Losartan-hydrochlorothiazide association promotes lasting blood pressure normalization and completely arrests long-term renal injury in the 5/6 ablation model

2007 ◽  
Vol 292 (6) ◽  
pp. F1810-F1818 ◽  
Author(s):  
Clarice Kazue Fujihara ◽  
Denise M. A. C. Malheiros ◽  
Roberto Zatz
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Adult Male ◽  
Renal Injury ◽  
Wistar Rats ◽  
Long Period ◽  
Morphological Studies ◽  
Renal Ablation ◽  
Ablation Model

The possible long-term renoprotective effects of treatment with thiazides, either as monotherapy or associated with renin-angiotensin suppressors, have not been assessed. We investigated the effect of hydrochlorothiazide (H), alone or combined with losartan (L), in the 5/6 renal ablation model (Nx). Adult male Munich-Wistar rats underwent Nx, remaining untreated for 1 mo. At this time, functional and morphological studies were performed in 21 rats (group Nxpre). The remaining rats were distributed among groups: Nx, no treatment; Nx+L, receiving L, 50 mg·kg−1·day−1 in the drinking water; Nx+H, receiving H, 6 mg·kg−1·day−1 in drinking water; and Nx+L+H, receiving both L and H as described. At 30 days of treatment, systemic and glomerular pressures were markedly elevated in group Nx. Both H and L attenuated hypertension, whereas combined L+H treatment completely normalized both pressures. Eight months after Nx, mortality approached 70% in untreated rats, whereas severe albuminuria, hypertension, glomerulosclerosis, and interstitial expansion were observed. H and L attenuated, but did not prevent, mortality, hypertension, and renal injury. Combined L+H treatment completely prevented mortality, normalized albuminuria and blood pressure, and arrested renal injury at levels found 1 mo after ablation, despite the unusually long period of observation. Combined L+H treatment may represent an effective therapeutic alternative to prevent progression of chronic nephropathies.

scholarly journals SUN-207 Modelling Long Term Glucocorticoid-Induced HPA Axis Suppression in Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Nicola Romano ◽  
Peter James Duncan ◽  
Oscar Nolan ◽  
Paul Roussel Le Tissier ◽  
Mike Shipston ◽  
...  
Keyword(s):  
Drinking Water ◽  
Mouse Model ◽  
Hpa Axis ◽  
Adult Male ◽  
Male Mice ◽  
Dexamethasone Treatment ◽  
Mortality And Morbidity ◽  
Fold Reduction ◽  
The Uk

Abstract Glucocorticoids are prescribed for >3 months to 1% of the UK population. 10-50% of these long-term glucocorticoid treated patients develop persistent HPA axis suppression associated with mortality and morbidity. We have developed a mouse model of glucocorticoid-induced HPA axis dysfunction to determine the mechanisms resulting in persistent HPA axis suppression. Experiment 1: 36 C57BL/6 adult male mice received Dexamethasone (DEX,~10µg/day) or vehicle (CTL) via drinking water for 28 days, following which treatment was stopped and tissues were harvested at 0, 7 and 28 days. DEX suppressed waking serum corticosterone at days 0 and 7, recovering by day 28. Adrenal size remained lower 28 days following DEX withdrawal. DEX had no effect on whole pituitary pomc, nr3c1 or crhr1 expression, although avpr1b was increased at day 0. In the adrenal, hsd3b2 and cyp11a1 expression were reduced at time 0; normalising by 28 days. Experiment 2: 24 POMC-GFP male mice were treated as above. Tissues were collected at day 0 (n=6), 7 (n=3) and 10 (n=3) following withdrawal. Pooled corticotrophs (groups of 3) were isolated by FACS and RNA extracted for qPCR. DEX reduced corticotroph pomc expression at time 0 (x20 fold reduction), with x5 fold suppression at day 7, which recovered with evidence of compensation by day 10. DEX increased expression of avpr1b but not crhr1. CONCLUSION: 28 days dexamethasone treatment in mice suppresses the HPA axis. HPA suppression is evident 7 days following withdrawal of dexamethasone in the adrenal, corticotroph population and corticosterone production. Further analysis will determine mechanisms for delays in HPA axis recovery.

