The use of desmopressin in the management of nocturnal enuresis in patients with spinal cord injury.
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AIM: The aim of this study is to evaluate the use of desmopressin acetate (DDAVP) in the management of nocturnal enuresis in patients with spinal cord injury (SCI), as well as arginine vasopressin (AVP) daily production, urine output, urine osmolarity and clean intermittent catheterization (CIC) before and after the use of desmopressin. METHODS: We studied 11 patients with SCI (7 men 4 women). All patients attended a rehabilitation program and used a wheelchair for locomotion. To improve bladder function and achieve socially acceptable continence all patients were placed on a regimen of anticholinergic drugs (oxybutynin 5 mg, 1x3 daily), evening antibiotic prophylaxis and CIC. The subjects were also on night CIC in order to avoid nocturnal incontinence. DDAVP was given intranasally (20 mg before bedtime) in association with other standard therapy. Urine samples were collected under sterile conditions from all patients at 6:00 a.m. and 6:00 p.m. Urine volume was measured and the amount of urine per hour was calculated. Blood samples were also taken to measure serum AVP, urea, creatinine and serum electrolyte. RESULTS: Our data suggest that nocturnal polyuria in SCI patients occurs due to a lack of diurnal variation of antidiuretic hormone (ADH) secretion. The use of desmopressin produced a statistically significant increase in urine production rate during the day (56.2 vs 81.2 mL/h, P<0.001) and a decrease in nocturnal urine production (59.2 vs 27.7 mL/h, P<0.001). Desmopressin treatment reflects also on urine osmolarity, which did not change during the day (496 vs 489 mOsm/mL, P>0.5) but showed a significant increase during the night (385 vs 862 mOsm/mL, P<0.001). There was a significant decrease in night CIC. No serious adverse effects were observed. CONCLUSION: Our results suggest that desmopressin administration is an beneficial treating option for patients with SCI when fluid restriction and other preventive measures are not able to control abnormal nocturnal polyuria. (+info)
Disturbed homeostasis in sodium-restricted mice heterozygous and homozygous for aldosterone synthase gene disruption.
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We have determined that differences in expression of aldosterone synthase (AS) affect responses to a low-salt diet. In AS-null mice (AS(-/-)), but not in wild-type, low salt significantly decreased plasma sodium and increased potassium. The increased urine volume (1.5xwild-type) and decreased urine osmolality (0.7xwild-type), present in AS(-/-) mice on normal salt, became more severe (2.3xwild-type and 0.5xwild-type) on low salt, but neither changed in wild-type. In both genotypes, plasma vasopressin was similar on normal and low salt, and desmopressin injection significantly increased urine osmolality. Renal mRNA levels for aquaporin 1 and 3 were unchanged by genotype or diet and epithelial sodium channel and Na(+)-K(+)-2Cl(-)-cotransporter by genotype. In AS(-/-) mice, aquaporin 2 mRNA increased on normal salt, whereas Na(+)Cl(-)-cotransporter and cortex K(+) channel mRNAs decreased on both diets. The low blood pressure of AS(-/-) mice was decreased further by low salt, despite additional increases in renin, intrarenal arterial wall thickness, and macula densa cyclogenase-2 mRNA. In AS(+/-) mice on normal salt, adrenal AS mRNA was slightly decreased (0.7xwild-type), but blood pressure was normal. On low salt, their blood pressure was less than wild-type (101+/-2 mm Hg versus 106+/-2 mm Hg), even though renin mRNA increased to 2xwild-type. We conclude that aldosterone is critical for urine concentration and maintenance of blood pressure and even a mild reduction of AS expression makes blood pressure sensitive to low salt, suggesting that genetic differences of AS levels in humans may influence how blood pressure responds to dietary salt. (+info)
Role of vasopressin in rat distal colon function.
