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Y Yagil

Publications and source records attributed to Y Yagil.

At least 37 records · Page 2Linked to original sources
PubMed1996

Development, genotype and phenotype of a new colony of the Sabra hypertension prone (SBH/y) and resistant (SBN/y) rat model of slat sensitivity and resistance.

OBJECTIVES: Variations in the blood pressure response to salt-loading, the lack of quality control measures, and the need to prepare the strains for genetic studies led to renewed secondary inbreeding of the original colony of Sabra hypertension prone (SBH) and resistant (SBN) rats in order to regain genotypic and phenotypic homogeneity of the substrains. METHODS: Animals from the original breeding colony were selectively inbred for basal normotension and for susceptibility or resistance to the development of hypertension following salt-loading with deoxycorticosterone acetate (DOCA)-salt. Efficacy of inbreeding was tested by genome screening with 416 microsatellite primer sets. Phenotyping was based on measurements of systolic blood pressure by the tail-cuff methodology in awake, undisturbed animals maintained on standard diet and after salt-loading with DOCA-salt. Telemetric measurements of blood pressure were performed in a small number of animals to validate tail-cuff measurements. RESULTS: Animals from the new colony were designated SBH/y and SBN/y to differentiate from the original colony. Fourteen generations have been inbred over the past 4 years. Of the 402 microsatellites that amplified, 183 (45.5%) were polymorphic between the two substrains, and not a single locus was found to be heterozygous in either substrain. Phenotypic characteristics are provided for SBH/ y and SBN/y rats with respect to tail-cuff systolic blood pressure. The values obtained, which were validated by telemetry, demonstrate classical features of salt sensitivity or resistance, respectively. CONCLUSIONS: The genetic homogeneity found in SBH/y and SBN/y, the phenotype demonstrating salt-sensitivity or salt-resistance in terms of development of hypertension, and the relatively high frequency of informative genetic markers identify this Sabra rat model as highly suited for studies concerning the molecular genetics of gene-environment interactions affecting blood pressure regulation.

Animals↗
PubMed1996

Aldosterone induction and epithelial distribution of CHIF.

CHIF is a recently cloned, corticosteroid-induced gene which evokes K+ channel activity in oocytes (B. Attali, H. Latter, N. Rachamim, and H. Garty. Proc. Natl. Acad. Sci. USA 92: 6092-6096, 1995). To further characterize the possible role of this gene in epithelial ion transport, we have studied its epithelial distribution and hormonal induction. Northern hybridizations indicate that the zonal distribution of CHIF mRNA in kidney is: papilla >>medulla>> cortex. High levels of CHIF were also detected in a primary culture from inner medullary collecting duct (IMCD). Perfusing rats with < 20 nM aldosterone through osmotic minipumps evoked a 22.4 +/- 1.9-fold increase in colonic CHIF. A significant increase was observed 3 h after administrating the corticosteroid, but maximal response was detected only after a 72-h incubation. This response appears to be mineralocorticoid specific; perfusing or injecting rats with maximal doses of dexamethasone did not evoke a further increase in CHIF mRNA. In contrast, high levels of CHIF are expressed in kidney papilla and IMCD primary culture, irrespective of corticosteroid treatment. Thus, like the apical Na+ channel and the H(+)-K(+)-adenosinetriphosphatase, CHIF is mineralocorticoid induced in the colon but constitutively expressed in kidney.

Aldosterone↗
PubMed1996

Disparate expression of the AVP gene in Sabra hypertension-prone and hypertension-resistant rats.

