Distal tubular electrolyte transport during inhibition of renal 11β-hydroxysteroid dehydrogenase

2001 ◽  
Vol 280 (1) ◽  
pp. F172-F179 ◽  
Author(s):  
Katharine J. Biller ◽  
Robert J. Unwin ◽  
David G. Shirley
Keyword(s):  
Distal Tubule ◽  
Hydroxysteroid Dehydrogenase ◽  
Treated Group ◽  
High Dose ◽  
Mineralocorticoid Receptors ◽  
Distal Nephron ◽  
Collecting Ducts ◽  
Micropuncture Study ◽  
Stimulation Of

To test the proposal that the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) confers aldosterone specificity on mineralocorticoid receptors in the distal nephron by inactivating glucocorticoids, we performed a free-flow micropuncture study of distal tubular function in adrenalectomized rats infused with high-dose corticosterone. One-half of the rats were additionally given intravenous carbenoxolone (CBX; 6 mg/h) to inhibit renal 11β-HSD activity. Although this maneuver lowered fractional Na+ excretion (1.1 ± 0.2 vs. 1.9 ± 0.2%, P < 0.01), Na+ reabsorption within the accessible distal tubule was found to be similar in the two groups of animals. In contrast, distal tubular K+ secretion was enhanced in CBX-treated rats: fractional K+ deliveries to the early and late distal collection sites in the corticosterone-alone group were 13 ± 1 and 20 ± 3%, respectively (not significant), whereas corresponding data in the CBX-treated group were 9 ± 1 and 24 ± 2% ( P < 0.01). This stimulation of distal K+ secretion provides the first direct in vivo evidence that 11β-HSD normally prevents corticosterone from exerting a mineralocorticoid-like effect in the distal tubule. The reduction in fractional Na+ excretion during inhibition of 11β-HSD, in the absence of a change in end-distal Na+delivery, suggests enhanced Na+ reabsorption in the collecting ducts.

Inhibition of renal 11β-hydroxysteroid dehydrogenase in vivo by carbenoxolone in the rat and its relationship to sodium excretion

1998 ◽  
Vol 95 (4) ◽  
pp. 435-443 ◽  
Author(s):  
K. J. SEWELL ◽  
D. G. SHIRLEY ◽  
A. E. MICHAEL ◽  
A. THOMPSON ◽  
D. P. NORGATE ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Poor Correlation ◽  
High Dose ◽  
Mineralocorticoid Receptors ◽  
Distal Nephron ◽  
Electrolyte Excretion ◽  
Dependent Inhibition ◽  
Anaesthetized Rats ◽  
High Doses

1.The type 2 isoform of 11β-hydroxysteroid dehydrogenase, an enzyme which converts cortisol or corticosterone to inactive 11-ketosteroid metabolites, is thought to be responsible for preventing access of endogenous glucocorticoids to mineralocorticoid receptors in the distal nephron; although direct in vivo evidence for this is still lacking. We have examined whether graded inhibition of renal 11β-hydroxysteroid dehydrogenase activities in vivo results in corresponding changes in urinary electrolyte excretion due to exposure of mineralocorticoid receptors to circulating endogenous glucocorticoids. 2.Anaesthetized rats were infused intravenously with vehicle alone or with one of three doses of carbenoxolone: 0.06, 0.6 or 6 ;mg/h. After measurement of renal electrolyte excretion, the kidneys were snap-frozen in liquid nitrogen and 11β-hydroxysteroid dehydrogenase activities were measured directly by enzyme assay in the presence of NAD+ or NADP+. 3.A dose-dependent inhibition of renal 11β-hydroxysteroid dehydrogenase activities was observed: the low, intermediate and high doses of carbenoxolone causing approximately 50%, 80% and > 90% inhibition respectively. Only with the high dose was an effect on renal function observed (decreased fractional Na+ excretion and urinary Na+/K+ ratio). 4.The poor correlation between the extent of inhibition of renal 11β-hydroxysteroid dehydrogenase and altered urinary Na+ excretion, apparent at the lower doses of carbenoxolone, suggests either that 11β-hydroxysteroid dehydrogenase has considerable functional reserve, or that it may not be the only mechanism determining mineralocorticoid receptor specificity in the distal nephron.

