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)

Cardiovascular disease (CVD) is the leading cause of death in dialysis patients. Among the main risk factors for CV mortality, hydro-saline retention is frequently observed in peritoneal dialysis (PD) patients, due to the transport mechanisms occurring within the peritoneal cavity. The analysis of sodium (Na) kinetics is a useful method to understand better the transport of fluids and solutes in PD. In the absence of peritoneal ultrafiltration (UF), Na removal by diffusion during a peritoneal dwell is extremely low. Therefore, to increase peritoneal Na removal, the attainment of peritoneal UF is a basic requisite; however, achieving this goal requires the use of solutions with hypertonic glucose concentrations. On the other hand, such a type of convective transport induces the transport of free-water, by aquaporin-1 channels located on the endothelial side of the peritoneal membrane; therefore, leading to a disproportionate removal of plasmatic water as compared with the removal of plasmatic Na (hyponatric removal). PD solutions containing icodextrin at 7.5% concentration determine UF with a different mechanism (colloid-osmotic), without inducing any free-water transport. However, clinical studies have failed to show a benefit of icodextrin solution in reducing blood pressure (BP) values and increasing Na removal. Therefore, the use of PD solutions with low Na concentrations (102-120 mmol/L) has been recently proposed as another available therapeutic strategy to prevent the development and reduce the prevalence of hydro-saline retention and hypertension in PD patients.
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PMID:[Sodium kinetics in peritoneal dialysis: from theory to clinical practice]. 1652 Oct 74

NO plays a role in the regulation of blood pressure through its effects on renal, cardiovascular, and central nervous system function. It is generally thought to freely diffuse through cell membranes without need for a specific transporter. The water channel aquaporin-1 transports low molecular weight gases in addition to water and is expressed in cells that produce or are the targets of NO. Consequently, we tested the hypothesis that aquaporin-1 transports NO. In cells expressing aquaporin-1, NO permeability correlated with water permeability. NO transport was reduced by 71% by HgCl2, an inhibitor of aquaporin-1. Transport of NO by aquaporin-1 saturated at 3 micromol/L NO and displayed a K(1/2) (the concentration of NO that produces half of the maximum transport rate) of 0.54 micromol/L. Reconstitution of purified aquaporin-1 into lipid vesicles increased NO influx by 316%. In endothelial cells, lowering aquaporin-1 expression with a small interfering RNA (siRNA) blunted aquaporin-1 expression by 54% and NO release by 44%. We conclude that NO transport by aquaporin-1 may allow cells to control intracellular NO levels and effects. NO transport by aquaporin-1 may play a role in central nervous system, vascular and renal function, and consequently blood pressure. Disruption of NO transport by aquaporin-1 offers an alternate cause for diseases currently explained by inadequate NO bioavailability.
Hypertension 2006 Jul
PMID:Aquaporin-1 transports NO across cell membranes. 1668 6

The kidney responds to high levels of ANG II, as may occur during malignant hypertension, by increasing sodium and water excretion. To study whether kidney medullary transporters contribute to this response, rats were made hypertensive using ANG II. Within 3 days of being given ANG II, systolic blood pressure (BP) was increased (200 mmHg), vs control (130 mmHg), and remained high through day 14. Kidney inner medullary (IM) tip and base and outer medulla were analyzed for transporter protein abundance. There were significant decreases in UT-A1 urea transporter, aquaporin-2 (AQP2) water channel, and NKCC2/BSC1 Na(+)-K(+)-2Cl(-) cotransporter. To determine whether the decreases were a response to hypertension, ANG II, or an ANG II-induced increase in aldosterone, rats were given 1) norepinephrine (to increase BP) and 2) ANG II plus spironolactone (to block the mineralocorticoid receptor). Norepinephrine (7 days) increased BP, urine volume, sodium excretion, and decreased urine osmolality and UT-A1, AQP2, and NKCC2/BSC1 abundances, similar to ANG II. ANG II alone or with spironolactone yielded similar increases in BP, urine volume, and urine osmolality, and decreases in UT-A1 and AQP2 proteins in the IM tip. Plasma vasopressin was unaffected by treatment. Water diuresis did not change UT-A1 but decreased AQP2 and NKCC2/BSC1 abundances. We conclude that decreases in UT-A1, AQP2, and NKCC2/BSC1 proteins may contribute to the diuresis and natriuresis that occur following ANG II or norepinephrine-induced acute hypertension and do not appear to involve ANG II stimulation of aldosterone or thirst.
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PMID:Urea transporter UT-A1 and aquaporin-2 proteins decrease in response to angiotensin II or norepinephrine-induced acute hypertension. 1678 41

