Racial Difference in the Activity of the Amiloride-Sensitive Epithelial Sodium Channel

Pratt, J. Howard; Ambrosius, Walter T.; Agarwal, Rajiv; Eckert, George J.; Newman, Shirley

doi:10.1161/01.hyp.0000039749.75068.f4

Cited by 40 publications

(27 citation statements)

References 41 publications

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“…The restoration of dipping in SS hypertensive subjects by hydrochlorothiazide treatment 50 suggests that less dramatic increases in distal tubular sodium reabsorption than those of aldosteronism are also important and that other distally acting diuretics (aldosterone antagonists and epithelial sodium channel blockers) should also affect dipping. Because of their pharmacodynamic specificities, these agents may also help in characterizing the activity of individual distal tubular sodium transport pathways, as in the study by Pratt et al, 59 which used amiloride as a probe of epithelial sodium channel activity. Other approaches involving measurements of renal tubular transporter activity in other cells, including circulating blood cells and the oral mucosa, may also have promise.…”

Section: Segmental Renal Tubular Sodium Transportmentioning

confidence: 99%

Nocturnal Sodium Excretion, Blood Pressure Dipping, and Sodium Sensitivity

2006

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M ore than 30 years ago, Guyton 1 described pressurenatriuresis: increasing arterial blood pressure promotes sodium excretion, decreasing blood volume and lowering blood pressure, whereas when blood pressure falls, sodium excretion decreases, and blood volume and blood pressure increase. 1,2 The linchpin of the model of Guyton et al 3 is the concept of feedback gain. Gain is the degree to which a feedback system can correct a perturbation, that is, the amount of correction of a deviation divided by the residual degree of deviation. When a control system corrects a perturbation minimally, its feedback gain is near 0. When it corrects it completely, its gain is infinite. As emphasized by Guyton et al,3 in integrated systems with infinite and finite gain components, the infinite gain function ultimately dominates. There are myriad blood pressure control systems, for example, arterial baroreceptors and chemoreceptors, the central nervous system ischemic response, the renin-angiotensin system, and capillary fluid shift, but all are ultimately trumped by pressure-natriuresis. In the experiments by Guyton et al, 3 pressure-natriuresis had near infinite gain over a wide range of urinary sodium excretion, such that the set point of blood pressure regulation was not affected by sodium intake over a period of several days or a few weeks.This pressure-natriuresis model describes a steady-state relationship. At short time intervals, blood pressure and sodium excretion may not be closely linked, but the body will always eventually bring the system back into balance. In this review, we wish to draw attention to differences in the relationship of blood pressure to sodium excretion during day and night and to how nighttime pressure-natriuresis and sodium sensitivity of blood pressure interact. We will suggest that these features of pressure-natriuresis have implications both for the clinical management of hypertension and research into the genetic underpinnings of the disease. Diurnal Rhythm of Sodium Excretion in Normotensive and Hypertensive SubjectsIn healthy people, sodium excretion reaches a maximum during the day and a minimum at night during sleep, and it has long been thought that blood pressure is the primary determinant of nighttime sodium excretion. 4 -7 Centonza et al 8 performed ambulatory blood pressure monitoring over a 26-hour period in normotensive subjects for whom sodium intake was fixed at a moderate amount (170 mmol/day). All of the subjects demonstrated a nocturnal dip in blood pressure with a concomitant dip in sodium excretion. Moreover, there were significant positive correlations between blood pressure and sodium excretion during the night and over 24 hours, as well as during periods of quiet supine wakefulness and postprandial sitting. No similar relationship was apparent when subjects carried out daily activities in the standing position. The authors concluded that the pressure-natriuresis relationship is blunted during upright posture, possibly because of the activation of neurohumoral systems. 8 St...

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Section: Segmental Renal Tubular Sodium Transportmentioning

confidence: 99%

Nocturnal Sodium Excretion, Blood Pressure Dipping, and Sodium Sensitivity

2006

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“…Black and white individuals were treated for 1 wk with a 5-mg/d dose of amiloride. The BP response was used to gauge ENaC activity (12). Measurements of BP were made after an overnight hospitalization in the General Clinical Research Center so as to minimize differences between the conditions at baseline and the posttreatment period.…”

