Age-matched Male Rats Research Articles

Beneficial effects of nebivolol and hydrochlorothiazide combination in spontaneously hypertensive rats

This study examined the combined effect of nebivolol (NEB) and hydrochlorothiazide (HCTZ) on cardiovascular function in spontaneously hypertensive rats (SHR). SHR normotensive male rats were randomly assigned to five groups (n = 8 per group): (i) SHR control group; (ii) NEB 2 mg/kg per day group; (iii) HCTZ 10 mg/kg per day group; (iv) NEB 2 mg/kg per day + HCTZ 10 mg/kg per day group; (v) Eight age-matched Wistar-Kyoto normotensive male rats served as the control group. All groups were treated orally for 8 weeks. The combination of NEB + HCTZ synergistically reduced systolic blood pressure and heart rate compared with either monotherapy. HCTZ increased water intake, which is a sign of diuresis. NEB reduced plasma angiotensin II concentration, which was increased in SHR and after HCTZ treatment. NEB + HCTZ increased plasma nitric oxide (NO) concentration and NO synthase activity, which were both reduced in SHR. NEB + HCTZ normalized femoral arterial vasorelaxation induced by acetylcholine, which was impaired in SHR. The combination of NEB + HCTZ provided a number of beneficial and additive effects due to the synergistic characteristics of both drugs, in an experimental rat model of hypertension.

An MRI-Histological Study of White Matter in Stroke-Free SHRSP

Hypertension is associated with cerebral small vessel disease (SVD) and with diffuse white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging (MRI). We tested whether stroke-prone spontaneously hypertensive rats (SHRSP), a model of chronic hypertension, exhibit WMH. Male SHRSP (age 10 months) without stroke symptoms were compared with age-matched male WKY rats. Stroke-prone spontaneously hypertensive rats exhibited no WMH on MRI scans (T2, T2*, diffusion tensor imaging) and no neuropathological lesions. While leptomeningeal arteries exhibited fibrohyaline wall thickening, with decreased smooth muscle actin relative to WKY, deep penetrating arterioles within the caudate nuclei had no vasculopathy. We conclude that WMH are not an obligate feature of stroke-free SHRSP aged up to 10 months.

Gender differences in the development of uremic cardiomyopathy following partial nephrectomy: Role of progesterone

Gender difference has been suggested as a risk factor for developing cardiovascular and renal diseases in humans and experimental animals. As a major sex hormone, progesterone was reported to compete with cardiotonic steroid binding to Na/K-ATPase. Our previous publication demonstrated that cardiotonic steroids (e.g., marinobufagenin) play an important role in the development of experimental uremic cardiomyopathy. We also observed that the putative mineralocorticoid antagonists, spironolactone and its major metabolite canrenone, antagonize binding of cardiotonic steroids to Na/K-ATPase in a competitive manner and also ameliorate experimental uremic cardiomyopathy induced by partial nephrectomy. In the following studies, we noted that progesterone displayed competitive inhibition of cardiotonic steroid binding to Na/K-ATPase and partially inhibited collagen synthesis induced by marinobufagenin in cultured cardiac fibroblasts. Therefore, we sought to examine whether female rats displayed less uremic cardiomyopathy than male rats when subjected to partial nephrectomy. Although partial nephrectomy caused the induction of smaller increases in blood pressure of female rats, they appeared to be similarly susceptible to cardiac remodeling induced by partial nephrectomy in terms of hypertrophy and fibrosis as age-matched male rats. The possible explanations for our findings are therefore discussed.

Effects of the dual PPAR‐α/γ agonist aleglitazar on glycaemic control and organ protection in the Zucker diabetic fatty rat

