Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity is currently considered as a chronic metabolic disease, associated with a high risk of cardiovascular complications. Leptin, an adipocyte-derived hormone has a variety target cells influencing a wide range of processes. Possible counteractions of hyperleptinaemia are currently investigated. The Na(+)-H(+) exchanger (NHE 1) is involved in multiple cellular functions and its activation has been related to hypertension and obesity. NHE 1 is present on erythrocytes and can be stimulated by various hormones. Erythrocytes have on their surface a variety of receptors with mostly unknown function. In the present paper, the effect of leptin on erythrocytes NHE 1 activity has been investigated. For this reason, the intracellular pH and sodium influxes were measured before and after addition of leptin in erythrocyte suspensions from normal and obese individuals. Amiloride, a specific NHE 1 inhibitor, and staurosporine a protein kinase C inhibitor were used to inhibit erythrocyte NHE 1. For the binding study leptin was labeled with fluorescein isothiocyanate (FITC) and the binding on erythrocytes was estimated by Scatchard analysis. NHE 1 activity increased in the presence of leptin but significantly less in the obese than in the control group. Furthermore the concentrations of leptin binding sites on the surface of erythrocytes were lower in erythrocytes drawn from obese individuals than in erythrocytes drawn from normal subjects. Since NHE 1 activity has been associated with insulin resistance and hypertension, the activation of this antiport by leptin may represent a link between adipose tissue hypertrophy and cardiovascular complications of obesity.
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PMID:The effect of leptin on Na(+)-H(+) antiport (NHE 1) activity of obese and normal subjects erythrocytes. 1160 19

The epithelial sodium channel (ENaC) is a principal site for sodium reabsorption and as such may participate importantly in blood pressure (BP) regulation. Amiloride, a direct inhibitor of ENaC, characteristically has mild antihypertensive properties, consistent with ENaC having more minor influences on BP regulation. Counter-regulatory influences may, however, prevent amiloride from effectively lowering BP. Aldosterone secretion is known to increase in response to the reduced sodium reabsorption that follows amiloride inhibition of ENaC, and because aldosterone upregulates ENaC function, we considered the possibility that secondary hyperaldosteronism mitigates the ability of amiloride to reduce BP. In the present study, the BP responses to amiloride (5 mg per day), spironolactone (25 mg per day), the combination of the 2 drugs, and placebo were studied in healthy normotensive subjects. Over 4 weeks of treatment, the combination of amiloride and spironolactone lowered systolic BP by 4.6+/-1.6 (mean+/-SEM) mm Hg (P=0.022) and diastolic BP by 2.2+/-1.2 mm Hg (P=0.30), whereas either drug alone had no significant effect on BP. The findings suggest that the 2 drugs with different modes of action-amiloride, a direct inhibitor of ENaC, and spironolactone, a mineralocorticoid receptor antagonist-may compliment each other's ability to inhibit ENaC and thereby reduce sodium reabsorption to a point at which BP decreases. On the other hand, we cannot rule out that the BP response resulted from the greater dose of total drug. The lowering of BP with small doses of inhibitors of ENaC serves as additional evidence for the importance of ENaC to the tonic maintenance of BP.
Hypertension 2001 Nov
PMID:Blood pressure responses to small doses of amiloride and spironolactone in normotensive subjects. 1171 9

An abnormal handling of renal magnesium has been suggested to cause salt-sensitive hypertension. The filtered magnesium is first reabsorbed in the proximal tubule. Amiloride has been shown to enhance renal magnesium conservation, but the regulatory mechanisms are unknown yet. High-salt (8% NaCl) diet decreased serum magnesium concentration, while increased urinary magnesium in Dahl salt-sensitive (DS) rat. Furthermore, the expression of nitric oxide synthase type 3 and nitric oxide (NO) content were decreased in high-salt loaded DS rat. In isolated proximal tubule cells, amiloride (0.1 mM) increased intracellular free magnesium concentration ([Mg(2+)](i)). However, the net [Mg(2+)](i) increase in the high-salt loaded DS rat was smaller than other groups. NOR1 (0.1 mM), a NO donor, restored the increase of [Mg(2+)](i) to the same level of other groups. On the contrary, L-NMMA (0.1 mM), an inhibitor of NO production, inhibited the increase of [Mg(2+)](i) in all groups. These results suggest that intracellular NO has an important role to up-regulate amiloride-elicited magnesium influx.
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PMID:Magnesium influx enhanced by nitric oxide in hypertensive rat proximal tubule cells. 1205 28