Transplacental Toxicity and Carcinogenesis Studies in Rats with Hexamethylenetetramine

1970 ◽  
Vol 56 (6) ◽  
pp. 325-334 ◽  
Author(s):  
Giuseppe Della Porta ◽  
José R. Cabral ◽  
Giorgio Parmiani
Keyword(s):  
Drinking Water ◽  
Body Weight ◽  
Wistar Rats ◽  
The Body ◽  
Carcinogenic Activity ◽  
Long Term Experiments ◽  
Pregnancy And Lactation ◽  
Successive Generations ◽  
And Control

In a previous paper (Fd Cosmet. Toxicol., 6: 707–715, 1968) it was reported that hexamethylenetetramine (HMT) had no carcinogenic activity in long-term experiments in mice and rats. In the present study, 12 ♀ and 6 ♂ Wistar rats were given 1% HMT in the drinking water starting 2 weeks before mating. The females were kept under treatment during pregnancy and lactation. A similar untreated group of 12 ♀ and 6 ♂ served as control. Twelve treated females and eleven controls became pregnant and gave birth to 124 and 118 babies respectively; no malformations were noted. From these animals, 24 for each sex were continued on the 1% HMT up to the 20th week of age or were kept untreated. The body weight of treated animals was significantly lower than that of controls one, only up to the 9th week of age for the males and up to the 13th week for the females. At the end of the treatment both groups were sacrificed; the weight of organs was identical in the treated and control animals; there were no gross or histological pathology. In a second experiment, rats were given 1% HMT in the drinking water for 3 successive generations, up to the age of 40 weeks in the F1 and F2 groups and of 20 weeks for F3. The three groups were composed of 13 ♂ and 7 ♀, 15 ♂ and 11 ♀, 12 ♂ and 12 ♂, respectively. In addition, a group of 16 ♂ and 16 ♀ descendants of 2% HMT treated parents, were given 2% HMT for 50 weeks. A group of 48 ♂ and 48 ♀ served as untreated controls. All groups were kept under observation for over 2 years of age. No evidence of carcinogenicity was found in any of the HMT-treated groups.

scholarly journals Impact of obesity on renal structure and function in the presence and absence of hypertension: evidence from melanocortin-4 receptor-deficient mice

2009 ◽  
Vol 297 (3) ◽  
pp. R803-R812 ◽  
Author(s):  
Jussara M. do Carmo ◽  
Lakshmi S. Tallam ◽  
John V. Roberts ◽  
Elizabeth L. Brandon ◽  
John Biglane ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Injury ◽  
Salt Sensitivity ◽  
Metabolic Abnormalities ◽  
Salt Diet ◽  
Melanocortin 4 Receptor ◽  
Renal Structure ◽  
Long Term Impact ◽  
And Function

The purpose of this study was to determine the long-term impact of obesity and related metabolic abnormalities in the absence and presence of hypertension on renal injury and salt-sensitivity of blood pressure. Markers of renal injury and blood pressure salt sensitivity were assessed in 52- to 55-wk-old normotensive melanocortin-4 receptor-deficient (MC4R−/−) mice and lean C57BL/6J wild-type (WT) mice and in 22-wk-old MC4R−/− and WT mice made hypertensive by NG-nitro-l-arginine methyl ester (l-NAME) in the drinking water for 8 wk. Old MC4R−/− mice were 60% heavier, hyperinsulinemic, and hyperleptinemic but had similar mean arterial pressure (MAP) as WT mice (115 ± 2 and 117 ± 2 mmHg) on normal salt diet (0.4% NaCl). A high-salt diet (4.0% NaCl) for 12 days did not raise MAP in obese or lean mice [ΔMAP: MC4R (−/−) 4 ± 2 mmHg; WT, 2 ± 1 mmHg]. Obese MC4R−/− mice had 23% greater glomerular tuft area and moderately increased GFR compared with WT mice. Bowman's space, total glomerular area, mesangial matrix, urinary albumin excretion (UAE), renal TGF-β and collagen expression were not significantly different between old MC4R−/− and WT mice. Renal lipid content was greater but renal macrophage count was markedly lower in MC4R−/− than WT mice. Mild increases in MAP during l-NAME treatment (∼16 mmHg) caused small, but greater, elevations in UAE, renal TGF-β content, and macrophage infiltration in MC4R−/− compared with WT mice without significant changes in glomerular structure. Thus despite long-term obesity and multiple metabolic abnormalities, MC4R−/− mice have no evidence of renal injury or salt-sensitivity of blood pressure. These observations suggest that elevations in blood pressure may be necessary for obesity and related metabolic abnormalities to cause major renal injury or that MC4R−/− mice are protected from renal injury by mechanisms that are still unclear.

