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

Under water restriction, arginine vasopressin (AVP) is released and promotes water reabsorption in the distal nephron, mainly through AVP V2-receptors. It has been proposed that renal kinins counteract the hydro-osmotic effect of AVP. We hypothesized that kinins acting through B2 receptors antagonize the urinary concentrating effect of AVP. To test this, bradykinin B2 receptor knockout mice (B2-KO) and 129/SvEv mice (controls) were placed in metabolic cages and urine collected for 24 hours (water ad libitum). After that, urine was again collected from the same mice during 24 hours of water restriction. Urinary volume (UV), urinary osmolarity (UOsm), and urinary Na+ (UNaV) and K+ (UKV) excretion were determined. On water restriction, UV in controls decreased by approximately 25%, whereas in B2-KO mice there was almost a 60% drop in urinary output (P=0.001 versus controls). In the controls, water restriction increased UOsm by 347 mOsm/kg H2O, approximately 14% above baseline (NS), whereas in knockout mice the increase was 3 times that seen in the controls: >1000 mOsm/kg H2O (P=0.001 versus controls). Compared with normohydration, UNaV and UKV in the water-restricted state increased more in controls than in B2-KO mice. This difference in electrolyte excretion could be explained by greater dehydration in the controls (dehydration natriuresis). In a second protocol, we tried to mimic the effect of endogenous AVP by exogenous administration of an AVP V2-receptor agonist, desmopressin (DDAVP). To suppress endogenous AVP levels before DDAVP administration, mice were volume-overloaded with dextrose and alcohol. UOsm was 685+/-125 and 561+/-58 mOsm/kg H2O in water-loaded controls and B2-KO mice, respectively. After DDAVP was injected subcutaneously at a dose of 1 microgram/kg, UOsm increased to 1175+/-86 mOsm/kg H2O (Delta+490 mOsm) in the controls and 2347+/-518 mOsm/kg H2O (Delta+1786 mOsm) in B2-KO mice (P<0.05 versus controls). We concluded that water restriction or exogenous administration of an AVP V2-receptor agonist has a greater urinary concentrating effect in B2-KO mice than in controls, suggesting that endogenous kinins acting through B2 receptors oppose the antidiuretic effect of AVP in vivo.
Hypertension 1999 Jun
PMID:An enhanced effect of arginine vasopressin in bradykinin B2 receptor null mutant mice. 1037 29

In vitro studies indicate that nitric oxide synthase (NOS) inhibitors alter sinus node automaticity. Moreover, whereas the systemic delivery of N(G)-monomethyl-L-arginine (L-NMMA), a NOS inhibitor, results in sinus bradycardia and arterial hypertension, its intracoronary administration has little effect on sinus heart rate. Therefore whether L-NMMA directly alters sinus node function in humans is not known. By using a crossover design, we evaluated the effect of intracoronary L-NMMA (20 micromol/min x 10 min) on corrected sinus node recovery time (CSNRT), heart rate, mean arterial blood pressure, electrocardiographic intervals, and coronary artery blood flow in nine men and 13 women aged 48+/-12 years. All were in sinus rhythm and had normal baseline CSNRTs. Baseline measurements were made during a dextrose infusion, and then L-NMMA was administered, and these parameters remeasured. In 11 patients, the infusions were near the origin of the sinus node artery (Concordant), whereas in the remaining 11, they were into the opposite coronary circulation (Discordant). After L-NMMA, significant prolongations in CSNRT were seen in Concordant (p < 0.001) and Discordant patients (p < 0.05), but were most pronounced in the Concordant group (p < 0.05). Although a significant reduction in coronary artery blood flow and nonsignificant changes in blood pressure and heart rate were observed after L-NMMA, these changes were not related to changes in CSNRT (r2 < or = 0.2; p > or = 0.2). These data support the notion that NO is a modifier of human sinus node automaticity.
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PMID:Prolonged sinus node recovery time in humans after the intracoronary administration of a nitric oxide synthase inhibitor. 1041 59

