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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amiloride hydrochloride is a new, orally administered, potassium-sparing diuretic with mild natriuretic and diuretic properties. Its primary site of action is the distal tubule of the nephron where it selectively blocks sodium transport, thereby inhibiting sodium-potassium exchange. The mechanism of action of amiloride is independent of aldosterone. It is excreted unmetabolized in the urine and feces. Peak serum levels are seen at three hours, and the serum half-life is six hours. The drug can probably be safely administered to patients with hepatic dysfunction but should be used cautiously, if at all, in patients with renal insufficiency. Amiloride is well tolerated, and serious toxicity is rare. It should prove useful in edematous states and hypertension. When amiloride is used in fixed combination with a thiazide diuretic the risk of hypokalemia is minimal.
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PMID:Mechanism of action, pharmacokinetics, adverse effects, and therapeutic uses of amiloride hydrochloride, a new potassium-sparing diuretic. 692 5

The effects of amiloride on oral glucose loading, serum potassium, renin, and aldosterone were evaluated in 10 patients with diet-controlled diabetes. Eight had mild hypertension, and 2 had normal blood pressure. Prior to receiving amiloride all were studied for renin and aldosterone responses while supine and after 2 hr ambulation. All had a normal response to change in position in the renin and aldosterone systems. Before administration of amiloride glucose tolerance tests were carried out, with simultaneous determinations for potassium and insulin. Amiloride 5 to 10 mg was given orally for 6 wk. Blood glucose and serum potassium levels were monitored weekly. After 6 wk renin and aldosterone responses were again determined, as were oral glucose tolerance and serum potassium and serum insulin levels. Amiloride did not induce hyperkalemia in these diabetic patients and did not alter the postamiloride relationship. It is concluded that amiloride is safe for patients with an intact renin aldosterone system, more especially those with normal renal function and diet-controlled diabetes mellitus.
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PMID:Effects of amiloride on oral glucose loading, serum potassium, renin, and aldosterone in diet-controlled diabetes. 698 47

Amiloride is a potassium-sparing diuretic used in spontaneous and diuretic-induced hypokalemia. The effect of amiloride was studied prospectively in 12 patients with primary hyperaldosteronism. Four patients had unilateral adrenal adenomas and eight had bilateral adrenal hyperplasia. All patients were hypertensive and their mean plasma potassium levels were low. Amiloride, 10 to 40 mg daily, was given for 6 mo. Mean plasma potassium levels rose (0.96 mEq/l, P less than 0.001) and remained normal throughout the study without potassium supplementation. Mean blood pressure was lowered by amiloride (22/10 mm Hg, P less than 0.001) but normotension required concomitant antihypertensive therapy in most patients. No significant adverse clinical or laboratory experiences could be directly attributed to amiloride therapy. There was no correlation between the response to therapy and the plasma aldosterone levels, aldosterone secretion rate, or presence of a unilateral adrenal adenoma. Our study demonstrates the efficacy of amiloride in the correction of hypokalemia and amelioration of hypertension in primary hyperaldosteronism.
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PMID:Amiloride in primary hyperaldosteronism. 705 5

Amiloride was administered to 13 male patients with mild essential hypertension and normal renal function. It effectively reduced supine and standing arterial pressures. The antihypertensive response was associated with a significant decrease in renal inulin clearance and a rise in plasma creatinine concentration, although both values at the end of seven weeks of therapy remained within normal limits. Serum potassium concentrations rose but did not reach hyperkalemic levels. Amiloride did not increase blood levels of glucose, uric acid, lipids, calcium, or urea nitrogen. We conclude that amiloride is an effective antihypertensive and antikaliuretic agents for patients with mild hypertension and normal renal function.
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PMID:Effects of amiloride on arterial pressure and renal function. 740 Mar 69

Ouabain-like factor (OLF) has been implicated to play an important role in certain forms of hypertension. We isolated OLF from the urine of salt-loaded healthy subjects by stepwise chromatographic procedures. The post-salt fraction (F IV) eluted from Sephadex G-25 was rechromatographed on Sephadex G-10. A late small-molecular-weight fraction F8 inhibited Na-K-ATPase in vitro (OLF activity). The effects of OLF on intracellular Ca2+ concentrations ([Ca2+]i) and pH (pHi) were examined in cultures of vascular smooth-muscle cells using the fluorescent probes fura-2 and 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF), respectively. Preincubation with OLF increased basal [Ca2+]i from 87 +/- 6 to 160 +/- 8 nM (p < 0.001) and enhanced arginine vasopressin-stimulated maximal [Ca2+]i (418 +/- 11 vs. 523 +/- 14 nM, p < 0.01). This effect was similar to that of ouabain. OLF also induced a rapid transient increase of [Ca2+]i (82 +/- 9 vs. 253 +/- 23 nM, p < 0.01); [Ca2+]i returned to levels slightly above baseline within approximately 4 min. OLF-stimulated [Ca2+]i was attenuated by verapamil (126 +/- 5 nM, p < 0.01) and was also reduced in Ca(2+)-free medium (104 +/- 9 nM, p < 0.01). As opposed to OLF, ouabain did not exhibit this fast transient effect on [Ca2+]i. Amiloride (10(-3) M) blocked the sustained effect of OLF on [Ca2+]i (77 +/- 11 vs. 86 +/- 12 nM, NS). OLF induced an increase of pHi from 7.09 +/- 0.03 to 7.28 +/- 0.04 (p < 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cellular mechanisms of action of a ouabain-like factor in vascular smooth-muscle cells. 750 17