To evaluate the effects of aleglitazar, a dual peroxisome proliferator-activated receptor-α/γ agonist, on the development of diabetes-related organ dysfunction, in relation to glycaemic and lipid changes, in Zucker diabetic fatty (ZDF) rats. Six-week-old, male ZDF rats received aleglitazar 0.3 mg/kg/day or vehicle as food admix for 13 weeks (n = 10 per group). Age-matched male Zucker lean rats served as non-diabetic controls. Plasma and renal markers were measured at several time points. Histopathology and quantitative immunohistochemistry were performed at 13 weeks. Glycated haemoglobin (5.4 vs. 9.2%) and blood glucose (8.3 ± 0.3 vs. 26.1 ± 1.0 mmol/l) were significantly reduced at 12 weeks with aleglitazar versus vehicle-treated ZDF rats (both p < 0.01), while aleglitazar preserved near-normal plasma insulin levels. Aleglitazar prevented the development of hypertriglyceridaemia (1.4 ± 0.1 vs. 8.5 ± 0.9 mmol/l) and reduced plasma non-esterified fatty acids (0.09 ± 0.02 vs. 0.26 ± 0.04 mmol/l) relative to vehicle-treated animals (both p < 0.01). Urinary glucose and protein concentrations were significantly reduced at 13 weeks with aleglitazar versus vehicle-treated rats (both p < 0.01). Consistent with its effect on glycaemic control, aleglitazar protected β-cell morphology, as evidenced by preservation of islet integrity, and reduction of β-cell apoptosis and islet fibrosis. Aleglitazar prevented renal glomerular hypertrophy, podocyte degeneration, glomerulosclerosis, tubulo-interstitial lesions and development of cataracts. Aleglitazar strongly improved glycaemic and lipid parameters while protecting key tissues, including the pancreas, kidneys and eyes, against diabetes-associated structural and functional changes in the ZDF rat.

PMO-129 Relaxin reduces portal hypertension through stimulation of hepatic nitric oxide production

IntroductionWe have previously reported that the multifunctional hormone relaxin (RLX) downregulated the activation state and contractility of hepatic myofibroblasts and reduced portal hypertension (PHT) in cirrhotic rats (Fallowfield J et...

Female rats are relatively more sensitive to reduced lipid versus reduced carbohydrate availability

Objectives:Because females have blunted counterregulatory responses to hypoglycemia relative to males, we hypothesized that females would have greater sensitivity to changes in lipid availability.Design and subjects:To assess this, we examined the feeding response to glucoprivation (2-deoxyglucose; 2DG) and lipoprivation (mercaptoacetate; MA) in age-matched male and female Long-Evans rats.Results:Males versus females had significantly greater food intake after 250 mg kg−1 of 2DG, but there were no sex differences with the 750 mg kg−1 dose of 2DG. Glucose responses to 250 mg kg−1 of 2DG were also significantly greater in males versus females. In contrast, females had a significant increase in food intake with all doses of MA versus saline, and had significantly greater food intake compared with males at the lowest and highest doses of MA with a trend towards significance with the intermediate dose. To determine whether estradiol (E2) is the mechanism underlying this sexual dimorphism, ovariectomized females were injected with vehicle or 2 μg of E2 every fourth day to mimic the variations in across the estrous cycle. Ovariectomized females significantly increased feeding and glucose after 250 mg kg−1 of 2DG over intact females and E2 had no effect on these responses. Although the feeding response to 2DG was not different, the glucose response to 2DG was still significantly greater in males versus ovariectomies females. However, ovariectomized females also did not increase food intake after MA, regardless of E2 treatment.Conclusions:These data collectively suggest that males are relatively more sensitive to glucose deprivation and females are relatively more sensitive to lipid deprivation. Further, these data rule out a role for cyclic changes in E2 in these sex differences.

Chronic exercise partially restores the transmural heterogeneity of action potential duration in left ventricular myocytes of spontaneous hypertensive rats

Hypertension leads to electrophysiological changes in the heart. Chronic exercise induced by a treadmill-running programme (TRP) is considered a potential non-pharmacological treatment for hypertension and may have implications in heart remodelling. However, it is not known whether the TRP is able to improve the electrophysiological properties of the heart in spontaneously hypertensive rats (SHR). In the present study, we investigated whether TRP affects the electrical properties of left ventricular (LV) myocytes isolated from different layers of the LV wall of SHR. Male SHR were divided into exercised (chronic treadmill running for 8 weeks; CEX-SHR) and sedentary (SED-SHR) groups. Age-matched normotensive Wistar male rats served as controls. Action potentials (AP) and transient outward potassium current (I(to) ) were recorded in subepicardial (EPI) and subendocardial (ENDO) LV myocytes. In normotensive controls, AP duration (APD) was longer in ENDO cells than in EPI cells. This sort of transmural heterogeneity in the LV was not observed in sedentary SHR and was partially restored in SHR subject to chronic exercise. This partial recovery was associated with an increase in I(to) density in EPI cells but not in ENDO cells. The electrophysiological changes observed in the CEX-SHR group were not accompanied by either amelioration of systolic blood pressure or a reduction in heart hypertrophy. These findings imply that a TRP is able to improve the electrophysiological parameters of isolated cardiac myocytes in SHR. This sort of adaptation contributes to the overall improvement of heart physiology in this model.