Digoxin prevents ouabain-induced hypertension in rats. In the present study, we tested whether this effect of digoxin depends on its sensitizing effect on baroreflex function or is due to an antagonistic action on exogenous ouabain or endogenous ouabain-like activity ("ouabain") in the brain. In Wistar rats, resting mean arterial pressure (MAP) was significantly increased by long-term subcutaneous (SC) ouabain (75 microg/d) plus high salt (8%) intake for 12 days (but not after only 5 days). In rats with chronic sinoaortic denervation (SAD), MAP was increased within 5 days of ouabain treatment to the same extent as MAP after 12 days of treatment in intact rats. The effect of ouabain and high salt was prevented when digoxin was given SC concomitantly via osmotic minipump (200 microg x kg(-1) x d(-1)). Resting MAP was not changed in rats treated with digoxin alone. In a second set of rats with chronic SAD or sham surgery, high salt intake was given for 14 days, with or without SC digoxin (200 microg x kg(-1) x d(-1)) or intracerebroventricular (ICV) antibody Fab fragments (200 microg/d), which bind "ouabain" with high affinity. On day 14, MAP, central venous pressure, heart rate, and renal sympathetic nerve activity were recorded in conscious rats at rest and in response to air-jet stress, IV phenylephrine and nitroprusside, and acute volume expansion with 5% dextrose IV. In rats with SAD versus sham surgery, high salt significantly increased resting MAP as well as excitatory responses of MAP, heart rate, and renal sympathetic nerve activity to air stress. These effects of high salt in rats with SAD were prevented by digoxin or Fab fragments. Arterial baroreflex function was blunted but cardiopulmonary baroreflex function was not affected in rats with SAD. Digoxin and Fab fragments had no effects on either function. In an in vitro assay for the inhibitory effects on Na+, K(+)-ATPase activity, 20 ng of ouabain caused 29% inhibition, but 20 ng of ouabain plus 13 or 53 ng of digoxin caused only 16% or 4% inhibition, respectively. These data indicate that the arterial baroreflex opposes sympathoexcitatory responses to ouabain and "ouabain" in the brain, thereby delaying ouabain- and preventing high salt-induced hypertension in Wistar rats. In addition to possible effects on the arterial baroreflex, digoxin appears to act centrally to prevent the sympathoexcitatory and pressor effects of increased brain "ouabain" or ouabain.
Hypertension 1999 Oct
PMID:Digoxin prevents ouabain and high salt intake-induced hypertension in rats with sinoaortic denervation. 1052 51

To overcome the physiological barrier in solid tumors (i.e., tumor hypertension), a large volume of material is required via an intratumoral injection. Alternatively, a method of reduction in tumor hypertension is also feasible. In this study, we focused on the physiological response after an intratumoral infusion of various therapeutic agents. Tumor interstitial fluid pressure (TIFP) was intermittently monitored for up to 7 days after treatment using AsPC-1 human pancreatic tumors in nude mice. Macroaggregated albumin (MAA), colloidal chromic 32P (32P-CP), albumin, dexamethasone, 5-fluoro-2'deoxyuridine, dextrose, saline, and trypan blue increased TIFP within approximately 5 min, and TIFP returned to the original level within 1 h, except in the case of MAA and 32P-CP. We also found that the maximal uptake for AsPC-1 tumors in both the exponential and plateau growth phases occurred at approximately 100 min postincubation; the maximum value in the exponential growth phase was approximately 2 times less than that of plateau growth phase (P < 0.01). Therefore, this study supports intralesional 32P-CP brachytherapy for nonresectional pancreatic cancer patients. This may offer a promising treatment modality for delivering high doses of tumor-selective radiation, mainly due to two physiological mechanisms: (a) the high adherence of 32P-CP to the infused regions; and (b) reduction in either tumor blood flow or TIFP by this therapeutic colloid.
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PMID:The effect of various therapeutic solutions including colloidal chromic 32P via an intratumoral injection on the tumor physiological parameters of AsPC-1 human pancreatic tumor xenografts in nude mice. 1054 54

