium channel ␤-subunit has been proposed as a gain-of-function mutation leading to salt-sensitive hypertension in blacks that is particularly responsive to the specific sodium channel antagonist amiloride. However, the positive associations derive from small convenience samples, and the amiloride challenge study lacked a control group. We determined whether the T594M allele was associated with hypertension and blood pressure (BP) response to amiloride in 2 well-characterized random population samples including 3137 Dallas County subjects and 1666 Jamaican blacks. In multivariate models, the T594M allele was not predictive of systolic BP (adjusted odds ratio for hypertension 1.1; 95% confidence interval, 0.7 to 1.8). Amiloride treatment did not lower the BP of 6 T594M heterozygotes significantly more than in 22 control subjects (Pϭ0.8). We conclude that the T594M allele does not contribute significantly to BP in blacks and does not predict a significantly superior response to amiloride therapy. Key Words: hypertension, genetic Ⅲ ion channels Ⅲ sodium P eople of African descent are particularly susceptible to developing salt-sensitive hypertension, but the molecular mechanisms are poorly understood. The renal epithelial sodium channel (ENaC) constitutes the final common pathway for the reabsorption of the final 2% of filtered sodium from the distal nephron. A missense mutation in the ␤-subunit of the human ENaC gene (T594M allele of SCNN1B or ␤-ENaC) has been found only in persons of African descent and has been implicated as a gain-of-function mutation causing impaired renal sodium excretion and salt-sensitive hypertension. 1-3 The allele was found to be present in 6% of blacks overall and to be highly enriched in a hypertensive clinic population compared with normotensive controls. 2 Additional evidence for an association with hypertension was reported in a larger clinic population. 4 However, the enthusiasm generated from these positive association studies 2,4,5 has been tempered by independent reports that failed to confirm such an association. 6,7 The conflicting data surrounding this allele might derive from inadequate sample size, sampling biases inherent in clinic populations, the variability in resting blood pressure (BP) over time, confounding effects of drug treatment, and the multiplicity of environmental exposures and signaling pathways involved in the regulation of resting BP.The BP responsiveness to certain drugs, which predominately target a single BP-regulating pathway, might link more directly with the genetic underpinnings of hypertension than resting BP alone. The potassium-sparing diuretic amiloride, a specific ENaC antagonist, is normally a weak antihypertensive agent but has been proposed as the ideal treatment for hypertension in blacks carrying the T594M allele. 3 In a study of 14 T594M heterozygotes with mild-to-moderate hypertension, amiloride monotherapy was as effective in controlling BP as usual empiric combination therapy with 2 or 3 stan...

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Section: Pharmacogenetic Studysupporting

confidence: 50%

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confidence: 99%

Epithelial Sodium Channel Allele T594M Is Not Associated With Blood Pressure or Blood Pressure Response to Amiloride

et al. 2006

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“…These functional analyses may explain the clinical phenotype of patients with the T594M mutation. The T594M mutation contributes to the elevation of blood pressure and suggests that consideration should be given to the use of amiloride in affected individuals (19).…”

Section: Discussionmentioning

confidence: 99%

“…This mutation has been reported to be the common in black people with essential hypertension in some studies (18,19), but not another (20). Some studies have reported that this mutation is common among black individuals with essential hypertension (18,19), but another study found no such association (20).…”

Section: Introductionmentioning

confidence: 92%

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Six Missense Mutations of the Epithelial Sodium Channel .BETA. and .GAMMA. Subunits in Japanese Hypertensives

et al. 2004

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Liddle's syndrome is an autosomal dominant disease characterized by sodium-sensitive early hypertension and mutations in either the -or -subunit of the amiloride-sensitive epithelial sodium channel encoded by SCNN1B and SCNN1G. We sequenced the 381 bp-coding regions in exon 13 of SCNN1B and the 381 bp-coding regions in exon 12 of SCNN1G in 948 and 953 Japanese patients with hypertension, respectively. In the SCNN1B gene, we identified three missense mutations, P592S (n 3), T594M (n 2), and E632K (n 1) in a heterozygous state in addition to four synonymous ones, Ile515 (n 1), Ser520 (n 19), Ser533 (n 1), and Thr594 (n 11). In the SCNN1G gene, we identified three missense mutations, A578V (n 1), P603S (n 1), and L609F (n 1) in a heterozygous state in addition to two synonymous ones, Ile550 (n 1) and Leu649 (n 91, heterozygous; n 2, homozygous). We did not identify the same mutations previously reported in

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Management of Resistant Hypertension

Kario¹

2015

Essential Manual of 24 Hour Blood Pressure Management

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Amiloride, a Specific Drug for Hypertension in Black People With T594M Variant?

Cited by 89 publications

References 14 publications

Epithelial Sodium Channel Allele T594M Is Not Associated With Blood Pressure or Blood Pressure Response to Amiloride

Epithelial Sodium Channel Allele T594M Is Not Associated With Blood Pressure or Blood Pressure Response to Amiloride

Six Missense Mutations of the Epithelial Sodium Channel .BETA. and .GAMMA. Subunits in Japanese Hypertensives

Management of Resistant Hypertension

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