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)

The epithelial Na+ channel (ENaC) is comprised of three homologous subunits: alpha, beta, and gamma, all of which are required for formation of the fully functional channel. This channel is responsible for salt reabsorption in the kidney, the airway, and the large bowel. Mutations in ENaC can cause human disease by increasing channel function in Liddle's syndrome, a form of hereditary hypertension, or by decreasing channel function in pseudohypoaldosteronism type I, a salt-wasting disease of infancy. We previously showed that ENaC is expressed on the cell surface as a minimally glycosylated, Triton-insoluble protein. In the present study we found that ENaC existed initially as a Triton-soluble protein that contained high-mannose glycosylation, presumably in the endoplasmic reticulum. This form of the protein disappeared as the Triton-insoluble, minimally glycosylated form became the more prevalent species. In pulse-chase studies of individually expressed subunits, we found that the Triton-soluble form of beta-ENaC accumulated initially, whereas the Triton-soluble form of alpha-ENaC decreased throughout the time course. However, when all three subunits were coexpressed, the alpha- and beta-subunits showed a similar pattern. The complex became Triton insoluble at some point after the endoplasmic reticulum, as incubation at 15 degrees C blocked the conversion to the insoluble form. Deletion of the carboxy-terminal tail of beta-ENaC causes Liddle's syndrome. This mutation increased the amount of newly synthesized Triton-insoluble ENaC heteromultimers but did not affect the half-life of insoluble protein. Therefore, subunit composition and mutations in individual subunits can influence biosynthesis of the ENaC complex.
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PMID:Effect of subunit composition and Liddle's syndrome mutations on biosynthesis of ENaC. 1036 97

Arterial blood pressure is critically dependent on sodium balance. The kidney is the key player in maintaining sodium homeostasis. Aldosterone-dependent epithelial sodium transport in the distal nephron is mediated by the highly selective, amiloride-sensitive epithelial sodium channel (ENaC). Direct evidence that dysfunction of ENaC participates in blood pressure regulation has come from the molecular analysis of two human genetic diseases, Liddle's syndrome and pseudohypoaldosteronism type 1 (PHA-1). Both, increased sodium reabsorption despite low aldosterone levels in Liddle's patients and decreased sodium reabsorption despite high aldosterone levels in PHA-1 patients, demonstrated that ENaC is an effector for aldosterone action. Gene-targeting and classical transgenic technology enable the generation of mouse models for these diseases and the analysis of the involvement of the epithelial sodium channel (ENaC) in the progress of these diseases. A first mouse model using alphaENaC transgenic knockout mice [alphaENaC(-/-)Tg] mimicked several clinical features of PHA-1, like salt-wasting, metabolic acidosis, high aldosterone levels, growth retardation and increased early mortality. Such mouse models will be necessary in testing the involvement of genetic and/or environmental factors like salt-intake in hypertension.
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PMID:Implication of ENaC in salt-sensitive hypertension. 1041 16

The monogenic forms of human hypertension have yielded to the power of modern genetic techniques in the last several years. With the successful expression cloning of the subunits of the epithelial sodium channel, a whole era has evolved in our basic understanding of the low renin forms of human hypertension. Of note, all of these hypertensive syndromes (Liddle's syndrome, glucocorticoid-remediable aldosteronism, and the apparent mineralocorticoid excess syndrome) share an underlying dysregulation of the activity of the epithelial sodium channel in the cortical collecting tubule. Loss of function defects due to mutations in the channel subunits themselves, or in the mineralocorticoid receptor (pseudohypoaldosteronism, type I) also affect blood pressure regulation consequent to renal salt wasting and dysregulation of the epithelial sodium channel in the cortical collecting tubule.
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PMID:Hypertension. 1043 75