Evaluation of Long Term Alcohol Consumption on Gastric Acid Secretion and the Histomorphometry of the Stomach in Adult Male Wistar Rats

2016 ◽  
Vol 4 (5) ◽  
pp. 7
Author(s):  
Ese C. Adegor ◽  
Anthony E. Ojieh ◽  
Ovocity Eghworo ◽  
Lawrence O. Ewhre ◽  
Tarela M. E. Daubry ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Acid Secretion ◽  
Gastric Acid Secretion ◽  
Gastric Acid ◽  
Adult Male ◽  
Wistar Rats ◽  
Male Wistar Rats

Relationship between long-term exposure to low-level arsenic in drinking water and the prevalence of abnormal blood pressure

2013 ◽  
Vol 262 ◽  
pp. 1154-1158 ◽  
Author(s):  
Chuanwu Zhang ◽  
Guangyun Mao ◽  
Suxia He ◽  
Zuopeng Yang ◽  
Wei Yang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Drinking Water ◽  
Low Level

scholarly journals Long-term effect of losartan administration on blood pressure, heart and structure of coronary artery of young spontaneously hypertensive rats

2009 ◽  
pp. 327-335 ◽  
Author(s):  
R Koprdová ◽  
M Cebová ◽  
F Kristek
Keyword(s):  
Blood Pressure ◽  
Coronary Artery ◽  
Wistar Rats ◽  
Term Effect ◽  
Heart Weight ◽  
Cross Sectional ◽  
Spontaneously Hypertensive ◽  
Long Term Effect ◽  
Inner Diameter

Alterations in geometry and structure of coronary arteries have marked consequences on blood flow to the respective area. We evaluated long-term effect of losartan on blood pressure (BP), heart weight/body weight (HW/BW), geometry and structure of septal branch of coronary artery (RS) of young SHR and Wistar rats. Four-week-old Wistar rats and SHR were used. Losartan was administered (20 mg/kg/day) in drinking water by gavage for 5 weeks. BP was measured by plethysmographic method. Cardiovascular system was perfused with a fixative (120 mm Hg). RS was processed for electron microscopy. Wall thickness of intima + media (WT), inner diameter (ID), cross-sectional area of intima + media (CSA), volume densities (VD) of endothelial cells (EC), extracellular matrix (ECM) of intima, smooth muscle cells (SMC) and ECM of media were evaluated. BP of 4-week-old SHR did not differ from that of Wistar rats. BP, HW/BW, WT, CSA, WT/ID, CSAs of SMC, ECM of media were increased in 9-weekold SHR, whereas their VD and CSA of EC were decreased. Losartan administration decreased BP and HW/BW in both groups. Geometry of RS was affected only in SHR (reduction of WT, CSA, WT/ID and increased of ID, circumferential tension, VD and CSA of EC). Losartan administration reduced BP and myocardial mass in both groups and beneficially affected geometry and structure of coronary artery in SHR.

scholarly journals Long-term Effect of Water Pollutants (Heavy Metals) on the Morphofunctional State of the Adult Rat's Pituitary Gland

2021 ◽  
Vol 6 (4) ◽  
pp. 172-178
Author(s):  
N. B. Hryntsova ◽  
◽  
A. M. Romanyuk
Keyword(s):  
Heavy Metals ◽  
Drinking Water ◽  
Pituitary Gland ◽  
Adult Male ◽  
The Body ◽  
Male Rats ◽  
Structural Components ◽  
Experimental Animals ◽  
Experimental Group