The T594M polymorphism of the epithelial sodium channel is found in approximately 5% of people of African origin and is significantly associated with high blood pressure. Although the T594M polymorphism could increase renal sodium absorption through affected channels, it is not known whether this polymorphism causes hypertension. Amiloride specifically inhibits overactive sodium channels and effectively controls blood pressure in Liddle's syndrome, in which hypertension is caused by separate epithelial sodium channel mutations. The aim of this study was to determine whether amiloride was effective in lowering blood pressure in individuals with the T594M polymorphism. In an open, controlled study, 14 black hypertensive individuals with the T594M polymorphism were withdrawn from their usual medication and treated with amiloride. On entry to the study, individuals taking a mean of 2 drugs had blood pressure of 142/89+/-3/3 mm Hg. Amiloride alone (10 mg BID) controlled blood pressure effectively to the same level (140/91+/-4/2 mm Hg). When amiloride was withdrawn for 2 weeks, there was a large increase in blood pressure of 17/8+/-4/2 mm Hg (systolic, P<0.05; diastolic, P<0.01). On restarting amiloride, blood pressure was again controlled to 140/88+/-6/2 mm Hg. These results demonstrate that 10 mg BID amiloride is effective in controlling blood pressure in hypertensive individuals of African origin who have the T594M polymorphism. Our study supports the concept that the T594M polymorphism contributes to the elevation of blood pressure and suggests that consideration should be given to the use of amiloride in affected individuals.
Hypertension 2002 Jul
PMID:Amiloride, a specific drug for hypertension in black people with T594M variant? 1210 31

In vitro studies suggest that collecting duct-derived (CD-derived) endothelin-1 (ET-1) can regulate renal Na reabsorption; however, the physiologic role of CD-derived ET-1 is unknown. Consequently, the physiologic effect of selective disruption of the ET-1 gene in the CD of mice was determined. Mice heterozygous for aquaporin2 promoter Cre recombinase and homozygous for loxP-flanked exon 2 of the ET-1 gene (called CD-specific KO of ET-1 [CD ET-1 KO] mice) were generated. These animals had no CD ET-1 mRNA and had reduced urinary ET-1 excretion. CD ET-1 KO mice on a normal Na diet were hypertensive, while body weight, Na excretion, urinary aldosterone excretion, and plasma renin activity were unchanged. CD ET-1 KO mice on a high-Na diet had worsened hypertension, reduced urinary Na excretion, and excessive weight gain, but showed no differences between aldosterone excretion and plasma renin activity. Amiloride or furosemide reduced BP in CD ET-1 KO mice on a normal or high-Na diet and prevented excessive Na retention in salt-loaded CD ET-1 KO mice. These studies indicate that CD-derived ET-1 is an important physiologic regulator of renal Na excretion and systemic BP.
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PMID:Collecting duct-specific knockout of endothelin-1 causes hypertension and sodium retention. 1531 87

The Tg737 degrees (rpk) autosomal recessive polycystic kidney disease (ARPKD) mouse carries a hypomorphic mutation in the Tg737 gene. Because of the absence of its protein product Polaris, the nonmotile primary monocilium central to the luminal membrane of ductal epithelia, such as the cortical collecting duct (CCD) principal cell (PC), is malformed. Although the functions of the renal monocilium remain elusive, primary monocilia or flagella on neurons act as sensory organelles. Thus we hypothesized that the PC monocilium functions as a cellular sensor. To test this hypothesis, we assessed the contribution of Polaris and cilium structure and function to renal epithelial ion transport electrophysiology. Properties of Tg737 degrees (rpk) mutant CCD PC clones were compared with clones genetically rescued with wild-type Tg737 cDNA. All cells were grown as polarized cell monolayers with similarly high transepithelial resistance on permeable filter supports. Three- to fourfold elevated transepithelial voltage (V(te)) and short-circuit current (I(sc)) were measured in mutant orpk monolayers vs. rescued controls. Pharmacological and cell biological examination of this enhanced electrical end point in mutant monolayers revealed that epithelial Na(+) channels (ENaCs) were upregulated. Amiloride, ENaC-selective amiloride analogs (benzamil and phenamil), and protease inhibitors (aprotinin and leupeptin) attenuated heightened V(te) and I(sc). Higher concentrations of additional amiloride analogs (ethylisopropylamiloride and dimethylamiloride) also revealed inhibition of V(te). Cell culture requirements and manipulations were also consistent with heightened ENaC expression and function. Together, these data suggest that ENaC expression and/or function are upregulated in the luminal membrane of mutant, cilium-deficient orpk CCD PC monolayers vs. cilium-competent controls. When the genetic lesion causes loss or malformation of the monocilium, ENaC-driven Na(+) hyperabsorption may explain the rapid emergence of severe hypertension in a majority of patients with ARPKD.
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PMID:Heightened epithelial Na+ channel-mediated Na+ absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia. 1653 71