Orexin-1 Receptor Mediation of Cocaine Seeking in Male and Female Rats

Previous studies have shown that female rats exhibit enhanced cocaine seeking during multiple phases of cocaine addiction compared with males. The orexin/hypocretin system recently has been implicated in drug addiction in male rats. Based on the known sex differences in cocaine addiction, in the current study we examined orexin-mediated cocaine seeking during self-administration, extinction, and reinstatement in age-matched male (initial weight 250-300 g) and female (initial weight 175-225 g) Sprague-Dawley rats by using the orexin-1 receptor (OX1R) antagonist 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea (SB-334867) (10-30 mg/kg). OX1R blockade had no effect on established cocaine self-administration, but attenuated cocaine seeking during extinction in both male and female rats. It is noteworthy that OX1R blockade potently attenuated cue-induced reinstatement in males but had no effect on females. SB-334867 also reduced cocaine seeking during pharmacological stress-induced (yohimbine, 2.5 mg/kg) and yohimbine + cue-induced reinstatement in both sexes. SB-334867 failed to affect reinstatement induced by cocaine (10 mg/kg) in either male or female rats, but selectively reduced cocaine + cue-induced reinstatement only in males. In separate experiments examining basal and cocaine-induced locomotion, SB-334867 attenuated locomotion in both male and female rats. Finally, assessment of plasma and brain levels of SB-334867 showed that estrus females had slightly higher plasma levels than diestrus females, but no overall sex differences or estrous cycle differences were observed in plasma or brain SB-334867 concentrations. These results show that OX1R signaling plays a role in mediating cocaine seeking, but differs between the sexes for cue-induced reinstatement.

Ginsenosides-Rbl exerts beneficial effects on left ventricular dysfunction and remodelling early after myocardial infarction

ObjectivesThe aim of this study was to investigate whether Ginsenosides-Rbl (Gs-Rb1) has improved left ventricular (LV) dysfunction and remodelling early after myocardial infarction (MI).MethodsSixty male 8-week-old Wistar mice with extensive...

Nicotine-induced conditioned place preference in adolescent rats

A number of clinical reports have noted that women are more vulnerable to tobacco abuse than men, and adolescent females are especially vulnerable to nicotine addiction. Conditioned place preference (CPP) is a widely used technique for determining the rewarding effects of drugs with abuse potential in animal models. Several studies have reported that nicotine was ineffective in eliciting CPP in rats; while others have observed conditioned place aversion (CPA) rather than preference for nicotine. One recent investigation established CPP in adolescent female rats, however at a reasonably high dose; while a second reported dose dependence of nicotine-induced CPP in male but not female rats. The present study was designed to determine the lowest dose necessary to induce CPP to nicotine in adolescent female rats. Nicotine-induced CPP was obtained at a subcutaneous dose of 0.03mg/kg (salt content) using a biased conditioning paradigm. Higher doses produced aversion and lower doses provided no rewarding or aversive effects. CPP persisted for at least 3weeks following conditioning in the absence of further nicotine treatment. In contrast with results from adolescent human females and males, age-matched male rats also evidenced CPP at this very low dose of nicotine. These results indicate that even a low dose of nicotine is reinforcing and addicting in both adolescent male and female rats and brings into question the suggestion that nicotine induces greater addicting capacity in adolescent girls than boys.