Arginine vasopressin (AVP) signals predominantly through the V1a receptor, which subserves vasoconstriction in the peripheral circulation, and is linked directly to stimulation of myocardial hypertrophic growth factors, and the V2 receptor, the main function of which is to alter the expression of aquaporin channels in the renal collecting ducts, which leads to water retention. Agents that antagonize or block these receptors could be expected to reduce vascular tone (assuming sufficient V1a signaling is present to be causing an effect), reduce direct mitogenic signaling in the myocardium (again assuming sufficient V1a effect is present), and increase water excretion (assuming sufficient V2 signaling is present). The case for antagonizing both sets of receptors depends on the clinical situation. Pure V1a antagonists might be useful in treatment of hypertension or heart failure, but they are of little use in hyponatremia unless it is caused by heart failure. V2 antagonists would be useful in any euvolemic or hypervolemic condition associated with hyponatremia and may help produce an effective and safe diuresis independent of serum sodium when used in conjunction with loop diuretics in patients with heart failure. Selective blockade of either receptor could lead to increased signaling at the unblocked receptor sites, potentially a problematic result, especially in heart failure where disease progression is affected by increased afterload, preload, and the direct myocardial effects of neurohormonal imbalance. Therefore, a strong rationale exists for the use of combined vasopressin antagonists in patients with heart failure, particularly if the agents are used on a chronic basis.
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PMID:Is there a cardiovascular rationale for the use of combined vasopressin V1a/V2 receptor antagonists? 1684 92

Collecting duct (CD)-derived endothelin-1 (ET-1) inhibits renal Na reabsorption and its deficiency increases blood pressure (BP). The role of CD endothelin B (ETB) receptors in mediating these effects is unknown. CD-specific knockout of the ETB receptor was achieved using an aquaporin-2 promoter-Cre recombinase transgene and the loxP-flanked ETB receptor gene (CD ETB KO). Systolic BP in mice with CD-specific knockout of the ETB receptor, ETA receptor (CD ETA KO) and ET-1 (CD ET-1 KO), and their respective controls were compared during normal- and high-salt diet. On a normal-sodium diet, CD ETB KO mice had elevated BP, which increased further during high salt feeding. However, the degree of hypertension in CD ETB KO mice and the further increase in BP during salt feeding were lower than that of CD ET-1 KO mice, whereas CD ETA KO mice were normotensive. CD ETB KO mice had impaired sodium excretion following acute sodium loading. Aldosterone and plasma renin activity were decreased in CD ETB KO mice on normal- and high-sodium diets, while plasma and urinary ET-1 levels did not differ from controls. In conclusion, the CD ETB receptor partially mediates the antihypertensive and natriuretic effects of ET-1. CD ETA and ETB receptors do not fully account for the antihypertensive and natriuretic effects of CD-derived ET-1, suggesting paracrine effects of this peptide.
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PMID:Collecting duct-specific knockout of the endothelin B receptor causes hypertension and sodium retention. 1686 9

Extracellular nucleotides (e.g., ATP) regulate many physiological and pathophysiological processes through activation of nucleotide (P2) receptors in the plasma membrane. Here we report that gene-targeted (knockout) mice that lack P2Y2 receptors have salt-resistant arterial hypertension in association with an inverse relationship between salt intake and heart rate, indicating intact baroreceptor function. Knockout mice have multiple alterations in their handling of salt and water: these include suppressed plasma renin and aldosterone concentrations, lower renal expression of the aldosterone-induced epithelial sodium channel alpha-ENaC, greater medullary expression of the Na-K-2Cl-cotransporter NKCC2, and greater furosemide-sensitive Na+ reabsorption in association with greater renal medullary expression of aquaporin-2 and vasopressin-dependent renal cAMP formation and water reabsorption despite similar vasopressin levels compared with wild type. Of note, smaller increases in plasma aldosterone were required to adapt renal Na+ excretion to restricted intake in knockout mice, suggesting a facilitation in renal Na+ retention. The results thus identify a previously unrecognized role for P2Y2 receptors in blood pressure regulation that is linked to an inhibitory influence on renal Na+ and water reabsorption. Based on these findings in knockout mice, we propose that a blunting in P2Y2 receptor expression or activity is a new mechanism for salt-resistant arterial hypertension.
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PMID:Mice lacking P2Y2 receptors have salt-resistant hypertension and facilitated renal Na+ and water reabsorption. 1757 58