The microvascular pulmonary endothelium barrier is critical in preventing interstitial fluid overflow and deterioration in gas diffusion. The role of endothelium in transporting small solutes in pathological conditions, such as congestive heart failure (CHF), has not been studied. Monitoring of pulmonary gas transfer during saline infusion in CHF was used to probe this issue. Carbon monoxide diffusion (DL(CO)), its membrane diffusion (D(M)) and capillary blood volume (V(C)) subcomponents, and mean right atrial (rap) and mean pulmonary wedge (wpp) pressures after saline or 5% D-glucose solution infusions were compared with baseline in 26 moderate CHF patients. Saline was also tested in 13 healthy controls. In patients, 750 mL of saline lowered DL(CO) (-8%, P<0.01 versus baseline), D(M) (-10%, P<0.01 versus baseline), aldosterone (-29%, P<0.01 versus baseline), renin (-52%, P<0.01 versus baseline), and hematocrit (-6%, P<0.05 versus baseline) and increased V(C) (20%, P<0.01 versus baseline), without changing rap and wpp. Saline at 150 mL produced qualitatively similar results regarding DL(CO) (-5%, P<0.01 versus baseline), D(M) (-7%, P<0.01 versus baseline), V(C) (9%, P<0.01 versus baseline), rap, wpp, aldosterone (-9%, P<0.05 versus baseline), and renin (-14%, P<0.05 versus baseline). Glucose solution (750 mL), on the contrary, increased DL(CO) (5%, P<0.01 versus 750 mL of saline) and D(M) (11%, P<0.01 versus 750 mL of saline) and decreased V(C) (-9, P<0.01 versus 750 mL of saline); aldosterone (-40%), renin (-41%), hematocrit (-3%), rap, and wpp behaved as they did after saline infusion. In controls, responses to both saline amounts were similar to responses in CHF patients regarding aldosterone, renin, hematocrit, rap, and wpp, whereas DL(CO), D(M), and V(C) values tended to rise. Hindrance to gas transfer (reduced DL(CO) and D(M)) with salt infusion in CHF, despite an increase in V(C) and no variations in pulmonary hydrostatic forces, indicates an upregulation in sodium transport from blood to interstitium with interstitial edema. Redistribution of blood from the lungs, facilitating interstitial fluid reabsorption, or sodium uptake from the alveolar lumen by the sodium-glucose cotransport system might underlie the improved alveolar-capillary conductance with glucose.
Hypertension 1999 Dec
PMID:Impeded alveolar-capillary gas transfer with saline infusion in heart failure. 1060 Nov 19

Serum mannose concentration increases in diabetic patients and correlates closely with blood glucose. In patients with glomerulonephritis, serum mannose and mannose/glucose ratio positively correlate with dyslipidemia and the extent of urinary protein excretion. We investigated whether changes in serum mannose mark subjects with features of metabolic syndrome, including obesity, hypertension, glucose intolerance, and dyslipidemia. The study comprised 20 patients with mean age of 68 (SD 11) years, body mass index 27.2 (SD 5.1) kg/m2, blood glucose 6.2 (SD 1.6) mmol/L, serum total cholesterol 6.3 (SD 1.2) mmol/L, triglyceride 2.0 (SD 0.08) mmol/L, uric acid 320 (SD 109) micromol/L, mannose 60.0 (SD 17) micromol/L, and mannose/glucose ratio 9.7 (SD 1.8) micromol/mmol. Serum mannose correlated with blood glucose (r=0.758, p=0.012), triglyceride (r=0.478, p=0.023), and HDL-cholesterol (r = approximately 0.427, p=0.022). Mannose/glucose ratio correlated with BMI (r=0.581, p=0.033), mannose (r=0.491, p=0.035), and uric acid (r=0.608, p=0.027). The rate of VLDL lipoprotein turnover may be instrumental in the regulation of serum mannose concentration. We conclude that an altered mannose metabolism is a novel consideration among the metabolic abnormalities in the metabolic syndrome.
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PMID:Metabolic syndrome is associated with changes in D-mannose metabolism. 1069 Oct 51

Insulin resistance is of pathogenic importance in several common human disorders including type 2 diabetes, hypertension, obesity and hyperlipidemia, but the underlying mechanisms are unknown. The spontaneously hypertensive rat (SHR) is a model of these human insulin resistance syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridemia, and hypertension map to a single region on rat chromosome 4. Genetic analysis of an SHR derived from a National Institutes of Health colony led to the identification of a causative mutation in the SHR Cd36. We have investigated glucose and fatty acid metabolism in the stroke-prone SHR (SHRSP). We demonstrate defects in insulin action on 2-deoxy-D-glucose transport (SHRSP 3.3 +/- 1.5 vs. 21.0 +/- 7.4 pmol x min(-1) x [20 microl packed cells](-1), SHRSP vs. WKY, respectively, P = 0.01) and inhibition of catecholamine-stimulated lipolysis (P < 0.05 at all concentrations of insulin) in adipocytes isolated from SHRSP. In contrast, basal levels of catecholamine-stimulated nonesterified free fatty acid (NEFA) release and plasma levels of NEFA are similar in SHRSP and WKY. These results are in agreement with the data on the SHR.4 congenic strain, which suggested that the QTL containing Cd36 mutations accounted for the entire defect in basal catecholamine action but only for approximately 40% of the SHR defect in insulin action. In the SHR, both abnormalities appear consequent of defective Cd36 expression. Because Cd36 sequence and expression are apparently normal in SHRSP, it is likely that the molecular mechanism for defective insulin action in this strain is caused by a gene(s) different than Cd36.
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PMID:Cd36 and molecular mechanisms of insulin resistance in the stroke-prone spontaneously hypertensive rat. 1111 30