Increase of Anteroventral Periventricular Kisspeptin Neurons and Generation of E2-Induced LH-Surge System in Male Rats Exposed Perinatally to Environmental Dose of Bisphenol-A

Perinatal exposure to environmental levels of bisphenol-A (BPA) impairs sexually dimorphic behaviors in rodents. Kisspeptin neurons in anteroventral periventricular nucleus (AVPV), which plays an important role in the activation of GnRH neurons and the initiation of LH-surge, have been suggested to be sexual dimorphism in rats. This study focused on exploring the influence of a perinatal exposure to an environmental dose of BPA on the development and maturation of male AVPV kisspeptin neurons and hypothalamus-pituitary-gonadal axis. Female rats were injected sc with 2 μg BPA/kg·d from gestation d 10 through lactation d 7. Anatomical and functional changes in AVPV kisspeptin neurons and hypothalamus-pituitary-gonadal axis were examined in prepubertal, pubertal, and adult male rats exposed perinatally to BPA (BPA-rats). Here, we show that in postnatal d (PND)30/50/90 BPA-rats, the number of AVPV kisspeptin-immunoreactive cells was persistently increased in comparison with age-matched control male rats. The number of GnRH-immunoreactive cells in PND30 BPA-rats declined approximately 40% compared with control male rats, whereas that in PND50/90 BPA-rats was increased in a G protein-coupled receptor 54-dependent manner. Estradiol could induce a stable LH-surge in PND90 BPA-rats and control female rats, which was sensitive to the G protein-coupled receptor 54 inhibitor. In PND30/50 BPA-rats, plasma level of LH was higher, but the level of testosterone was lower than control male rats. These findings provide evidence that perinatal exposure to an environmental dose of BPA causes a sustained increase in AVPV kisspeptin neurons in male rats, leading to the generation of estradiol-induced LH-surge system.

Effects of Triclocarban on Intact Immature Male Rat: Augmentation of Androgen Action

Triclocarban (TCC; 3,4,4'-trichlorocarbanilide) is an antimicrobial agent used widely in various personal hygiene products including soaps. Recently, TCC has been shown to enhance testosterone-induced effects in vitro and to enlarge accessory sex organs in castrated male rats. This study was designed to evaluate the effects of TCC on intact age-matched male rats and on human prostate LNCaP and C4-2B cells. Seven-week-old male Sprague-Dawley rats received either a normal diet or a diet supplemented with TCC (0.25% in diet) for 10 days. Triclocarban induced hyperplasia of accessory sex organs in the absence of significant qualitative histological changes. Serum luteinizing hormone (LH) and testosterone were not significantly altered by TCC treatment. In prostate cancer-derived LNCaP and C4-2B cells, TCC potentiated androgen actions via androgen receptor-dependent actions. In conclusion, TCC significantly affects intact male reproductive organs and potentiates androgen effects in prostate cancer cells.

The antihypertensive effect of ethyl acetate extract from red raspberry fruit in hypertensive rats

Objectives:To evaluate the antihypertensive effect of Xinjiang red raspberry fruit ethyl acetate extract (EER) on spontaneously hypertensive rats (SHR) and its possible mechanism from antioxidant perspective.Materials and Methods:The SHR rats were randomly divided into 3 groups, and treated with EER low dose (EERL, 100 mg/kg/d), high dose (EERH, 200 mg/kg/d), and water (SHR) through gastric gavage daily for 5 weeks. Another 8 age-matched male Wistar–Kyoto rats were used as normotensive group (WKY). The systolic blood pressure (SBP) was measured by noninvasive tail-cuff method once a week. At the end of the treatment, blood samples were collected and serum concentrations of nitric oxide (NO), superoxide dismutase (SOD), malondialchehyche (MDA), and plasma endothelin (ET) were determined.Results:Treatment of SHR rats with EER lowered the blood pressure compared with that treated with water (SHR), and the high dose showed more significant reduction in blood pressure. Treatment of SHR rats with EER increased serum NO and SOD levels and lowered ET and MDA levels. As compared with control group, NO levels were increased significantly in EERL (P < 0.01), SOD was elevated more significantly in both EERL and EERH (P < 0.01); MDA was decreased significantly in EERH group (P < 0.05), whereas plasma ET decreased more significantly in the EERH group (P < 0.05).Conclusions:The red raspberry extracts demonstrated a dose-dependent antihypertensive effects in SHR and this may be related to increased NO activation and improved vascular endothelial dysfunction via antioxidation. These results confirmed that raspberries rich in polyphenols have potential cardiovascular protective effects.