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The specific role of vasopressin in colonic crypt function and its possible synergistic action with aldosterone were studied. Sprague-Dawley rats fed a high-Na+ (HS; 150 mM NaCl) or a low-Na+ (LS; 150 microM NaCl) diet were deprived of water or infused with vasopressin, and some animals were treated with specific vasopressin receptor subtype V1 and V2 antagonists. The expression of the epithelial Na+ channel (ENaC), alpha-smooth muscle actin (alpha-SMA) and aquaporin-2 (AQP-2) were determined by immunolocalization in distal colonic mucosa. The pericryptal Na+ concentration was determined by confocal microscopy, using a low-affinity Na+-sensitive fluorescent dye (sodium red) and crypt permeability was measured by the rate of escape of fluorescein isothiocyanate-labelled dextran (10 kDa) from the crypt lumen into the pericryptal space in isolated rat distal colonic mucosa. A high plasma concentration of vasopressin raised alpha-SMA expression in the pericryptal sheath (P < 0.05), increased the pericryptal Na+ accumulation in this space (P < 0.01) and caused a reduction of crypt wall permeability (P < 0.01). All these effects were reversed by selective blockade of V1 and V2 receptors. No synergistic effects with aldosterone were observed. Dehydration and vasopressin infusion increased AQP-2 expression in distal colonic mucosa (P < 0.05). This action of vasopressin was prevented by tolvaptan, a specific V2 receptor antagonist (P < 0.05). It is concluded that vasopressin has trophic effects in the rat distal colon, increasing pericryptal myofibroblast growth which affects crypt absorption, and these effects are independent of the presence of aldosterone. (+info)
Treatment of severe sepsis: where next? Current and future treatment approaches after the introduction of drotrecogin alfa.
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Severely septic patients continue to experience excessive morbidity and mortality despite recent advances in critical care. Although significant resources have been invested in new treatments, almost all have failed to improve outcomes. An improved understanding of sepsis pathophysiology, including the complex interactions between inflammatory, coagulation, and fibrinolytic systems, has accelerated the development of novel treatments. Recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated) (DAA), is currently the only US Food and Drug Administration (FDA)-approved medicine for the treatment of severe sepsis, and only in patients with a high risk of death. This review will discuss the treatment of severe sepsis, focusing on recent discoveries and unresolved questions about DAA's optimal use. Increasing pharmacological experience has generated enthusiasm for investigating medicines already approved for other indications as treatments for severe sepsis. Replacement doses of hydrocortisone and vasopressin may reduce mortality and improve hypotension, respectively, in a subgroup of patients with catecholamine-refractory septic shock. In addition to discussing these new indications, this review will detail the provocative preliminary data from four promising treatments, including two novel modalities: antagonizing high mobility group box protein and inhibiting tissue factor (TF). Observational data from the uncontrolled administration of heparin or statins in septic patients will also be reviewed. (+info)
Increased renal responsiveness to vasopressin and enhanced V2 receptor signaling in RGS2-/- mice.
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The antidiuretic effect of vasopressin is mediated by V2 receptors (V2R) that are located in kidney connecting tubules and collecting ducts. This study provides evidence that V2R signaling is negatively regulated by regulator of G protein signaling 2 (RGS2), a member of the family of RGS proteins. This study demonstrates that (1) RGS2 expression in the kidney is restricted to the vasopressin-sensitive part of the nephron (thick ascending limb, connecting tubule, and collecting duct); (2) expression of RGS2 is rapidly upregulated by vasopressin; (3) the vasopressin-dependent accumulation of cAMP, the principal messenger of V2R signaling, is significantly higher in collecting ducts that are microdissected from the RGS2(-/-) mice compared with their wild-type littermates; and (4) analysis of urine output of mice that were exposed to water restriction followed by acute water loading revealed that RGS2(-/-) mice exhibit an increased renal responsiveness to vasopressin. It is proposed that RGS2 is involved in negative feedback regulation of V2R signaling. (+info)
The treatment of primary nocturnal enuresis in Malaysia.