We recently re-inbred the original colony of SBH-SBN rats, a model of salt-induced hypertension. In the course of phenotyping the new colony, SBH/y were found to excrete a lower urine flow with a higher urine osmolality than SBN/y. Thus disparate water handling between the substrains, a phenotype characteristic of the original colony, was retained throughout the selection procedure and transmitted down the generations to the new colony. As water handling is directly linked to arginine vasopressin (AVP) and in view of potential linkage of this phenotype to salt sensitivity or resistance in terms of the development of hypertension, the AVP axis was further investigated in the new substrains. Basal plasma AVP levels were higher in SBH/y (2.86 +/- 0.22 pg/ml; n = 10) than in SBN/y (1.98 +/- 0.11 pg/ml; n = 10, P < 0.05). Water deprivation for 48 h increased plasma AVP levels severalfold in both substrains to similar levels. Niravoline, a kappa receptor agonist that inhibits central release of AVP, produced at 0.6 and 0.9 mg/kg a more profound diuretic effect in SBN/y than in SBH/y, suggesting greater pituitary release of AVP into the circulation of SBH/y. AVP mRNA contents were compared in SBH/y and SBN/y rats in whole hypothalamic extracts and in the supraoptic (SON) and paraventricular (PVN) nuclei by RNA protection assay. Under basal conditions, AVP mRNA content (in ng) in the hypothalamus of SBH/y was 4.48 +/- 0.52 (n = 29) and of SBN/y was 3.13 +/- 0.35 (n = 30), P < 0.05; in the SON of SBH/y, AVP mRNA content was 3.62 +/- 0.44 (n = 11) and of SBN/y was 2.21 +/- 0.54 (n = 10), P < 0.05; in the PVN of SBH/y, AVP mRNA content was 0.78 +/- 0.16 (n = 9) and of SBN/y was 0.77 +/- 0.13 (n = 11, not significant). Thus the differences in hypothalamic AVP mRNA were primarily in the SON. Water deprivation as well as salt loading (8% NaCl) induced a significant elevation in AVP mRNA content in SBN/y but a blunted response in SBH/y. These data suggest that there is genetically transmitted enhanced hypothalamic expression of the AVP gene in SBH/y compared with SBN/y which results, under basal conditions, in greater pituitary release of AVP, in higher plasma AVP levels, and in increased renal concentrating activity. As AVP has been implicated in various forms of hypertension, these findings render AVP a candidate gene for salt sensitivity or resistance in the Sabra rat model of hypertension.

Animals↗
PubMed1995

The hypotensive effect of an oral adenosine analog with selectivity for the A2 receptor in the spontaneously hypertensive rat.

Adenosine is a potent arterial vasodilator that, because of a short duration of action and acid lability, is ineffective in the oral treatment of hypertension. Y-341 is a synthetic adenosine analog that is acid stable and has a prolonged duration of action. It is highly selective for the A2 receptor, which is prevalent in the vascular smooth muscle and mediates vasodilation. To determine the efficacy of Y-341 as an antihypertensive agent, the effect of Y-341 on arterial pressure was studied in spontaneously hypertensive rats (SHR) in the awake state, 3 to 4 days after arterial cannulation. Y-341 (3 mg/kg) was dissolved in 5% DMSO and administered by gavage. Blood pressure and heart rate were monitored continuously at predetermined intervals. Fifteen minutes after administration, Y-341 reduced MAP from 180 +/- 4 to 126 +/- 2 mm Hg (n = 9, P < .001). There was no significant change in heart rate. The hypotensive effect was sustained over 8 h. Vehicle (n = 5) had no effect on blood pressure. The hypotensive effect was dose dependent when the dose of Y-341 was increased from 3 to 6 and 12 mg/kg. When Y-341 was administered at 3 mg/kg/day in a single dose for 5 consecutive days, there was no significant change in the magnitude of the hypotensive response over time.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1995

22-Oxacalcitriol does not interfere with parathyroid hormone-induced phosphaturia or cyclic-AMP excretion.

The vitamin D analogue, 22-oxacalcitriol [22-oxa-1,25(OH)2 vitamin D3], has pleiotropic effects similar to or greater than calcitriol but has markedly fewer calcemic and phosphatemic effects. To test the hypothesis that the lesser phosphatemic effect of 22-oxacalcitriol is due, at least in part, to a lack of interference with the phosphaturic effect of parathyroid hormone, acute clearance experiments were performed in parathyroidectomized rats receiving continuous 1-34 parathyroid hormone (PTH) infusion together with 22-oxacalcitriol (200 pmol.100 g body weight-1.min-1) or vehicle. In contrast to the previously reported inhibitory effect of calcitriol on PTH-induced phosphaturia, fractional excretion of phosphorus increased similarly in both groups, from 0.05 +/- 0.01 to 0.26 +/- 0.02 (p < 0.01) in the vehicle-infused animals and from 0.04 +/- 0.01 to 0.24 +/- 0.02 (p < 0.01) in the 22-oxacalcitriol-treated rats (p between groups not significant [n.s.]). Urinary cyclic AMP excretion also increased similarly, from 45.5 +/- 5.2 to 101.6 +/- 21.6 (p < 0.01) and from 45.4 +/- 5.6 to 102.6 +/- 16.7 pmol/min (p < 0.01), respectively (p between groups n.s.). In search for a nongenomic mechanism that might account for the disparate effects of 22-oxacalcitriol and calcitriol, OK cells, which are reminiscent of the mammalian proximal tubule cell, were stimulated with calcitriol and 22-oxacalcitriol and free intracellular calcium concentration was determined. At high concentrations, calcitriol caused a dose-dependent increase in [Ca2+]i; 22-oxacalcitriol had no effect on [Ca2+]i at any concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The effects of adenosine on transepithelial resistance and sodium uptake in the inner medullary collecting duct.