Nebivolol Attenuates Redox-Sensitive Glomerular and Tubular Mediated Proteinuria in Obese Rats

Obesity and insulin resistance-related proteinuria is associated with oxidative stress and impaired tissue bioavailable nitric oxide. Recent data suggest that nicotinamide adenine dinucleotide phosphate oxidase-mediated oxidative injury to the proximal tubule, like that seen in the glomerulus, contributes to proteinuria in insulin-resistant states. The vasodilator β-blocker nebivolol reduces nicotinamide adenine dinucleotide phosphate oxidase activity, increases bioavailable nitric oxide, and improves insulin sensitivity. To test the hypothesis that a treatment strategy that reduces oxidative stress and attenuates obesity-associated increases in glomerular and proximal tubule derived protein, we treated young Zucker obese (ZO) and age-matched Zucker lean male rats with nebivolol (10 mg · kg(-1) · d(-1)) for 21 d. Compared with Zucker lean, ZO controls exhibited increased proteinuria and γ-glutamyl transpeptidase, reductions in systemic insulin sensitivity in association with increased renal renin, (pro)renin receptor, angiotensin II type 1 receptor, and mineralocorticoid receptor immunostaining, oxidative stress, and glomerular tubular structural abnormalities that were substantially improved with in vivo nebivolol treatment. Nebivolol treatment also led to improvements in glomerular podocyte foot-process effacement and improvement in podocyte-specific proteins (nephrin and synaptopodin) as well as proximal tubule-specific proteins (megalin and lysosomal-associated membrane protein-2) and proximal tubule ultrastructural remodeling in the ZO kidney. Our findings support the notion that obesity and insulin resistance lead to increased glomerulotubular oxidative stress and resultant glomerular and tubular sources of excess urine protein. Furthermore, the results of this study suggest the beneficial effect of nebivolol on proteinuria was derived from improvements in weight and insulin sensitivity and reductions in renal oxidative stress in a state of obesity and insulin resistance.

S1819 PKCɛ: A Critical Mediator of Mitochondria-Dependent Cell Death in Acute Pancreatitis

properties of colon specific DRG neurons. Results: We found that the visceromoter response to CRD in 6-to-8 week old female rats was significantly greater than that in age-matched male Sprague-Dawley rats (p<0.05 at 30, 40 and 50 mmHg). Patch clamp recordings showed significant differences between the colon-specific DRG neurons from female and male rats. The membrane input resistance in female DRG neurons was significantly lower than that in male DRG neurons (195±27 vs 424±54 Mohm, p<0.05); action potential duration and action potential threshold of DRG neurons were significantly greater in females than those in males (6.0±0.7 vs 3.6±0.5 msec, and -15.8±1.3 vs -22.3±1.4 mV, respectively, p<0.05). We obtained colon-specific DRG neurons 24-hours after daily treatment of male rats with i.m. progesterone (10mg/kg) for seven-days. Progesterone treatment significantly depolarized the resting membrane potential (-59±1 vs -51±1mV, p<0.05), increased input resistance (424±54 vs 872±88Mohm, p<0.05), decreased rheobase (0.42±0.05 vs 0.09±0.01 nA, p<0.05), increased action potential duration (3.6±0.5 vs 5.2±0.3msec, p<0.05) and decreased action potential threshold (-22.3±1.4 vs -26.6±1.0 mV, p<0.05). All these changes in the active and passivemembrane properties of DRGneurons indicate an increase in the excitability of DRG neurons. In support of this, we found that the visceromoter response to CRD was significantly greater in male rats 24-hours after 7-days of daily treatment with PG, when compared with baseline (p<0.05). However, the visceromoter response returned to normal range 7-days after the end of progesterone treatment. Conclusions: We conclude that the baseline visceromoter response to colorectal distension in female rats is greater than that in age-matched male rats. Daily treatment of male rats with exogenous PG sensitizes the DRG neurons and enhances the visceromoter response. The female sex hormone progesterone may be one of the factors that promote visceral hypersensitivity in females predisposing them to a higher incidence of visceral pain.