Cardiomyocytes bind, internalize, and activate recombinant human prorenin through mannose 6-phosphate/insulin-like growth factor II (M6P/IGFII) receptors. To investigate whether this also applies to native human prorenin, neonatal rat myocytes were incubated for 4 hours at 37 degrees C with various prorenin-containing human body fluids. Uptake and activation by M6P/IGFII receptors were observed for plasma prorenin from subjects with renal artery stenosis and/or hypertension and for follicular fluid prorenin. The total amount of cellular renin and prorenin (expressed as percentage of the levels of renin and prorenin in the medium) after 4 hours of incubation was 4 to 10 times lower than after incubation with recombinant human prorenin. Although plasma contains alkaline phosphatases capable of inactivating the M6P label as well as soluble M6P/IGFII receptors that block prorenin binding in a competitive manner and proteins (eg, insulin, IGFII) that increase the number of cell-surface M6P/IGFII receptors, these factors were not responsible for the modest uptake of native human prorenin. Uptake did not occur during incubation of myocytes with plasma prorenin from anephric subjects or with amniotic fluid prorenin, and this was not due to the presence of excessively high levels of M6P/IGFII receptors and/or phosphatase activity in these fluids. In conclusion, myocytes are capable of binding, internalizing, and activating native human prorenin of renal and ovarian origin through M6P/IGFII receptors. Differences in prorenin glycosylation and/or phosphorylation as well as the concentration of soluble M6P/IGFII receptors and growth factors affecting cell-surface M6P/IGFII receptor density determine the amount of prorenin entering the heart and thus cardiac angiotensin II production.
Hypertension 2001 Feb
PMID:Cardiomyocytes bind and activate native human prorenin : role of soluble mannose 6-phosphate receptors. 1123 Mar 61

Hypertonic-hyperoncotic saline solutions (HHS) have been used for small-volume resuscitation and to treat intracranial hypertension and cerebral edema in neurocritical care. Little is known on the response of brain cells to direct exposure in HHS, which may occur in blood-brain barrier disruption. We studied the effects of HHS on healthy and glutamate-injured brain cells in vitro. To model a hypertonic-hyperoncotic environment, rat hippocampal neurons and cerebral astrocytes were exposed to hypertonic saline and hydroxyethyl starch (HES) added to medium for 15 minutes (final osmolarity: 350 mOsm/L in the neuronal, 373 mOsm/L in the glial medium; 2.5 mg/mL HES in both media). To simulate excitotoxicity, cells were exposed to 100 microM glutamate for 8 minutes before exposure to HHS. Cell viability was analyzed by morphology and vital dye staining; intracellular water space (WS) and glucose use were measured by scintillation spectrometry using 3-O-methyl[14C]-D-glucose and [3H]2-deoxy-D-glucose ([3H]2-DG). After 24 hours, exposure to HHS added to medium caused a 30% reduction in viability of healthy neurons (P < .05), but did not exacerbate the glutamate-induced 50% decrease in neuronal survival. One hundred percent astrocyte viability remained unchanged. The WS of astrocytes and surviving neurons was negligibly altered. Exposure to HHS added to medium caused a 35% reduction in [3H]2-DG in healthy and glutamate-injured neurons (P < .05), but did not affect [3H]2-DG in astrocytes. Our data show that HHS may potentially injure hippocampal neurons. Preserved WS values imply that live cells maintained volume regulation capabilities, indicating a lack of dehydration 24 hours after exposure to HHS. Impaired glucose use predisposes neurons to disturbed metabolism, which may influence neuronal outcome after brain injury.
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PMID:Hypertonic-hyperoncotic saline differentially affects healthy and glutamate-injured primary rat hippocampal neurons and cerebral astrocytes. 1129 53


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