In some northern regions of Ukraine there is an increased accumulation of salts of heavy metals in soil and drinking water, which negatively affect the health of the population and become a risk factor for many diseases. The role of the pituitary gland in the regulation of functional disorders of hormonal homeostasis in various pathological conditions is extremely important. The purpose of the study is to study the morphological, morphometric and biochemical rearrangements of the structural components of the adenohypophysis of adult male rats under conditions of long-term exposure to salts of heavy metals. Materials and methods. The experiment was performed on 24 white adult male rats, which were divided into 1 control and 1 experimental group. The experimental group consisted of rats, which for 90 days consumed ordinary drinking water, saturated with a combination of salts of heavy metals: zinc (ZnSO4 · 7H2O) – 5 mg/l, copper (CuSO4 · 5H2O) – 1 mg/l, iron (FeSO4) – 10 mg/l, manganese (MnSO4 · 5H2O) – 0.1 mg/l, lead (Pb (NO3) 2) – 0.1 mg/l and chromium (K2Cr2O7) – 0.1 mg/l. Results and discussion. Long-term effects on the body of experimental animals of salts of heavy metals caused a pronounced compensatory-adaptive changes in the pituitary gland of experimental animals of hypoxic nature. Morphological changes in the organ were accompanied by plethora of venous bed, deterioration of rheological properties of blood, increase in the area of connective tissue component of the gland, violation of histoarchitectonics of epithelial trabeculae, edema in the parenchyma, increase in linear indicators of the pituitary gland. Toxic effects of salts of heavy metals negatively affected the cellular composition of the adenohypophysis: there was an increase in the number of chromophobes and a decrease in the number of chromophilic acidophiles and basophils compared with control animals. At the same time, the increase in linear parameters, area of nuclei and cytoplasm of adenocytes can be attributed both to their compensatory hypertrophy and due to edema processes in the gland caused by deepening hypoxic effects and impaired blood flow from the organ as a result of venous plethora. Conclusion. Morphometric and biochemical parameters of the structural components of the anterior lobe of the adenohypophysis at 90 days of exposure to salts of heavy metals, of course, indicate a significant stress of adaptive processes by the adenohypophysis in response to stressors (salts of heavy metals)

scholarly journals Resistance to Remnant Nephropathy in the Wistar-Furth Rat

1999 ◽  
Vol 10 (4) ◽  
pp. 814-821
Author(s):  
WAYNE R. FITZGIBBON ◽  
EDDIE L. GREENE ◽  
JASJIT S. GREWAL ◽  
FLORENCE N. HUTCHISON ◽  
SALLY E. SELF ◽  
...  
Keyword(s):  
Renal Injury ◽  
Renal Mass ◽  
Wistar Rats ◽  
Renal Damage ◽  
Mass Reduction ◽  
Mesangial Proliferation ◽  
Antihypertensive Regimen ◽  
Renal Ablation ◽  
Study Support ◽  
And Control

Abstract. The Wistar-Furth rat, an inbred strain resistant to actions of mineralocorticoids, was used to study the concept that mineralocorticoids contribute to progressive renal injury. It was postulated that if chronic nephropathy depends on aldosterone and if Wistar-Furth rats are resistant to aldosterone, remnant nephropathy would be attenuated in Wistar-Furth rats. Wistar-Furth rats and control Wistar rats were subjected to 5/6 nephrectomy or a sham procedure and then followed for 4 wk. Renal ablation resulted in hypertension at 4 wk in both strains (164 ± 5 [Wistar-Furth] versus 184 ± 7 [Wistar] mmHg mean arterial pressure), with sham animals remaining normotensive (134 ± 6 mmHg). Renal damage in response to 5/6 nephrectomy was greatly decreased in Wistar-Furth rats compared with Wistar rats. Albuminuria was markedly less in Wistar-Furth rats (12.7 ± 4.2 [Wistar-Furth] versus 97.4 ± 22.6 [Wistar] mg/d per 100 g body wt, P < 0.01). Glomerular damage, consisting of mesangial proliferation, mesangial lysis, and segmental necrosis, was observed in 42% of glomeruli from Wistar rats but in 0% of glomeruli from Wistar-Furth rats (P < 0.01). To address the possibility that higher BP in partially nephrectomized Wistar rats mediated the greater renal damage, the study was repeated, with Wistar rats (not Wistar-Furth rats) being treated with a hydralazine-reserpine-hydrochlorothiazide regimen. Although this antihypertensive regimen equalized BP (conscious systolic) (144 ± 8 mmHg [Wistar] versus 157 ± 7 mmHg [Wistar-Furth] at 4 wk), albuminuria remained more than 10-fold greater in Wistar rats. In summary, renal damage upon 5/6 nephrectomy was markedly reduced in Wistar-Furth rats, a finding not attributable to reduced systemic BP. Since Wistar-Furth rats have been shown previously to be resistant to the actions of mineralocorticoids, the data from the present study support the hypothesis that aldosterone mediates, at least in part, the renal injury attendant to renal mass reduction.

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