RAPID COMMUNICATIONIn vivo inhibition of renal 11β-hydroxysteroid dehydrogenase in the rat stimulates collecting duct sodium reabsorption

2001 ◽  
Vol 101 (2) ◽  
pp. 195-198 ◽  
Author(s):  
M. A. BAILEY ◽  
R. J. UNWIN ◽  
D. G. SHIRLEY
Keyword(s):  
Collecting Duct ◽  
Hydroxysteroid Dehydrogenase ◽  
Sodium Reabsorption ◽  
High Dose ◽  
Mineralocorticoid Receptors ◽  
Distal Nephron ◽  
Urinary Recovery ◽  
Distal Tubules ◽  
Adrenalectomized Rats

In order to test the proposal that the aldosterone specificity of mineralocorticoid receptors in the collecting duct depends on inactivation of glucocorticoids by the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD), we have assessed the effect of pharmacological inhibition of 11β-HSD on collecting duct Na+ reabsorption in vivo. Adrenalectomized rats (n = 14) were infused intravenously with high-dose corticosterone, and late-distal tubules were perfused orthogradely with artificial tubular fluid containing [14C]inulin and 22Na; urinary recoveries of the radioisotopes were monitored. Half of the rats received intravenous carbenoxolone to inhibit renal 11β-HSD activity. The urinary recovery of [14C]inulin was complete in both groups of animals (101ŷ2% versus 101ŷ3%), but the recovery of 22Na was lower in carbenoxolone-treated rats (34ŷ5%) than in the corticosterone-alone group (54ŷ4%, P < 0.01). These data, which provide the first demonstration of enhanced Na+ reabsorption in the distal nephron during inhibition of renal 11β-HSD in vivo, strongly support the proposal that 11β-HSD normally prevents endogenous glucocorticoid from exerting mineralocorticoid-like effects.

Stimulation of distal potassium secretion by low lumen chloride in the presence of barium

1985 ◽  
Vol 248 (5) ◽  
pp. F638-F649 ◽  
Author(s):  
D. H. Ellison ◽  
H. Velazquez ◽  
F. S. Wright
Keyword(s):  
Chloride Concentration ◽  
Distal Tubule ◽  
Perfusion Fluid ◽  
Transport Pathway ◽  
Luminal Membrane ◽  
Potassium Secretion ◽  
Transepithelial Voltage ◽  
Tubule Fluid ◽  
Stimulation Of

Potassium secretion into the renal distal tubule is increased when chloride in the tubule fluid is replaced by another anion. The present experiments were done to determine whether this increment in transported potassium traverses a conductive pathway from cell to lumen. Transport rates of potassium, sodium, chloride, and fluid by the renal distal tubule of rats were examined in vivo by continuous microperfusion. The effects of substituting gluconate for chloride in the presence and absence of 5 mM barium in the perfusion fluid were determined. When gluconate replaced chloride in the perfusion solutions, potassium secretion increased (by 44%) without a significant change in transepithelial voltage. Barium in the lumen increased the magnitude of the lumen-negative transepithelial voltage (by 30%) and reduced potassium secretion (by 56%) by inhibiting conductive potassium movement. Barium also decreased both sodium (by 51%) and chloride (by 37%) absorption. Barium did not reduce the stimulation of potassium secretion caused by reducing lumen chloride concentration. Potassium secretion increased (by 77%) when lumen chloride was reduced in the presence of 5 mM barium. We interpret these results by postulating that a cotransport mechanism linking potassium and chloride is present in the luminal membrane of distal tubule cells, that this mechanism operates in parallel with a conductive transport pathway for potassium, and that the K-Cl cotransport mechanism is not inhibited by barium.