S1822 Inhibition of BMP/SMAD1/5/8 Signaling Pathway Deteriorates Cerulein-Induced Acute Pancreatitis

properties of colon specific DRG neurons. Results: We found that the visceromoter response to CRD in 6-to-8 week old female rats was significantly greater than that in age-matched male Sprague-Dawley rats (p<0.05 at 30, 40 and 50 mmHg). Patch clamp recordings showed significant differences between the colon-specific DRG neurons from female and male rats. The membrane input resistance in female DRG neurons was significantly lower than that in male DRG neurons (195±27 vs 424±54 Mohm, p<0.05); action potential duration and action potential threshold of DRG neurons were significantly greater in females than those in males (6.0±0.7 vs 3.6±0.5 msec, and -15.8±1.3 vs -22.3±1.4 mV, respectively, p<0.05). We obtained colon-specific DRG neurons 24-hours after daily treatment of male rats with i.m. progesterone (10mg/kg) for seven-days. Progesterone treatment significantly depolarized the resting membrane potential (-59±1 vs -51±1mV, p<0.05), increased input resistance (424±54 vs 872±88Mohm, p<0.05), decreased rheobase (0.42±0.05 vs 0.09±0.01 nA, p<0.05), increased action potential duration (3.6±0.5 vs 5.2±0.3msec, p<0.05) and decreased action potential threshold (-22.3±1.4 vs -26.6±1.0 mV, p<0.05). All these changes in the active and passivemembrane properties of DRGneurons indicate an increase in the excitability of DRG neurons. In support of this, we found that the visceromoter response to CRD was significantly greater in male rats 24-hours after 7-days of daily treatment with PG, when compared with baseline (p<0.05). However, the visceromoter response returned to normal range 7-days after the end of progesterone treatment. Conclusions: We conclude that the baseline visceromoter response to colorectal distension in female rats is greater than that in age-matched male rats. Daily treatment of male rats with exogenous PG sensitizes the DRG neurons and enhances the visceromoter response. The female sex hormone progesterone may be one of the factors that promote visceral hypersensitivity in females predisposing them to a higher incidence of visceral pain.

Urinary excretion of angiotensinogen in male and female Sprague Dawley rats during angiotensin II infusion and high salt diet

We have found that urinary angiotensinogen (AGT) excretion (uAGT) differs between male(♂)and female(♀) Sprague Dawley (SD) rats on a normal salt diet (♂: 60±26 vs ♀: 4.5 ±0.2ng/day, p&lt;0.05). In this study, we examined if the effects of a high salt (HS) diet on uAGT exhibits sexual dimorphism during Angiotensin (ANG) II dependent hypertension. Four groups of age‐matched (8 weeks) male (n= 20) and female (n=17) SD rats were studied: 1) high salt diet (HS; 8%NaCl); 2) ANG II (80ng/min, sc; for 14 days); 3) ANG II + HS; 4) ANG II + HS + Candesartan. (CAND, 25 mg/L in drinking water). uAGT levels were measured by enzyme immunoassay. HS diet alone did not raise uAGT levels (♂: 107±23 vs. ♀: 5±2ng/day) from baseline; however, AGT increased significantly during ANG II infusion (♂: 1107±1061 vs ♀: 206±74ng/day, p&lt;0.01) and was augmented even further in ANG II + HS (♂: 4363±1673 vs. ♀: 8022±1300ng/day, p=ns). Candesartan ameliorated this effect with a better response in female than in male rats.(♂: 240±28 vs. ♀: 10±4 ng/day, p&lt; 0.01). The results demonstrate a sexual dimorphism in the uAGT excretion rate during baseline conditions and HS diet characterized by higher levels in the males. The augmentation of uAGT with HS + ANG II is ameliorated more effectively by ARB treatment in female ANG II hypertensive rats than in males.NIH (P20 RR 017659), Tulane‐BIRCWH (K12HD043451)

Blood pressure independent sexual dimorphism in proteinuric response to high salt intake in Sprague‐Dawley rats.