Increased Na+/H+ antiport activity has been implicated in the pathogenesis of hypertension and vascular disease in diabetes mellitus. The independent effect of elevated extracellular glucose concentrations on Na+/H+ antiport activity in cultured rat vascular smooth muscle cells (VSMC) was thus examined. Amiloride-sensitive 22Na+ uptake by VSMC significantly increased twofold after 3 and 24 h of exposure to high glucose medium (20 mM) vs. control medium (5 mM). Direct glucose-induced Na+/H+ antiport activation was confirmed by measuring Na(+)-dependent intracellular pH recovery from intracellular acidosis. High glucose significantly increased protein kinase C (PKC) activity in VSMC and inhibition of PKC activation with H-7, staurosporine, or prior PKC downregulation prevented glucose-induced increases in Na+/H+ antiport activity in VSMC. Northern analysis of VSMC poly A+ RNA revealed that high glucose induced a threefold increase in Na+/H+ antiport (NHE-1) mRNA at 24 h. Inhibiting this increase in NHE-1 mRNA with actinomycin D prevented the sustained glucose-induced increase in Na+/H+ antiport activity. In conclusion, elevated glucose concentrations significantly influence vascular Na+/H+ antiport activity via glucose-induced PKC dependent mechanisms, thereby providing a biochemical basis for increased Na+/H+ antiport activity in the vascular tissues of patients with hypertension and diabetes mellitus.
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PMID:Glucose-induced changes in Na+/H+ antiport activity and gene expression in cultured vascular smooth muscle cells. Role of protein kinase C. 820 Oct 1

Amiloride-sensitive epithelial Na(+) channels (ENaC) are responsible for trans-epithelial Na(+) transport in the kidney, lung, and colon. The channel consists of three subunits (alpha, beta, gamma) each containing a proline rich region (PPXY) in their carboxyl-terminal end. Mutations in this PPXY domain cause Liddle's syndrome, an autosomal dominant, salt-sensitive hypertension, by preventing the channel's interactions with the ubiquitin ligase Neural precursor cell-expressed developmentally down-regulated protein (Nedd4). It is postulated that this results in defective endocytosis and lysosomal degradation of ENaC leading to an increase in ENaC activity. To show the pathway that degrades ENaC in epithelial cells that express functioning ENaC channels, we used inhibitors of the proteosome and measured sodium channel activity. We found that the inhibitor, MG-132, increases amiloride-sensitive trans-epithelial current in Xenopus distal nephron A6 cells. There also is an increase of total cellular as well as membrane-associated ENaC subunit molecules by Western blotting. MG-132-treated cells also have increased channel density in patch clamp experiments. Inhibitors of lysosomal function did not reproduce these findings. Our results suggest that in native renal cells the proteosomal pathway is an important regulator of ENaC function.
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PMID:Enac degradation in A6 cells by the ubiquitin-proteosome proteolytic pathway. 1127 12

Pathophysiological features of both primary aldosteronism and pseudohyperaldosteronism are hyperactive amiloride-sensitive epithelial Na(+) channels (ENaC) and refractory hypertension. Peripheral blood lymphocytes express ENaC, which functions and is regulated similarly to ENaC expressed by renal principal cells. Thus it was hypothesized that individuals with either of these hypertensive etiologies could be identified by assessment of the function and regulation of peripheral blood lymphocyte ENaC, by whole cell patch clamp. We also tested the hypothesis that specific inhibition of hyperactive ENaC with amiloride could ameliorate the hypertension. To test these hypotheses, we solicited blood samples from normotensive, controlled hypertensive, and refractory hypertensive individuals. Lymphocytes were examined electrophysiologically to determine whether ENaC was hyperactive. All positive findings were from refractory hypertensive individuals. Nine refractory hypertensive patients had amiloride added to their hypertensive therapy. Amiloride normalized the blood pressure of four subjects. These individuals all had hyperactive ENaC. Amiloride had no effect on individuals with normal ENaC. These findings suggest that whole-cell patch clamp of peripheral blood lymphocytes can be used to identify accurately and rapidly hypertensive individuals who will respond to amiloride therapy.
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PMID:Hyperactive ENaC identifies hypertensive individuals amenable to amiloride therapy. 1166 19

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


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