Our basic understanding of Na(+) transport mechanisms provides unique insights into epithelial transport processes. Unusual clinical syndromes can arise from mutations of these ion transporters. These genetic disorders affect Na(+) balance, resulting in both N(a+) retaining and Na(+) wasting conditions. A major focus has been the epithelial sodium channel (ENaC), which can be activated by mutations (eg, Liddle's syndrome), changes in the response to mineralocorticoids (apparent mineralocorticoid excess syndrome), or production of mineralocorticoids (glucocorticoid-remediable aldosteronism). As a result, we now have clearly defined Mendelian syndromes in which ENaC activity is "dysregulated." This dysregulation leads to systemic hypertension associated with suppressed plasma renin activity, which can be attributed to a primary renal mechanism. Applying these insights to the far more common disorder of low-renin hypertension may shed new light on the underlying pathophysiology of this common form of human hypertension.
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PMID:Aldosterone-related genetic effects in hypertension. 1098 Nov 63

Exercise is important for HIV-positive people, but what type of exercise to use is still under debate in the scientific community. Scientific studies found that aerobic exercise increases CD4 counts. Scientists recommend aerobics at any stage of HIV infection. Start at an easy intensity level and do not disrupt the routine; stopping can suppress the immune system. Intensive exercise can also be immunosuppressive. Some cases of AIDS-wasting syndrome have been reversed using weight training and vitamins, antioxidants, or anabolic steroids. Some trainers believe that all cases of wasting can be reversed by this regime, as long as diarrhea is controlled and fever is not present. Aerobic exercise can actually be detrimental to HIV-positive patients because it increases the stress hormone, cortisol, which destroys muscle mass. Stretching exercises, such as yoga and tai chi, can reduce levels of cortisol. Another personal trainer advocates the use of anabolic steroids for HIV-positive people. Injectable steroids used with exercise work best, but exercise alone can also be beneficial for fighting depression, AIDS-related wasting, and high blood pressure. An unpublished scientific study found a temporary drop in neutrophils and monocytes, two kinds of white blood cells, after aerobic exercise. These scientists still recommend moderate exercise done at an individual pace.
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PMID:Don't just sit there. 1136 19

Use of the commonly prescribed protease inhibitor Crixivan appears to result in a bizarre adverse effect, despite its desirable effects on T-cell count and viral load. This adverse effect is more common in women than men, and includes the following symptoms: (1) limb wasting, (2) fat gain in the torso, (3) breast enlargement, (4) skin thinning, (4) vein enlargement, (5) irregular periods, (6) high blood pressure and high blood glucose, (6) fatigue, and (7) decreased sex drive. It is believed that 5 to 10 percent of patients taking Crixivan suffer from some of these symptoms, but the percentage would probably be much higher if the number of women alone were studied. Some physicians have been unsupportive about complaints of these symptoms, and have told their patients to exercise or that the changes may be due to aging. One suggestion for dealing with these symptoms is to get body composition measurements prior to starting a protease-containing regimen. Exercise continues to remain important, primarily to prevent wasting. However, dieting is not recommended since it does not reduce the fat deposits and it does contribute to wasting of the limbs. If the symptoms become intolerable, a change in regimen may be needed.
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PMID:The new body of AIDS: Crixivan bellies, legs, and humps. 1136 90

The relationship between salt homeostasis and blood pressure has remained difficult to establish from epidemiological studies of the general population. Recently, mendelian forms of hypertension have demonstrated that mutations that increase renal salt balance lead to higher blood pressure, suggesting that mutations that decrease the net salt balance might have the converse effect. Gitelman's syndrome, caused by loss of function mutations in the Na-Cl cotransporter of the distal convoluted tubule (NCCT), features inherited hypokalemic alkalosis with so-called "normal" blood pressure. We hypothesized that the mild salt wasting of Gitelman's syndrome results in reduced blood pressure and protection from hypertension. We have formally addressed this question through the study of 199 members of a large Amish kindred with Gitelman's syndrome. Through genetic testing, family members were identified as inheriting 0 (n=60), 1 (n=113), or 2 (n=26) mutations in NCCT, permitting an unbiased assessment of the clinical consequences of inheriting these mutations by comparison of the phenotypes of relatives with contrasting genotypes. The results demonstrate high penetrance of hypokalemic alkalosis, hypomagnesemia, and hypocalciuria in patients inheriting 2 mutant NCCT alleles. In addition, the NCCT genotype was a significant predictor of blood pressure, with homozygous mutant family members having significantly lower age- and gender-adjusted systolic and diastolic blood pressures than those of their wild-type relatives. Moreover, both homozygote and heterozygote subjects had significantly higher 24-hour urinary Na(+) than did wild-type subjects, reflecting a self-selected higher salt intake. Finally, heterozygous children, but not adults, had significantly lower blood pressures than those of the wild-type relatives. These findings provide formal demonstration that inherited mutations that impair renal salt handling lower blood pressure in humans.
Hypertension 2001 Jun
PMID:Mutations in the Na-Cl cotransporter reduce blood pressure in humans. 1140 95

