Male gender increases sensitivity to proteinuria induced by mild NOS inhibition in rats: role of sex hormones

Men are at greater risk for renal injury than women. We studied whether male rats are more sensitive to the hypertensive and proteinuric effects of chronic nitric oxide sythase (NOS) inhibition than female rats. In addition, we studied whether androgens or estrogens are responsible for differences in sensitivity to proteinuria induced by chronic NOS inhibition. Females and males were treated with 10, 20, 30, and 100 mg/l N ω-nitro-l-arginine (l-NNA) during 24 wk. Systolic blood pressure (SBP) and proteinuria were measured regularly and compared with time-control measurements in control females and males. In females and males treatment with 10 mg/l l-NNA had no effect on SBP or proteinuria. Treatment with 20, 30, and 100 mg/l l-NNA resulted in a dose-dependent increase in SBP that was similar in males and females. However, females treated with 20 and 30 mg/ll-NNA were resistant to the development of proteinuria: maximum values were 16 ± 7 and 46 ± 21, respectively, vs. 16 ± 3 mg/day in controls, whereas males treated with those doses showed an increase in proteinuria [139 ± 35 ( P< 0.05) and 318 ± 82 ( P < 0.01), respectively, vs. 55 ± 11 mg/day in controls]. Treatment with 100 mg/ll-NNA increased proteinuria similarly in both females and males. To study the role of sex hormones in differences in sensitivity to proteinuria induced by mild chronic NOS inhibition, treatment with 20 mg/l l-NNA was repeated in ovariectomized (Ovx) and orchidectomized rats. Ovariectomy did not affect the increase in SBP caused by 20 mg/l l-NNA, but, in contrast to intact females, this dose of l-NNA did cause Ovx rats to develop proteinuria (51 ± 16 vs. 16 ± 7 mg/day in control Ovx rats; P < 0.05). Orchidectomy completely prevented the increased SBP as well as proteinuria induced by 20 mg/ll-NNA in male rats. In conclusion, male rats are more sensitive than female rats to develop proteinuria induced by mild chronic NOS inhibition. Estrogens provide some protection in females, whereas androgens are responsible for the increased sensitivity of male rats to proteinuria induced by mild chronic NOS inhibition. Risk factors associated with a compromised nitric oxide system may be more detrimental to the kidney in men than in women.

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The biochemical estimation of the nitric oxide system in prenatally stressed rats

Regional blood circulation and microcirculation ◽

10.24884/1682-6655-2021-20-3-61-69 ◽

2021 ◽

Vol 20 (3) ◽

pp. 61-69

Author(s):

L. E. Belyaeva ◽

H. N. Pauliukevich

Keyword(s):