Stimulation of B and T cells by in vivo high dose immunoglobulin administration in normal mice

1991 ◽  
Vol 4 (2) ◽  
pp. 325-339 ◽  
Author(s):  
Anne Sundblad ◽  
François Huetz ◽  
Denis Portnoï ◽  
Antonio Coutinho
Keyword(s):  
T Cells ◽  
High Dose ◽  
Stimulation Of

scholarly journals Pharmacodynamic Activity and Efficacy of Linezolid in a Rat Model of Pneumococcal Pneumonia

2002 ◽  
Vol 46 (5) ◽  
pp. 1345-1351 ◽  
Author(s):  
Martha J. Gentry-Nielsen ◽  
Keith M. Olsen ◽  
Laurel C. Preheim
Keyword(s):  
Rat Model ◽  
Pneumococcal Pneumonia ◽  
Free Fraction ◽  
Lavage Fluid ◽  
Treated Group ◽  
High Dose ◽  
Time Curve ◽  
A Value

ABSTRACT Linezolid is a new oxazolidinone antibiotic with potent activity against gram-positive bacteria, including Streptococcus pneumoniae. The pharmacodynamic activity and in vivo efficacy of linezolid were compared to those of ceftriaxone in an immunocompetent rat model of pneumococcal pneumonia. Rats infected intratracheally with 8 × 107 CFU of a penicillin-sensitive (MIC, 0.032 μg/ml) strain of S. pneumoniae were treated for 5 days beginning 18 h postinfection. Groups of rats were sham treated with oral phosphate-buffered saline or received oral liquid linezolid at 25 or 50 mg/kg of body weight twice a day (b.i.d.) or subcutaneous ceftriaxone at 100 mg/kg once daily. Mortality was monitored for 10 days postinfection; blood culturing was performed on day 1 (pretreatment) and on days 3, 5, and 10 postinfection for the determination of bacteremia. Serum also was collected for the determination of pharmacokinetic and pharmacodynamic parameters at 30 min and at 3, 5, and 12 h (linezolid) or 3, 5, and 24 h (ceftriaxone) postdose. The cumulative mortality rates were 100% for the sham-treated group, 58.3% for the low-dose linezolid group, 8.3% for the high-dose linezolid group, and 0% for the ceftriaxone group. Rats in each of the antibiotic treatment groups had significantly fewer bacteria (P < 0.00001) in their bronchoalveolar lavage fluid (BALF) on day 3 postinfection than sham-treated rats. There also were significantly fewer organisms in the BALF of rats treated with ceftriaxone than in the BALF of rats treated with either dose of linezolid. Oral linezolid at 50 mg/kg b.i.d. therefore was as effective as ceftriaxone in experimental pneumococcal pneumonia, whereas the 25-mg/kg b.i.d. dose was significantly less effective. All pharmacodynamic parameters reflected efficacy and were significantly different for the two dosage regimens of linezolid (P < 0.01). However, the free-fraction pharmacodynamic parameters predictive of outcome were a value of >39% for the percentage of time in the experimental dosing interval during which the linezolid concentration exceeded the MIC and a value of >147 for the ratio of the area under the serum concentration-time curve to the MIC.

scholarly journals The Molecular Mechanism of Chronic High-Dose Corticosterone-Induced Aggravation of Cognitive Impairment in APP/PS1 Transgenic Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Shen-Qing Zhang ◽  
Long-Long Cao ◽  
Yun-Yue Liang ◽  
Pu Wang
Keyword(s):  
Preclinical Model ◽  
High Dose ◽  
Term Administration ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Stimulation Of ◽  
Bace 1

Clinical studies have found that some Alzheimer’s disease (AD) patients suffer from Cushing’s syndrome (CS). CS is caused by the long-term release of excess glucocorticoids (GCs) from the adrenal gland, which in turn, impair brain function and induce dementia. Thus, we investigated the mechanism of the effect of corticosterone (CORT) on the development and progression of AD in a preclinical model. Specifically, the plasma CORT levels of 9-month-old APP/PS1 Tg mice were abnormally increased, suggesting an association between GCs and AD. Long-term administration of CORT accelerated cognitive dysfunction by increasing the production and deposition of β-amyloid (Aβ). The mechanism of action of CORT treatment involved stimulation of the expression of BACE-1 and presenilin (PS) 1 in in vitro and in vivo. This observation was confirmed in mice with adrenalectomy (ADX), which had lower levels of GCs. Moreover, the glucocorticoid receptor (GR) mediated the effects of CORT on the stimulation of the expression of BACE-1 and PS1 via the PKA and CREB pathways in neuroblastoma N2a cells. In addition to these mechanisms, CORT can induce a cognitive decline in APP/PS1 Tg mice by inducing apoptosis and decreasing the differentiation of neurons.