It has been previously demonstrated that adenosine induces natriuresis when administered directly into the renal circulation of the rat. It was postulated that the mechanism was inhibition of tubule Na+ reabsorption. In the current study, the hypothesis was tested that adenosine inhibits ion reabsorption across the inner medullary collecting duct (IMCD), a tubule segment which is rich in adenosine receptors. IMCD epithelium from rat kidney was grown in primary culture as a confluent monolayer on Costar filters, allowing selective access to the basolateral and apical surfaces of the cells. Transepithelial resistance was taken as a measure of epithelial permeability and ion conductance. Na+ uptake was studied using 22Na+ and used to determine the permeability of the epithelial monolayer specifically to Na+. Exposure of the basolateral aspect of the monolayer to adenosine (10(-8)-10(-7) M) increased transepithelial resistance in a dose- and time-dependent manner; in parallel, adenosine (10(-7)-10(-6) M) reduced apical Na+ uptake from 20 +/- 5 to 10 +/- 2 nmol/cm2. 1,3-Dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (PACPX, 5 x 10(-9) M), an adenosine antagonist with selectivity for the A1 receptor, inhibited the rise in transepithelial resistance and the decrease in Na+ uptake following the addition of adenosine. The effects of adenosine on transepithelial resistance were reproduced with the A1 receptor selective adenosine analogue N6-cyclohexyladenosine (CHA, 10(-8)-10(-7) M) but not with the A2 selective analogues, 5'-N-ethylcarboxamidoadenosine (NECA) or CGS 21680. CHA (10(-7) M) inhibited apical Na+ uptake by 50%, an effect abolished by PACPX. (ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1994

Human kidney proximal tubules are the main source of plasma glutathione peroxidase.

The sites of synthesis of extracellular (E) glutathione peroxidase (GPX), a unique selenoglycoprotein present in plasma, are not known. To investigate the possibility that the kidney is the main source for the plasma GPX, we examined GPX activities and selenium concentrations in the plasma of patients with renal failure on dialysis and nephrectomized patients before and after kidney transplantation. Plasma GPX activities in these patients were 42, 22, and 180% of normal EGPX activity, respectively, whereas plasma Se levels were within the normal range. Twenty-four hours after nephrectomy of anesthetized rats, plasma GPX activity was 30.0 +/- 6.4% of the activity at zero time. Northern hybridization analysis of eight human tissues probed with EGPX and cellular glutathione peroxidase (CGPX) cDNA revealed that the ratio of EGPX to CGPX was highest in the kidney. cRNA in situ hybridization studies on kidney slices showed that only proximal tubular epithelial cells and parietal epithelial cells of Bowman's capsule contained EGPX transcripts. Caki-2, a proximal tubular renal carcinoma cell line, makes and actively secretes EGPX. Taken together, these results strongly suggest that kidney proximal tubular cells are the main source for GPX activity in the plasma.

Animals↗
PubMed1994

Effects of CS-905, a novel dihydropyridine calcium channel blocker, on arterial pressure, renal excretory function, and inner medullary blood flow in the rat.

CS-905 is a dihydropyridine calcium channel antagonist which stands out for its prolonged hypotensive effect, and which is currently under investigation for the treatment of hypertension. The aim of the current series of studies was to investigate the effects of CS-905 on renal function in relation to its effects on arterial pressure. In anesthetized spontaneously hypertensive rats (SHR), intravenous bolus injection of CS-905 reduced mean arterial pressure (MAP) in a dose-dependent fashion. In parallel, there was a dose-related increase in urine flow (V), sodium excretion (UNaV), renal plasma flow (RPF), and glomerular filtration rate (GFR). In chronically cannulated unanesthetized SHR, single-dose CS-905 by gavage produced a sustained reduction in MAP, a significant increase in V and UNaV, no effect on RPF, and an increase in GFR. Continuous intrarenal infusion of CS-905 in anesthetized normotensive Munich Wistar rats at doses that did not affect MAP caused a marked diuresis and natriuresis, without affecting RPF or GFR. To determine whether the diuretic and natriuretic effects of CS-905 were mediated by changes in inner medullary blood flow, the effect of CS-905 on vasa recta blood flow (Qvr) was studied by fluorescent videomicroscopy in anesthetized normotensive Munich Wistar rats during continuous intrarenal infusion. At low infusion rates, CS-905 was diuretic and natriuretic while increasing Qvr. With a high infusion rate, although the diuretic and natriuretic effects of CS-905 were maximal, Qvr decreased. These findings suggest that the diuretic and natriuretic effects of CS-905 are dissociated from and cannot be accounted for by changes in RPF, GRF, or Qvr, and are most likely secondary to a direct action of CS-905 on renal tubule handling of sodium and water.

Anesthesia↗
PubMed1994

The effects of adenosine on water and sodium excretion.