The T594M allele of the epithelial sodium channel beta-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 (P=0.8). 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.
Hypertension 2006 Mar
PMID:Epithelial sodium channel allele T594M is not associated with blood pressure or blood pressure response to amiloride. 1643 44

Amiloride-sensitive Na+ channels belong to the epithelial Na+ channel (ENaC)-degenerin superfamily of ion channels. In addition to their key role in sodium handling, they serve diverse functions in many tissues. Improper functioning of ENaC has been implicated in several diseases, including salt-sensitive hypertension (Liddle's syndrome), salt-wasting syndrome (pseudohypoaldosteronism type I), pulmonary edema, and cystic fibrosis. We have utilized planar lipid bilayers, a well-defined system that allows simultaneous control of "internal" and "external" solutions, to study ENaCs.
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PMID:Epithelial sodium channel in planar lipid bilayers. 1692 41

Amiloride was originally described in 1967 as a potassium-sparing diuretic, the mechanism of action of which is to block the epithelial sodium channel (ENaC) within the distal tubule of the kidney. In addition, higher doses of amiloride were found to be capable of inhibiting the Na(+)/H(+) exchangers (NHE) and the Na(+)/Ca(2+) exchangers. In time, several amiloride analogs have been synthesized to have a marked increase in their specificity to inhibit the ENaC, the NHE or the Na(+)/Ca(2+) exchangers. Although the NHE inhibitors have received the most recent attention, large-scale clinical trials using NHE inhibitors in ischemic cardiac states have shown them to be either ineffective or associated with an unacceptable risk profile. Aldosterone excess in animal models is known to cause cardiovascular injury, and blockade of mineralocorticoid receptors in human beings with heart disease improves outcomes. However, the exact mechanisms of aldosterone injury in animal models of hypertensive disease and protection with mineralocorticoid receptor antagonists in human trials of heart failure remain unknown. These effects are unexplained by changes in BP, potassium, or sodium balance. An additional possibility is that aldosterone action and mineralocorticoid receptor blockade is conferred by alterations in ENaC activity. Emerging experimental evidence suggests the possibility that systemic or central ENaC inhibition or both may be an alternative to the treatment of hypertension and cardiovascular disease states. Clinical trials to evaluate further the potential beneficial cardiovascular effects of ENaC blockade are needed. This article reviews the case for ENaC inhibition as a potential target for cardiovascular and renal protection in human beings.
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PMID:Epithelial sodium channel inhibition in cardiovascular disease. A potential role for amiloride. 1719 22

1. Although increasing evidence suggests that salt-sensitive hypertension is a disorder of the central nervous system (CNS), little is known about the critical proteins (e.g. ion channels or exchangers) that play a role in the pathogenesis of the disease. 2. Central pathways involved in the regulation of arterial pressure have been investigated. In addition, systems such as the renin-angiotensin-aldosterone axis, initially characterized in the periphery, are present in the CNS and seem to play a role in the regulation of arterial pressure. 3. Central administration of amiloride, or its analogue benzamil hydrochloride, has been shown to attenuate several forms of salt-sensitive hypertension. In addition, intracerebroventricular (i.c.v.) benzamil effectively blocks pressor responses to acute osmotic stimuli, such as i.c.v. hypertonic saline. Amiloride or its analogues have been shown to interact with the brain renin-angiotensin-aldosterone system (RAAS) and to effect the expression of endogenous ouabain-like compounds. Alterations of brain RAAS function and/or endobain expression could play a role in the interaction between amiloride compounds and arterial pressure. Peripheral treatments with benzamil, even at higher doses than those given centrally, have little or no effect on arterial pressure. These data provide strong evidence that benzamil-sensitive proteins (BSPs) of the CNS play a role in cardiovascular responsiveness to sodium. 4. Mineralocorticoids have been linked to human hypertension; many patients with essential hypertension respond well to pharmacological agents antagonizing the mineralocorticoid receptor and certain genetic forms of hypertension are caused by chronically elevated levels of aldosterone. The deoxycorticosterone acetate (DOCA)-salt model of hypertension is a benzamil-sensitive model that incorporates several factors implicated in the aetiology of human disease, including mineralocorticoid action and increased dietary sodium. The DOCA-salt model is ideal for investigating the role of BSPs in the pathogenesis of hypertension, because mineralocorticoid action has been shown to modulate the activity of at least one benzamil-sensitive protein, namely the epithelial sodium channel. 5. Characterizing the BSPs involved in the pathogenesis of hypertension may provide a novel clinical target. Further studies are necessary to determine which BSPs are involved and where, in the nervous system, they are located.
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PMID:A role for benzamil-sensitive proteins of the central nervous system in the pathogenesis of salt-dependent hypertension. 1838 84


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