Of all the risk factors to cardiovascular disease (CVD), age is the most powerful: CVD incidence and prevalence rise progressively at all ages beyond young adulthood. This reflects the central role of time, and hence duration, in the atherogenic process. It also reflects age-related changes in physiology - notably alterations in body mass and composition favoring increased adiposity and in sex hormone secretion (combining adverse effects of androgens on lipoprotein lipid levels in males, lowering HDL, and of the decline in estrogens in postmenopausal females, raising LDL). The interactions among the passage of time, these physiological changes and perhaps aging per se, and pathological forces such as cigarette smoking, hypertension, and genetically determined dyslipoproteinemia conspire to accelerate the rate of atherogenesis. Thus clinical atherosclerosis and its complications rise exponentially with increasing age in the population at large. However, the relationship between dyslipoproteinemia and CVD risk in the individual patient actually declines with advancing age. This apparent paradox reflects confounding introduced by the advent of disease processes that cause wasting and inflammation such as cancer, infection, diabetes, trauma, and even CVD that actually lower lipid levels, frequently to the level of hypocholesterolemia. Thus, while with age the population-attributable risk of hypercholesterolemia (and/or low HDL) rises, the cholesterol-attributable risk in the individual falls. As a result the prescription of lipid-lowering therapy in elderly patients requires exquisite individualization: patients most likely to benefit are those with existing CVD (i.e., in secondary prevention) who nevertheless enjoy robust health and are highly motivated to comply with demanding regimens of diet and exercise plus drugs where needed to reach target LDL levels (less than 100 mg/dl). At the other extreme are those least likely to benefit: patients who are frail and failing from CVD or other wasting diseases of old age that present a more immediate threat to survival.
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PMID:Aging and Atherosclerosis: Changing Considerations in Cardiovascular Disease Prevention as the Barrier to Immortality is Approached in Old Age. 1141 41

Our basic understanding of sodium mechanisms provides unique insights into epithelial transport processes, and unusual clinical syndromes can arise from mutations of these ion transporters. These genetic disorders affect sodium balance, with both sodium-retaining and sodium-wasting conditions being the consequence. A major focus of such studies has been the epithelial sodium channel, which can be activated by mutations in the channel subunits or mineralocorticoid receptor, and changes in the response to or production of mineralocorticoids. As a result, there are now clearly defined Mendelian syndromes in which epithelial sodium channel activity is 'dysregulated', with the subsequent development of systemic hypertension with suppressed plasma renin activity that can be attributed to a primary renal mechanism. Applying these insights to the far more common disorder of low renin hypertension may shed new light on the underlying pathophysiology of this common form of human hypertension, and more clearly define the interactions of dietary constituents such as sodium and potassium in the regulation of blood pressure.
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PMID:Genetic forms of human hypertension. 1145 30

Aldosterone has crucial role for sodium conservation in the kidney, salivary glands, sweat glands and colon. It exerts its effects via the mineralocorticoid receptor (MR) which belongs to the member of the nuclear receptor superfamily. Recently, genetic disorders have been reported to be caused by gain or loss of function of the MR. The amino acid substitution of the ligand-binding domain(S810L) of the MR resulted in the early-onset hypertension exacerbated by pregnancy. This mutation results in constitutive MR activity and alters receptor specificity for progesterone. Pseudohypoaldosteronism type 1 (PHA1) is characterized by congenital aldosterone resistance of the kidney and/or other mineralocorticoid target tissues, resulting in excessive salt wasting. The heterozygous nonsense or missense mutations were identified in the patients with autosomal dominant PHA1 and a sporadic PHA1. This suggests that the full expression of the MR is necessary for salt conservation.
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PMID:[Genetic disorders caused by gain or loss of function of the mineralocorticoid receptor]. 1185 27


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