Section: Increased Na ϩ Reabsorption In Proximal Nephron Accompanied mentioning

confidence: 99%

Central Role for ENaC in Development of Hypertension

Pratt¹

2005

Journal of the American Society of Nephrology

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Na؉ reabsorption by the epithelial Na ؉ channel (ENaC) in cortical collecting duct provides the final renal adjustment to Na A n increase in Na ϩ and water retention is required for the development of most forms of hypertension as was proposed by Guyton years ago (1) and to this day has never really been refuted. In instances in which the mechanism for the hypertension is known, in which an identified gene mutation defines it, generally speaking an increase in the function of the epithelial Na ϩ channel (ENaC) leads to the Na ϩ retention and elevation in BP (2). The bigger question and the issue addressed in the current review is the extent to which ENaC participates in the development of common forms of hypertension. A strong case can be made for the fact that ENaC is pivotally positioned, both anatomically and physiologically, to convey a dominant influence on the prevalence of hypertension. Studies of hypertension in relation to ENaC and its major regulator, aldosterone, are reviewed here, and a general mechanism for development of hypertension is formulated. Finally, a clinical trial of the effectiveness of ENaC inhibition to lower BP in patients with hypertension is described. Common Molecular Variations in ENaC and Risk for HypertensionThe discovery of mutations in ␤-and ␥-subunits of ENaC to explain Liddle syndrome (3,4), a severe form of low-renin hypertension (5), was soon followed by a search for common genetic variants in ENaC subunits that affect susceptibility in less rare forms of hypertension. Of course variants were identified, and they were almost universally more common in black individuals, which fit nicely with the higher prevalence of low-renin hypertension in black individuals. After a number of years of study by several investigative groups, however, it remains unestablished that a given variant influences the risk for hypertension.The first molecular variant to show an association with hypertension was T594M in the C-terminus of ␤-ENaC (Figure 1) in a study of black individuals who lived in London (6) (the variant is rare in white individuals). Frequencies of the variant were found to be 8.3% in hypertensive individuals and 2.4% in normotensive individuals. In addition, plasma renin activity was lower in carriers of T594M. Subsequent studies by others have for the most part failed to replicate the same relationship to hypertension (7,8). In another study, seven molecular variants, all in ␤-ENaC, with overall allele frequencies of 44% in black individuals and 1% in white individuals, showed no association with hypertension and showed no effect on function using two different in vitro techniques (7). In our own laboratory, we found a G442V variant in the extracellular loop (Figure 1) in ␤-ENaC (again occurring almost exclusively in black individuals) significantly associated with an index of ENaC activity, the urinary aldosterone/K ϩ ratio, in normotensive young people, but it did not associate with hypertension in a study of adults (8). We also found that the A663T variant inPublished onli...

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“…We note, however, that it is well established that without and with potassium supplementation, urinary excretion of potassium is lower in blacks than in whites. [11][12][13][14][15] This racial difference has been attributed to low potassium intake in blacks, albeit no data have been provided to substantiate this idea. This topic is addressed in detail in a recent communication.…”

Section: Kimura Et Al Potassium and Platelet Reactivity 971mentioning

confidence: 99%

Potassium Chloride Supplementation Diminishes Platelet Reactivity in Humans

Kimura¹,

Xiao-bin²,

Skurnick³

et al. 2004

Hypertension

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Abstract-The prevalence of occlusive stroke is inversely correlated with potassium intake. We explored the hypothesis that a high potassium intake attenuates platelet reactivity, as expressed in ADP-evoked platelet aggregation. We studied healthy men (nϭ31) and women (nϭ42), blacks (nϭ33) and whites (nϭ40). In this cohort, we supplemented the habitual intake of 17 men and 21 women with 60 mmol KCl/70 kg body weight per day for 3 days and maintained 14 men and 21 women on their habitual intake. We then compared the change in ADP concentration causing 50% of the maximal initial rate (EC 50 ) of platelet aggregation in the potassium-supplemented versus control groups. Potassium supplementation attenuated platelet reactivity, expressed by an increase in EC 50 of platelet aggregation (Pϭ0.0005), which was primarily attributable to an increase in EC 50 in whites (Pϭ0.0004). Urinary potassium excretion was significantly lower in blacks than in whites under basal conditions and after potassium supplementation. We conclude that potassium supplementation diminishes platelet reactivity, a phenomenon that provides a link between platelet biology and occlusive stroke. Key Words: stroke Ⅲ cardiovascular disease Ⅲ atherosclerosis T he potential cardiovascular benefits of dietary potassium in the general population have been considered primarily from the perspectives that potassium may serve as a sodium substitute in the diet and that a high potassium intake enhances natriuresis. 1 Accordingly, the beneficial effect of a high dietary potassium intake on the cardiovascular system would presumably be mediated by the concomitant reduction in dietary sodium intake, coupled with enhanced sodium excretion, as well as other mechanisms that may ultimately lower blood pressure. 2 The question that follows is whether or not the cardiovascular effect of a high potassium intake may also be mediated through blood pressure-independent mechanisms, given that large-scale studies strongly suggest that dietary potassium intake is inversely correlated with occlusive stroke, a relationship that is independent of the effect of potassium intake on blood pressure. [3][4][5][6][7] Further, in the Systolic Hypertension in the Elderly Program (SHEP) within the treatment group, the risk for cardiovascular events, including stroke and myocardial infarction, was significantly higher in subjects with hypokalemia (serum potassium Ͻ3.5 mmol/L) associated with diuretic use. 8 Collectively, these findings suggest a link between systemic potassium homeostasis and atherosclerosis and thrombosis. 9,10 We note, however, that potassium is primarily an intracellular ion, so that dietary intake and diuretic use are likely to have an effect on intracellular potassium pool even without detectable changes in serum potassium.Because thromboembolic processes largely depend on platelet biology, we hypothesized that a high potassium intake would diminish platelet reactivity. This concept was explored in the present work. Materials and Methods SubjectsWe studied healthy men (...

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Racial Difference in the Activity of the Amiloride-Sensitive Epithelial Sodium Channel

Cited by 40 publications

References 41 publications

Nocturnal Sodium Excretion, Blood Pressure Dipping, and Sodium Sensitivity

Nocturnal Sodium Excretion, Blood Pressure Dipping, and Sodium Sensitivity

Central Role for ENaC in Development of Hypertension

Potassium Chloride Supplementation Diminishes Platelet Reactivity in Humans

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