The effects of adenosine on glomerular filtration rate and renal blood flow are well documented, but its effects on water and sodium excretion are less well established. Previous studies in the rat have shown that i.v. and intra-aortic administration of adenosine decrease water and sodium excretion. The validity of these findings was challenged recently when it was found that intrarenal administration of adenosine in the rat induced marked diuresis and natriuresis. The aim of the current study was to investigate further the effects of intrarenal administration of adenosine on renal excretory function in the rat. Intrarenal infusion of 2 to 15 micrograms/min of adenosine, although having no effect on systemic arterial pressure, induced a 4-fold increase in water and sodium excretion. Intravenous infusion of adenosine at equivalent doses in the same species and under similar experimental conditions resulted in a 1-fold increase in water excretion, and only a transient increase in sodium excretion, whereas intraaortic adenosine had no effect on either variable. During infusion of adenosine by all three routes, there was a significant decline in glomerular filtration rate, but no change in renal plasma flow. The diuretic and natriuretic effects of adenosine during intrarenal infusion were of a similar order of magnitude in animals maintained for 3 weeks on no sodium, normal sodium or high sodium diet, and did not correlate with plasma renin activity. Simultaneous infusion of 10(-7) M 9-cyclopentyl-1,3-dipropylxanthine, a selective adenosine A1 receptor antagonist, markedly inhibited the diuretic and natriuretic effects of intrarenal adenosine. Intrarenal infusion of N6-cyclohexyladenosine, an adenosine A1 receptor agonist, but not of N' ethylcarboxamidoadenosine, a potent A2 receptor agonist, significantly increased water and sodium excretion. These findings suggest that, in the rat, the diuretic and natriuretic effects of adenosine are 1) fully expressed only during intrarenal administration, 2) absent during intra-aortic administration, 3) not related to prior sodium intake or sodium balance, 4) mediated by the adenosine A1 receptor and 5) dissociated from its effects on glomerular filtration and renal plasma flow.

Adenosine↗
PubMed1994

Effects of bile duct ligation on calcium excretion in the rat.

In an earlier study we showed that bile duct-ligated rats were highly susceptible to gentamicin nephrotoxicity and that oral calcium administration had a pronounced protective effect. The mechanism by which this occurs is unclear. Because cations compete with gentamicin for tubule binding sites, it has been suggested that the increased susceptibility of the kidney to gentamicin after bile duct ligation might result from decreased cation excretion. The aim of this study was to determine the effect of bile duct ligation on calcium excretion in relation to overall renal function. Male Sprague-Dawley rats underwent bile duct ligation and division. Pair-fed sham-operated rats served as controls. Metabolic and clearance studies were carried out at 3, 5, 7, 14 and 21 days after surgery. Urine output was higher in bile duct-ligated rats, and they excreted more calcium at 3, 5, 7 and 14 days, while excreting less sodium than controls. We conclude that after bile duct ligation, there is increased calcium excretion, which is independent of the abnormality in sodium excretion. Enhanced nephrotoxicity with aminoglycosides in the bile duct-ligated rat model cannot be explained by decreased calcium excretion.

Animals↗
PubMed1992

Differential effect of basolateral and apical adenosine on AVP-stimulated cAMP formation in primary culture of IMCD.

It has been recently established that adenosine interferes with the ability of arginine vasopressin (AVP) to generate adenosine 3',5'-cyclic monophosphate (cAMP) in inner medullary collecting duct (IMCD) cells in culture. The aim of the current study was to determine whether this interaction of adenosine with AVP is mediated by adenosine from the basolateral (B) and/or the apical (A) surface of the tubule cell. Cells from rat IMCD were grown to confluence in monolayers on porous filters. Adenosine (5 x 10(-8)-10(-4) M) applied to the B or A surface of the cell had no detectable effect on basal cAMP formation. AVP, 10(-9)-10(-6) M, increased cAMP formation from both B and A surfaces of the cell. When AVP was applied to the B surface, 10(-6) M adenosine inhibited AVP-stimulated cAMP formation from the B side only, whereas adenosine at 10(-4) M inhibited cAMP formation from both B and A sides. The inhibitory effect of adenosine was reproduced with N6-cyclohexyladenosine (CHA) from both B and A surfaces. 5'-(N-ethylcarboxamido)adenosine (NECA) and 2',5'-dideoxyadenosine (DDA) inhibited cAMP formation from the B surface only. When AVP was applied to the A surface, the inhibitory effects of adenosine were the same as when AVP was applied to the B surface; CHA, NECA, and DDA inhibited AVP-stimulated cAMP formation from both the B and A surfaces. 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX), an adenosine antagonist with selectivity for the A1 receptor, prevented the inhibitory effects of adenosine, CHA, and NECA on AVP-stimulated cAMP formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