We examined if changes in blood pressure and proteinuria during chronic salt intake exhibit sex disparities in age‐matched male (♂; N=10) and female (♀; N=10) Sprague‐Dawley (SD) rats subjected to either normal (0.7% NaCl) or high salt (8% NaCl) diets for 2‐weeks. Metabolic studies, systolic blood pressures (SBP) measured by tail‐cuff method and proteinuria in 24‐h urine samples, were performed. Baseline SBP was not different between genders (♂:119.1±3 vs. ♀:119.0±4 mmHg) or after 2‐weeks on HS diet (♂:129.0±5 vs. ♀:125.6±6 mmHg). HS intake induced proteinuria in both sexes; however it was greater in male than in female rats [Day ‐1(♂:5±1 vs. ♀:3±1); Day 9 (♂:36±3 vs. ♀:17±2 mg/day); p&lt;0.01]. By day 13, body weights were higher in ♂ than ♀ rats; however there was no difference with salt load [(male NS: 330±8 versus male HS: 324±7 g); ♀ NS: 217±12 vs. ♀ HS: 226±4 g)]. There were no sex dependent differences in food intake after it factored by body weight (♂ NS: 11±1 g/kg BW; ♂ HS: 12±1 g/kg BW; female NS: 11±2 g/kg BW; female HS: 13±1 g/kg BW; p=no significant). SBP under HS intake did not exhibit sexual dimorphism; however the augmented proteinuria in male rats may reflect a greater predisposition to develop renal injury with high salt consumption than female rats.Grants from the APS (2009 Frontiers in Physiology Research Host Awardees Program); NIH (P20‐RR‐017659; Tulane‐BIRCWH K12HD043451 award).

Cisplatin increases urinary sodium excretion in rats: gender-related differences

OBJECTIVE. There are well-documented reports of cisplatin-associated hyponatremia in the literature, but there are no data on gender-dependent differences. The aim of the present study was to define characteristics of 24-hour urinary sodium excretion in young adult Wistar rats of both genders and to evaluate the gender-related effect of cisplatin. MATERIALS AND METHODS. Twelve control Wistar rats (6 males and 6 females) and 12 cisplatin-treated Wistar rats (6 males and 6 females) after a single and repeated injection of cisplatin (once a day for 3 days) at a dose of 2.5 mg/kg body weight into the caudal vein were examined. The experiment was carried out by measuring 24-h urinary sodium, potassium, chloride, magnesium, creatinine excretion and pH in the urine of age-matched male and female rats. RESULTS. The 24-h urinary sodium excretion, sodium/chloride ratio, and diuresis showed no gender-related differences in control rats. After a single administration of 2.5 mg/kg cisplatin, 24-h urinary sodium excretion was not significantly higher in cisplatin-treated rats than in gender-matched controls. After repeated cisplatin administration, 24-h urinary sodium excretion was significantly higher in cisplatin-treated male rats as compared to matched controls (P<0.05). No such effect was found in cisplatin-treated female rats. CONCLUSION. The study data show that cisplatin enhances urinary sodium excretion in male but not in female rats. The mechanism of such a gender-related effect is not yet clear. Further investigations are necessary to elucidate the mechanism of this pharmacological effect of cisplatin.

Sex-Specific Role of Thioredoxin in Neuroprotection Against Iron-Induced Brain Injury Conferred by Estradiol

Accumulation of iron after intracerebral hemorrhage causes free radical formation and oxidative damage resulting in liquefaction. The aim of this study was the investigation of molecular mechanisms underlying estrogen-mediated neuroprotective effect against iron-induced brain injury in vivo. Age-matched male and female Sprague-Dawley rats were stereotaxically infused with either ferrous citrate (FC) or saline (10 muL) into the right caudate nucleus. Beta-estradiol 3-benzoate (E(2)) capsule was implanted subcutaneously at 24 hours before infusion of FC. The severity of brain injury and neurological deficits were measured by histological quantification and forelimb asymmetry test, respectively. The role of thioredoxin (Trx) in E(2)-mediated neuroprotective effect was examined by intrastriatal administration of a Trx reductase inhibitor, 5,5-dithiobis-(2-nitrobenzoic acid), and small interfering RNA. FC induced greater brain injury in male rats than females. E(2) treatment reduced FC-induced brain injury in both sexes. E(2) significantly increased protein level and activity of Trx in the caudate nucleus of females but not males. Administration of female rats with 5,5-dithiobis-(2-nitrobenzoic acid) or Trx small interfering RNA to the caudate nucleus decreased the protective effect of E(2) against FC-induced injury. The protein and mRNA levels of estrogen receptor alpha, but not estrogen receptor beta, were more abundant in the caudate nucleus of female rats. Increase of brain Trx activity might play an important role in the E(2)-mediated neuroprotective effect against FC-induced brain injury in female rats. Understanding of the sex differences in the Trx-mediated neuroprotective effect by E(2) might help in improving treatment of brain dysfunction after hemorrhagic stroke and/or head trauma.