Nitric Oxide ◽

Blood Serum ◽

Oxide System ◽

No Synthase ◽

Female Rats ◽

Male Rats ◽

Nitric Oxide Synthesis ◽

Chronic Unpredictable Stress ◽

Prenatally Stressed ◽

Nitric Oxide System

Introduction. Pregnancy development following unfavorable conditions could facilitate disorders of nitric oxide (NO) production during offspring’s postnatal life and «program» offspring’s cardiovascular diseases. Investigation of particular features and mechanisms of nitric oxide synthesis and action disorders following prenatal stress will promote expansion of considerations about pathogenesis of different cardiovascular diseases and propose new approaches to their prevention and management.The aim of the investigation is to assess the nature of nitric oxide synthesis and action in mature rats whose mothers were exposed to chronic «unpredictable» stress during pregnancy. Materials and methods. Pregnant rats were subdivided into the «control» and «stress» groups (in 20 animals). The rats from the «stress» group were exposed to multiple different stressors at various intervals, such as 1-day famine; 20-min. immobilization in the water at room temperature; 1-day contact with cats’ excrements. In the blood serum of 3-mo offspring (n=96, including «control» males – 24, «control» females – 26, «stress» males – 22, «stress» females – 24) concentration of the stable products of NO degradation – nitrates/nitrites (NO3–/NO2–), endothelial (eNOS) and inducible (iNOS) isoforms of the NO-synthase, inhibitor of NO-synthase asymmetric dimethylargininne (ADMA), cyclic guanosine monophosphate (cGMP), lipid peroxidation products – diene conjugates (DC) and malonic dialdehyde (MDA) and C-reactive protein (hsCRP) was detected. Results. The decrease of eNOS and cGMP concentration (by 12.9 and 31.9 %, respectively), increase of iNOS, hsCRP and ADMA concentration (by 49.9, 20.3 и 63.1 %, respectively) without statistically significant fluctuation in the NO3–/NO2– level and accumulation of DC and MDA by 21.1 % and 1.5 times in a prenatally stressed male rats’ blood serum were found (as compared with «control» male rats). In a blood serum of female rats, whose mothers were exposed to chronic «unpredictable» stress during pregnancy, a tendency to eNOS concentration decreasing, and increase of iNOS by 30.6 %, hsCRP by 23.9 % and MDA by 2.3 times without statistically significant changes in cGMP, ADMA, NO3–/NO2–, and DC concentration were detected (as compared with «control» female rats). Conclusion. Identified changes of the nitric oxide system synthesis and action in the prenatally stressed male rats could argue the high risk of their cardiovascular system lesion.

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Sex hormones and renal nitric oxide synthases.

Journal of the American Society of Nephrology ◽

10.1681/asn.v881240 ◽

1997 ◽

Vol 8 (8) ◽

pp. 1240-1246

Author(s):

J Neugarten ◽

Q Ding ◽

A Friedman ◽

J Lei ◽

S Silbiger

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Replacement Therapy ◽

Sex Hormones ◽

Estrogen Replacement Therapy ◽

Renal Medulla ◽

Female Rats ◽

Male Rats ◽

Intact Male ◽

Oxide Synthase

The present study was undertaken to determine whether sex hormones influence nitric oxide synthase levels in the kidney. Five groups of rats were studied: males, castrated males, females, oophorectomized females, and oophorectomized females receiving estradiol replacement therapy. Endothelial nitric oxide synthase (eNOS) levels in the kidney were measured by Western blotting. eNOS levels were significantly greater in the renal medulla of female rats compared with male rats (3545 +/- 473 versus 2418 +/- 205 densitometry units (DU), P < 0.05). Oophorectomy reduced renal medullary eNOS levels to that of intact male rats (2566 +/- 304 DU, P = NS). Estrogen replacement therapy significantly increased medullary eNOS levels in oophorectomized animals (3249 +/- 377 versus 2302 +/- 213 DU, P < 0.05). Renal inducible nitric oxide synthase (iNOS) levels were measured after induction with lipopolysaccharide. iNOS levels were significantly greater in the renal medulla of female rats compared with male rats (677 +/- 253 versus 252 +/- 12 DU, P < 0.05). Oophorectomy reduced renal medullary iNOS levels to that of intact male rats (295 +/- 57 DU, P = NS). In contrast, estrogen replacement therapy significantly increased medullary iNOS levels in oophorectomized animals (682 +/- 356 versus 160 +/- 92 DU, P < 0.05). Steady-state levels of mRNA for iNOS were found to be higher in the inner medulla of female rats compared with male rats (1519 +/- 211 versus 899 +/- 105 DU, P < 0.05). In contrast to these findings, sex hormones failed to influence nitric oxide production or iNOS levels in lipopolysaccharide-stimulated mesangial cells in culture. These results suggest that gender may influence renal medullary synthesis of nitric oxide.

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Inhibition of Nitric Oxide Synthase by L-NAME Promotes Cisplatin-Induced Nephrotoxicity in Male Rats

ISRN Toxicology ◽

10.1155/2013/242345 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 6

Author(s):

Fatemeh Moslemi ◽

Mehdi Nematbakhsh ◽

Fatemeh Eshraghi-Jazi ◽

Ardeshir Talebi ◽

Hamid Nasri ◽

...