scholarly journals In Vitro and In Vivo Activity of AS101 against Carbapenem-Resistant Acinetobacter baumannii

2021 ◽  
Vol 14 (8) ◽  
pp. 823
Author(s):  
Tsung-Ying Yang ◽  
Sung-Pin Tseng ◽  
Heather Nokulunga Dlamini ◽  
Po-Liang Lu ◽  
Lin Lin ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Antibacterial Activities ◽  
Treated Group ◽  
Infection Model ◽  
High Dose ◽  
Mouse Infection Model ◽  
Carbapenem Resistant ◽  
Time Kill

The increasing trend of carbapenem-resistant Acinetobacter baumannii (CRAB) worldwide has become a concern, limiting therapeutic alternatives and increasing morbidity and mortality rates. The immunomodulation agent ammonium trichloro (dioxoethylene-O,O′-) tellurate (AS101) was repurposed as an antimicrobial agent against CRAB. Between 2016 and 2018, 27 CRAB clinical isolates were collected in Taiwan. The in vitro antibacterial activities of AS101 were evaluated using broth microdilution, time-kill assay, reactive oxygen species (ROS) detection and electron microscopy. In vivo effectiveness was assessed using a sepsis mouse infection model. The MIC range of AS101 for 27 CRAB isolates was from 0.5 to 32 µg/mL, which is below its 50% cytotoxicity (approximately 150 µg/mL). Bactericidal activity was confirmed using a time-kill assay. The antibacterial mechanism of AS101 was the accumulation of the ROS and the disruption of the cell membrane, which, in turn, results in cell death. The carbapenemase-producing A. baumannii mouse sepsis model showed that AS101 was a better therapeutic effect than colistin. The mice survival rate after 120 h was 33% (4/12) in the colistin-treated group and 58% (7/12) in the high-dose AS101 (3.33 mg/kg/day) group. Furthermore, high-dose AS101 significantly decreased bacterial population in the liver, kidney and spleen (all p < 0.001). These findings support the concept that AS101 is an ideal candidate for further testing in future studies.

In vivo adaptation of bicarbonate reabsorption by rat distal tubules during acid loading

1994 ◽  
Vol 267 (5) ◽  
pp. F737-F747 ◽  
Author(s):  
D. Z. Levine ◽  
M. Iacovitti ◽  
S. Buckman ◽  
D. Vandorpe ◽  
V. Harrison ◽  
...  
Keyword(s):  
Water Flux ◽  
Distal Tubule ◽  
Bafilomycin A1 ◽  
Bicarbonate Reabsorption ◽  
Distal Tubules ◽  
Acid Loading ◽  
Fasted Rats ◽  
Predominant Effect ◽  
Stimulation Of

We carried out in vivo microperfusion experiments in acid-loaded rats to characterize the adaptive response of the unidirectional components secretory flux (Jsec) and reabsorptive flux (Jreab)] of distal tubule bicarbonate reabsorption and to test the hypothesis that Jreab is dependent on bafilomycin A1-sensitive H(+)-adenosinetriphosphatase activity. During 18 h of severe acidosis there was a significant decrease in Jsec (-15 +/- 3 vs. -38 +/- 5 pmol.min-1.mm-1, P < 0.05) and a significant increase in Jreab (37 +/- 6 vs. 0 +/- 5 pmol.min-1.mm-1, P < 0.05), which was insensitive to 10(-5) M bafilomycin A1, 10(-5) M Sch-28080, and 3 mM amiloride. After 3 days of acid loading, these same inhibitors reduced Jreab by approximately 60%. However, when water flux was completely inhibited by isosmotic perfusion, a significant Jreab (15 +/- 2 pmol.min-1.mm-1) resistant to 10(-5) M bafilomycin A1 persisted, as in severe acidosis. In reabsorbing distal tubules of overnight-fasted rats, Sch-28080 elicited no inhibition, whereas bafilomycin A1 and amiloride had significant effects (28 +/- 5, 24 +/- 4, respectively, vs. 50 +/- 4 pmol.min-1.mm-1 for fasted rats, P < 0.05). Thus, although Jsec is reduced in the transition from mild to severe metabolic acidosis of 18-h duration, the predominant effect is a stimulation of bafilomycin A1-resistant Jreab.