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To determine treatment outcomes in Malaysian children with primary nocturnal enuresis using both non-pharmacological methods and oral desmopressin. Data was collected prospectively from children aged 6-18 years who were referred to the Hospital UKM Enuresis Clinic. Treatment was given to those with a baseline wetting frequency of at least six wet nights/14 nights. Three modalities were offered: fluid management, reward system and oral desmopressin. Response was recorded as partial (> or = 50% reduction in WN from baseline) or full (completely dry). Seventy-one healthy children completed 12 weeks of therapy. Twenty-three children (32.4%) responded to non-pharmacological methods alone (4 full and 19 partial). Another 37 children (51.2%) responded to oral desmopressin (32 to 0.2mg, 4 to 0.4mg and 1 to 0.6mg). Thirty-two percent became dry whilst on therapy. The mean wetting frequency during treatment was significantly reduced (p < 0.01) compared to the baseline mean for both the non-pharmacological group and the desmopressin group. Discontinuation of desmopressin after 12 weeks increased the wetting frequency but this was still significantly lower than at baseline (p < 0.01). No adverse ents were recorded. Treatment of primary nocturnal enuresis in Malaysian children is both effective and well tolerated using fluid management strategies, reward systems and oral desmopressin. (+info)
Vasopressin V2 receptor expression along rat, mouse, and human renal epithelia with focus on TAL.
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In renal epithelia, vasopressin influences salt and water transport, chiefly via vasopressin V(2) receptors (V(2)Rs) linked to adenylyl cyclase. A combination of vasopressin-induced effects along several distinct portions of the nephron and collecting duct system may help balance the net effects of antidiuresis in cortex and medulla. Previous studies of the intrarenal distribution of V(2)Rs have been inconclusive with respect to segment- and cell-type-related V(2)R expression. Our study therefore aimed to present a high-resolution analysis of V(2)R mRNA expression in rat, mouse, and human kidney epithelia, supplemented with immunohistochemical data. Cell types of the renal tubule were identified histochemically using specific markers. Pronounced V(2)R signal in thick ascending limb (TAL) was corroborated functionally; phosphorylation of Na(+)-K(+)-2Cl(-) cotransporter type 2 (NKCC2) was established in cultured TAL cells from rabbit and in rats with diabetes insipidus that were treated with the V(2)R agonist desmopressin. We found solid expression of V(2)R mRNA in medullary TAL (MTAL), macula densa, connecting tubule, and cortical and medullary collecting duct and weaker expression in cortical TAL and distal convoluted tubule in all three species. Additional V(2)R immunostaining of kidneys and rabbit TAL cells confirmed our findings. In agreement with strong V(2)R expression in MTAL, kidneys from rats with diabetes insipidus and cultured TAL cells revealed sharp, selective increases in NKCC2 phosphorylation upon desmopressin treatment. Macula densa cells constitutively showed strong NKCC2 phosphorylation. Results suggest comparably significant effects of vasopressin-induced V(2)R signaling in MTAL and in connecting tubule/collecting duct principal cells across the three species. Strong V(2)R expression in macula densa may be related to tubulovascular signal transfer. (+info)
Forskolin stimulates phosphorylation and membrane accumulation of UT-A3.
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UT-A1 is regulated by vasopressin and is localized to the apical membrane and intracellular compartment of inner medullary collecting duct (IMCD) cells. UT-A3 is also expressed in the IMCD and is regulated by forskolin in heterologous systems. The goal of the present study is to investigate mechanisms by which vasopressin regulates UT-A3 in rat IMCD. In fresh suspensions of rat IMCD, forskolin increases the phosphorylation of UT-A3, similar to UT-A1. Biotinylation studies indicate that UT-A3 is located in the plasma membrane. Forskolin treatment increases the abundance of UT-A3 in the plasma membrane similar to UT-A1. However, these two transporters do not form a complex through a protein-protein interaction, suggesting that transporter function is unique to each protein. While immunohistochemistry localized UT-A3 to the basal and lateral membranes, a majority of the staining was cytosolic. Immunohistochemistry of vasopressin-treated rat kidney sections also localized UT-A3 primarily to the cytosol with basal and lateral membrane staining but also showed some apical membrane staining in some IMCD cells. This suggests that under normal conditions, UT-A3 functions as the basolateral transporter but in a high cAMP environment, the transporter may move from the cytosol to all plasma membranes to increase urea flux in the IMCD. In summary, this study confirms that UT-A3 is located in the inner medullary tip where it is expressed in the basolateral membrane, shows that UT-A3 is a phosphoprotein in rat IMCD that can be trafficked to the plasma membrane independent of UT-A1, and suggests that vasopressin may induce UT-A3 expression in the apical plasma membrane of IMCD. (+info)