Keyword(s):

Nitric Oxide ◽

Weight Loss ◽

Serum Levels ◽

Female Rats ◽

Male Rats ◽

Group 2 ◽

Synthase Inhibitor ◽

Oxide Synthase ◽

Group 1

Objective. Nitric oxide (NO) has numerous important functions in the kidney. The role of NO in cisplatin (CP)-induced nephrotoxicity is not completely understood. This study was designed to determine the role of NO synthase inhibitor (L-NAME) on the severity of CP-induced nephrotoxicity in rats. Methods. Sixty four male (M) and female (F) Wistar rats were randomly divided into eight groups. The sham groups (group 1, male, n=6 and group 2, female, n=6) received saline. Groups 3 (male, n=8) and 4 (female, n=8) were treated with L-NAME (4 mg/kg, i.p.), and groups 5 (male, n=8) and 6 (female, n=8) received CP (3 mg/kg) for 7 days. Groups 7 (male, n=8) and 8 (female, n=8) were treated with L-NAME and CP for 7 days. Results. The CP-alone treated rats showed weight loss and increase in serum levels of blood urea nitrogen (BUN) and creatinine (Cr). Coadministration of L-NAME and CP did not improve weight loss, and it increased the levels of BUN and Cr in male but not in female rats (P<0.05). CP alone increased kidney damage significantly (P<0.05 ), however, the damage induced by combination of CP and L-NAME was gender-related. Conclusion. NOS inhibition by L-NAME increased CP-induced nephrotoxicity, which was gender-related.

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Gender difference in flow-induced dilation and regulation of shear stress: role of estrogen and nitric oxide

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.5.r1571 ◽

1998 ◽

Vol 275 (5) ◽

pp. R1571-R1577 ◽

Cited By ~ 32

Author(s):

An Huang ◽

Dong Sun ◽

Akos Koller ◽

Gabor Kaley

Keyword(s):

Nitric Oxide ◽

Shear Stress ◽

Gender Difference ◽

Peripheral Resistance ◽

Female Rats ◽

Male Rats ◽

Ovariectomized Rats ◽

Perfusate Flow ◽

Male Wistar Rats

Previous studies show that agonist-induced, nitric oxide (NO)-mediated arteriolar dilations are greater in female than in male rats. Thus we hypothesized that flow-dependent arteriolar dilation, which is in part mediated by NO, is also greater in females than in males. Gracilis muscle arterioles from 12-wk-old female and male Wistar rats were isolated, cannulated, and pressurized. At 80 mmHg of perfusion pressure, the active diameter and passive diameter (PD) of arterioles of female and male rats were 58.3 ± 3.4 and 53.2 ± 2.6 μm as well as 103.6 ± 4.0 and 115.3 ± 4.8 μm, respectively. Dilations to step increases in perfusate flow from 0 to 25 μl/min were significantly greater in arterioles of female rats and ovariectomized rats with estrogen replacement (OVE) than in male and ovariectomized female (OV) rats (98.6 ± 0.6 and 97.4 ± 1.1% vs. 72.6 ± 3.3 and 72.5 ± 3.6% of PD at 25 μl/min). Calculation of wall shear stress (WSS) revealed that the maintained WSS was significantly lower in arterioles of female than in those of male rats (∼20 vs. ∼35 dyn/cm2). After indomethacin pretreatment, N ω-nitro-l-arginine methyl ester (l-NAME; 10−4 M) eliminated flow-dependent dilation in arterioles of male and OV rats but only attenuated (by ∼50%) the responses in arterioles of female and OVE rats. In vessels of these latter two groups of rats, the remaining flow-induced dilation was completely eliminated by administration of 10−5 M Hb or 10−3 Ml-NAME. The greater flow/shear stress-induced dilation of arterioles of female rats indicates a gender difference in the regulation of WSS, which is likely to be due to the greater release of NO in female vessels requiring the chronic presence of estrogen. These findings suggest an important role for estrogen in the regulation of peripheral resistance in females.