The aquaporin-2 (AQP2) plays a key role in AVP-induced absorption of water, and its urinary excretion is related to its function. We aimed to test if the assumption of water with different mineral content can modify the expression of AQP2, leading to a change in AQP2 urinary concentration, in 20 healthy young subjects. Each subject received an oral water load (LM or HM) of 250 mL/hour for four hours, and several variables were measured. Plasmatic osmolality after water assumption was significantly reduced with no differences after the low (LM) or the high mineral (HM) water load. Urinary osmolality and plasmatic vasopressin concentration were significantly reduced after an assumption of both kinds of water. However, serum vasopressin was lower after HM water assumption than after LM. AQP2 urinary excretion was significantly reduced after water assumption with respect to the basal level and it was lower after LM than after HM water assumption. The different mineral content of water was investigated as a factor contributing to the development of hypertension. Considering that AQP2 can play a role in pathogenesis of hypertension, our demonstration that AVP-mediated AQP2 urinary excretion is strictly influenced by the consumption of water with different mineral content suggests a new, interesting field of investigation related to the link between blood pressure alterations and nutritional habits.
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PMID:Aquaporin-2 (AQP2) urinary excretion and assumption of water with different mineral content in healthy subjects. 1765 19

Cerebral edema is an intrinsic response to a variety of structural and metabolic insults. It is a major contributing factor in the development of intracranial hypertension and brain herniation, underscoring the need for early identification through an integration of clinical and neuroimaging findings, followed by timely institution of measures to reduce brain edema and intracranial hypertension. The management of cerebral edema requires a comprehensive approach in which pharmacologic treatments play a central role. These include glucocorticoids, hyperosmolar agents, diuretics, and sedative-anesthetic agents. Basic, translational, and clinical studies are needed to further unravel mechanisms underlying brain edema, with the goal of identifying new treatment strategies. Promising targets include modulators of endothelial cell tight junction proteins and of aquaporin channel expression within the blood-brain barrier.
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PMID:Pharmacologic management of brain edema. 1909 38

Human glomerulonephritis (GN) is characterized by sustained proteinuria, sodium retention, hypertension, and edema formation. Increasing quantities of filtered protein enter the renal tubule, where they may alter epithelial transport functions. Exaggerated endocytosis and consequent protein overload may affect proximal tubules, but intrinsic malfunction of distal epithelia has also been reported. A straightforward assignment to a particular tubule segment causing salt retention in GN is still controversial. We hypothesized that 1) trafficking and surface expression of major transporters and channels involved in volume regulation were altered in GN, and 2) proximal tubular endocytosis may influence locally as well as downstream expressed tubular transporters and channels. Effects of anti-glomerular basement membrane GN were studied in controls and megalin-deficient mice with blunted proximal endocytosis. Mice displayed salt retention and elevated systolic blood pressure when proteinuria had reached 10-15 mg/24 h. Surface expression of proximal Na(+)-coupled transporters and water channels was in part [Na(+)-P(i) cotransporter IIa (NaPi-IIa) and aquaporin-1 (AQP1)] increased by megalin deficiency alone, but unchanged (Na(+)/H(+) exchanger 3) or reduced (NaPi-IIa and AQP1) in GN irrespective of the endocytosis defect. In distal epithelia, significant increases in proteolytic cleavage products of alpha-epithelial Na(+) channel (ENaC) and gamma-ENaC were observed, suggesting enhanced tubular sodium reabsorption. The effects of glomerular proteinuria dominated over those of blunted proximal endocytosis in contributing to ENaC cleavage. Our data indicate that ENaC-mediated sodium entry may be the rate-limiting step in proteinuric sodium retention. Enhanced proteolytic cleavage of ENaC points to a novel mechanism of channel activation which may involve the action of filtered plasma proteases.
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PMID:Effects of receptor-mediated endocytosis and tubular protein composition on volume retention in experimental glomerulonephritis. 1919 26

Although deoxycorticosterone acetate (DOCA)-salt hypertension is a volume dependent model of hypertension, it shows polyuria and natriuresis. It is expected that dysregulation of aquaporin water channels (AQPs) and sodium transporters associated with natriuretic peptide (NP) system may play an escape role in sodium retaining state. One week after left unilateral nephrectomy, rats were subcutaneously implanted with silastic DOCA (200 mg/kg) strips. Physiologic saline was supplied as a drinking water to all animals. 4 weeks after operation, the protein expression of AQPs, sodium transporters, and endopeptidase (NEP) was determined in the kidneys by semiquantitative immunoblotting and immunohistochemistry. The mRNA expression of NP system was determined by real-time polymerase chain reaction. The amount of urinary ANP excretion was measured by radioimmunoassay. In DOCA-salt rats, urine osmolality was decreased while urinary excretion of sodium was increased. The expression of AQP1-3 as well as that of alpha-1 subunit of Na,K-ATPase, NHE3, NKCC2 and NCC was decreased in the kidney. The mRNA expression of ANP, brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) was increased in the kidney. The expression of NEP was decreased, and urinary ANP excretion was increased. Downregulation of AQPs and sodium transporters may contribute to mineralocorticoid escape in DOCA-salt hypertension. Increased expression of natriuretic peptides associated with downregulation of NEP may play a role in natriuresis.
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PMID:Altered regulation of renal sodium transporters and natriuretic peptide system in DOCA-salt hypertensive rats. 1942 59


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