11 beta-Hydroxysteroid dehydrogenase mRNA expression in rat kidney

1991 ◽  
Vol 260 (5) ◽  
pp. F764-F767
Author(s):  
J. L. Yau ◽  
A. D. Van Haarst ◽  
M. P. Moisan ◽  
S. Fleming ◽  
C. R. Edwards ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Binding Sites ◽  
Mineralocorticoid Receptor ◽  
Rat Kidney ◽  
Hydroxysteroid Dehydrogenase ◽  
Mineralocorticoid Receptors ◽  
Tubular Cells ◽  
Renal Tubular

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) protects nonspecific renal mineralocorticoid receptors from exposure to circulating glucocorticoid in vivo by catalyzing the conversion of corticosterone to inactive 11-dehydrocorticosterone. Although 11 beta-OHSD bioactivity and aldosterone binding sites are found in distal tubular cells, mineralocorticoid receptor and 11 beta-OHSD immunoreactivities are not colocalized. However, there are several kidney isoforms of 11 beta-OHSD, not all of which may be immunoreactive, whereas only a single mRNA species has been described. Using in situ hybridization we found 11 beta-OHSD mRNA is highly expressed in all renal tubular epithelia in the rat. It is therefore likely that 11 beta-OHSD is colocalized with mineralocorticoid receptors in distal tubular cells.

Effect of vasopressin on renal lithium reabsorption: a micropuncture and microperfusion study

1996 ◽  
Vol 271 (1) ◽  
pp. F223-F229 ◽  
Author(s):  
S. J. Walter ◽  
D. G. Shirley ◽  
R. J. Unwin
Keyword(s):  
Arginine Vasopressin ◽  
Concentration Ratio ◽  
Lithium Concentration ◽  
Distal Tubule ◽  
Treated Group ◽  
Thick Ascending Limb ◽  
Loop Of Henle ◽  
Brattleboro Rats ◽  
Lithium Clearance

Micropuncture techniques were used to investigate the nephron site(s) responsible for the vasopressin-induced reductions in lithium clearance and fractional lithium excretion (FELi) in anesthetized Brattleboro rats lacking endogenous vasopressin. In rats treated intravenously with the vasopressin analogue 1-desamino-8-D-arginine vasopressin (DDAVP; 40 pg/min), FELi was significantly lower than in untreated animals (0.23 +/- 0.01 vs. 0.28 +/- 0.02, P < 0.05). Free-flow micropuncture showed that fractional lithium delivery (FDLi) to late proximal convolutions was identical in the two groups, whereas at the early distal tubule both FDLi (0.28 +/- 0.02 vs. 0.33 +/- 0.01, P < 0.05) and the tubular fluid-to-plasma lithium concentration ratio (1.18 +/- 0.04 vs. 1.36 +/- 0.06, P < 0.05) were lower in the DDAVP-treated group. No differences between the groups with respect to lithium handling beyond the early distal tubule were observed. In rats subjected to in vivo microperfusion of loops of Henle, intravenous infusion of DDAVP (40 pg/min) increased fractional lithium reabsorption in the loop from 0.56 +/- 0.03 to 0.66 +/- 0.04 (P < 0.05) and from 0.39 +/- 0.02 to 0.45 +/- 0.02 (P < 0.05) at perfusion rates of 10 and 15 nl/min, respectively. We conclude that DDAVP stimulates lithium reabsorption in the loop of Henle and suggest that this results from an increased transepithelial potential difference in the thick ascending limb.

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