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Role of Ventromedial Hypothalamus in Sucrose-Induced Obesity on Metabolic Parameters

Annals of Neurosciences ◽

10.1177/09727531211005738 ◽

2021 ◽

pp. 097275312110057

Author(s):

Archana Gaur ◽

G.K. Pal ◽

Pravati Pal

Keyword(s):

Insulin Resistance ◽

Weight Gain ◽

Food Intake ◽

Ventromedial Hypothalamus ◽

Female Rats ◽

Metabolic Parameters ◽

Male Rats ◽

Significant Weight Gain ◽

The Metabolic Syndrome

Background: Obesity is because of excessive fat accumulation that affects health adversely in the form of various diseases such as diabetes, hypertension, cardiovascular diseases, and many other disorders. Our Indian diet is rich in carbohydrates, and hence the sucrose-induced obesity is an apt model to mimic this. Ventromedial hypothalamus (VMH) is linked to the regulation of food intake in animals as well as humans. Purpose: To understand the role of VMHin sucrose-induced obesity on metabolic parameters. Methods: A total of 24 adult rats were made obese by feeding them on a 32% sucrose solution for 10 weeks. The VMH nucleus was ablated in the experimental group and sham lesions were made in the control group. Food intake, body weight, and biochemical parameters were compared before and after the lesion. Results: Male rats had a significant weight gain along with hyperphagia, whereas female rats did not have a significant weight gain inspite of hyperphagia. Insulin resistance and dyslipidemia were seen in both the experimental and control groups. Conclusion: A sucrose diet produces obesity which is similar to the metabolic syndrome with insulin resistance and dyslipidemia, and a VMH lesion further exaggerates it. Males are more prone to this exaggeration.

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Role of NPR-C natriuretic receptor in nitric oxide system activation induced by atrial natriuretic peptide

Regulatory Peptides ◽

10.1016/j.regpep.2006.04.002 ◽

2006 ◽

Vol 135 (1-2) ◽

pp. 63-68 ◽

Cited By ~ 22

Author(s):

María Ángeles Costa ◽

Rosana Elesgaray ◽

Ana María Balaszczuk ◽

Cristina Arranz

Keyword(s):

Nitric Oxide ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Oxide System ◽

System Activation ◽

Nitric Oxide System ◽

Atrial Natriuretic

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Regulation of renal CYP4A expression and 20-HETE synthesis by nitric oxide in pregnant rats

AJP Renal Physiology ◽

10.1152/ajprenal.00065.2003 ◽

2003 ◽

Vol 285 (2) ◽

pp. F295-F302 ◽

Cited By ~ 24

Author(s):

Mong-Heng Wang ◽

Jishi Wang ◽

Hsin-Hsin Chang ◽

Barbara A. Zand ◽

Miao Jiang ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Rat Kidney ◽

Late Pregnancy ◽

Inhibitory Effect ◽

Female Rats ◽

Male Rats ◽

Pregnant Rats ◽

Renal Vasoconstriction ◽

Dependent Inhibition

20-Hydroxyeicosatetraenoic acid (20-HETE), which promotes renal vasoconstriction, is formed in the rat kidney primarily by cytochrome P-450 (CYP) 4A isoforms (4A1, 4A2, 4A3, 4A8). Nitric oxide (NO) has been shown to bind to the heme moiety of the CYP4A2 protein and to inhibit 20-HETE synthesis in renal arterioles of male rats. However, it is not known whether NO interacts with and affects the activity of CYP4A1 and CYP4A3, the major renal CYP4A isoforms in female rats. Incubation of recombinant CYP4A1 and 4A3 proteins with sodium nitroprusside (SNP) shifted the absorbance at 440 nm, indicating the formation of a ferric-nitrosyl-CYP4A complex. The absorbance for CYP4A3 was about twofold higher than that of CYP4A1. Incubation of SNP or peroxynitrite (PN; 0.01–1 mM) with CYP4A recombinant membranes caused a concentration-dependent inhibition of 20-HETE synthesis, with both chemicals having a greater inhibitory effect on CYP4A3-catalyzed activity. Moreover, incubation of CYP4A1 and 4A3 proteins with PN (1 mM) resulted in nitration of tyrosine residues in both proteins. In addition, PN and SNP inhibited 20-HETE synthesis in renal microvessels from female rats by 65 and 59%, respectively. We previously showed that microvessel CYP4A1/CYP4A3 expression and 20-HETE synthesis are decreased in late pregnancy. Therefore, we investigated whether such a decrease is dependent on NO, the synthesis of which has been shown to increase in late pregnancy. Administration of NG-nitro-l-arginine methyl ester (l-NAME) to pregnant rats for 6 days ( days 15- 20 of pregnancy) caused a significant increase in systolic blood pressure, which was prevented by concurrent treatment with the CYP4A inhibitor 1-aminobenzotriazole (ABT). Urinary NO2/NO3 excretion decreased by 40 and 52% in l-NAME- and l-NAME + ABT-treated groups, respectively. Interestingly, renal microvessel 20-HETE synthesis showed a marked increase following l-NAME treatment, and this increase was diminished with coadministration of ABT. These results demonstrate that NO interacts with CYP4A proteins in a distinct manner and it interferes with renal microvessel 20-HETE synthesis, which may play an important role in the regulation of blood pressure and renal function during pregnancy.

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Protective effects of estrogen on gender-specific development of diet-induced hypertension

Journal of Applied Physiology ◽

10.1152/jappl.2001.91.5.2005 ◽

2001 ◽

Vol 91 (5) ◽

pp. 2005-2009 ◽

Cited By ~ 21

Author(s):

Christian K. Roberts ◽

Nosratola D. Vaziri ◽

R. James Barnard

Keyword(s):

Body Weight ◽

Female Rats ◽

Male Rats ◽

Gonadal Hormone ◽

Normal Female ◽

Humoral Factors ◽

Diet Modification ◽

Ovx Rats ◽

Hormone Status ◽

Induced Hypertension

Dietary and humoral factors are thought to be involved in the development of hypertension. This study investigated the interaction between diet and gonadal hormone status in the development and reversibility of hypertension. Normal male and female and ovariectomized (OVX) female Fischer rats were placed on either a high-fat (primarily saturated), refined carbohydrate (sucrose) (HFS) or a low-fat, complex carbohydrate (LFCC) diet at 2 mo of age, and body weight and systolic blood pressure (BP) were measured. Male and OVX female rats were initially on the diets for 7 mo, whereas normal female rats were on the diets for 2 yr. After this initial phase, a group of rats from each of the normal HFS groups were converted to the LFCC diet for a period of 1 mo (males) and 2 mo (females). The OVX females were subcutaneously implanted with a 0.5-mg estradiol (E2) pellet for 1 mo. A significant rise in arterial BP occurred within 12 mo in female and only 2 mo in male rats on the HFS diet, exceeding 140 mmHg after 24 and 7 mo, respectively. Conversion from the HFS to the LFCC diet led to a normalization of BP in both female and male rats. HFS diet-induced hypertension was accelerated by OVX in female rats, approaching the pattern seen in male rats. The effect of OVX was completely reversed by E2replacement. BP did not significantly change in any of the LFCC groups at any time point, and E2 replacement had no effect on BP in the OVX LFCC group. All HFS groups had significantly greater body weight, with differences occurring sooner in the male and OVX rats compared with the female rats. Diet modification resulted in a partial but significant reduction of body weight, but E2replacement did not. These results demonstrate that long-term consumption of HFS diet induces hypertension in both genders and is reversible by diet modification. Hypertension is significantly delayed in females with functional ovaries. This protection is lost by OVX and restored by estrogen replacement. Thus hormone status contributes to the delayed onset of diet-induced hypertension in females compared with males.

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