Effects of sex differences on constitutive nitric oxide synthase expression and activity in response to pressure overload in rats

Clinical studies have documented sex differences in left ventricular (LV) hypertrophy patterns, but the mechanisms are so far poorly defined. This study aimed to determine whether 1) severe pressure overload altered expression and/or activity of cardiac constitutive nitric oxide synthase (NOS1 and NOS3) and 2) these changes were modulated according to sex. Analyses were performed 0.4–20 wk after thoracic aortic constriction (TAC) in male and female Wistar rats. Male rats with TAC exhibited early signs of cardiac dysfunction, as shown by echocardiographic and LV end-diastolic pressure measurements, whereas females with TAC exhibited higher LV hypertrophy (+96% vs. males at 20 wk; P < 0.05). After TAC, cardiac NOS1 expression was rapidly induced (0.4 wk) and stable afterward in males ( P < 0.05 vs. sham groups), whereas it was delayed in females. Accordingly, specific NOS1 activity was increased by 2 wk in male rats with TAC (+122%; P < 0.001 vs. sham groups) and only by 20 wk in females (+220%; P < 0.001 vs. sham groups). NOS1 activity was correlated with NOS1 level. Regarding cardiac NOS3, expression was unaffected by TAC, and the decrease in activity observed at early and late times in male and female rats with TAC, respectively, is shown to be related to NOS3 allosteric regulator caveolin-1 level. The data demonstrated a unique sex-dependent regulation of the constitutive NOSs in response to TAC in rats; such a difference might play a role in the sex-dependent adaptability of the heart in response to pressure overload.

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Diabetes induces sex-dependent changes in neuronal nitric oxide synthase dimerization and function in the rat gastric antrum

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00406.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. G725-G733 ◽

Cited By ~ 75

Author(s):

Pandu R. R. Gangula ◽

William L. Maner ◽

Maria-Adelaide Micci ◽

Robert E. Garfield ◽

Pankaj Jay Pasricha

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Neuronal Nitric Oxide Synthase ◽

Gastric Antrum ◽

Female Rats ◽

Male Rats ◽

Organ Bath ◽

Intragastric Pressure ◽

Male And Female ◽

Oxide Synthase

Diabetic gastroparesis is a disorder that predominantly affects women. However, the biological basis of this sex bias remains completely unknown. In this study we tested the hypothesis that a component of this effect may be mediated by the nitrergic inhibitory system of the enteric nervous system. Age-matched male and female Sprague-Dawley rats were studied 8 or 12 wk after streptozotocin (55 mg/kg body wt ip)-induced sustained hyperglycemia and compared with controls. Solid gastric emptying (GE) studies were performed in all the groups. Changes in gastric antrum neuronal nitric oxide synthase (nNOS) mRNA and protein levels were analyzed by real-time PCR and Western immunoblotting, respectively. nNOS dimerization studies were performed using low-temperature SDS-PAGE. In vitro nitrergic relaxation (area under curve/mg tissue wt) was studied after the application of electric field stimulation in an organ bath. Changes in intragastric pressure (mmHg·s) in freely moving rats in the presence or absence of NG-nitro-l-arginine methyl ester (nitric oxide synthase inhibitor) were examined by an ambulatory telemetric method. After diabetes induction, GE is delayed in both male and female rats. However, diabetic females exhibited significant delayed GE than in diabetic males. Compared with male controls, gastric nNOS expression and nitrergic relaxation were substantially elevated in healthy female control rats, accompanied by significantly reduced intragastric pressure. The active dimeric form and dimer-to-monomer ratio of nNOSα were also higher in healthy females compared with male rats ( P < 0.05). Diabetic females, but not males, showed significant ( P < 0.05) impairment in both gastric nNOSα dimerization and nitrergic relaxation, accompanied by an increase in intragastric pressure. Our data provide evidence that females may have a greater dependency on the nitrergic mechanisms in health. Furthermore, diabetes seems to affect the nitrergic system to a greater extent in females than in males. Together, these changes may account for the greater vulnerability of females to diabetic gastric dysfunction.

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17β-Estradiol Regulates Constitutive Nitric Oxide Synthase Expression Differentially in the Myocardium in Response to Pressure Overload

Endocrinology ◽

10.1210/en.2007-0228 ◽

2007 ◽

Vol 148 (10) ◽

pp. 4579-4584 ◽

Cited By ~ 22

Author(s):

Xavier Loyer ◽

Thibaud Damy ◽

Zuzana Chvojkova ◽

Estelle Robidel ◽

Françoise Marotte ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Left Ventricular Hypertrophy ◽

Cardiac Function ◽

Ventricular Hypertrophy ◽

Pressure Overload ◽

Left Ventricular ◽

Constitutive Nitric Oxide Synthase ◽

Oxide Synthase ◽

Expression And Activity

Estrogens [E(2)] exert direct and indirect effects that can modulate the development of cardiac disease. However, the precise mechanisms that are involved remain undefined. Our objective was to investigate whether E(2) affected the activity and expression of constitutive nitric oxide synthase (NOS) isoforms (NOS3 and NOS1) in cardiac hypertrophy induced by thoracic aortic constriction (TAC). Ovariectomized (Ovx) and nonovariectomized Wistar rats were subjected to TAC. Ovx animals received E(2) or placebo 3 wk after surgery for 11 wk. Afterward cardiac function and degree of left ventricular hypertrophy were assessed by echocardiography. NOS activity and expression were studied by biochemical techniques. TAC led to significant left ventricular hypertrophy (>90%) irrespective of hormonal status. Cardiac performance declined more in TAC+Ovx (−20%, P < 0.015) than in the two other TAC groups [TAC and TAC+Ovx+E(2)]. Total NOS activity decreased significantly in the Ovx groups. In response to TAC, total NOS activity increased whatever the E(2) status. Specific NOS3 activity dramatically decreased in the Ovx groups (−55%, P < 0.009) and was unaltered by TAC. By using coimmunoprecipitation assays, we showed that NOS3/caveolin-1 complexes negatively regulated NOS3 activity as a function of E(2) status. On the other hand, NOS1 expression and activity were markedly increased in hypertrophied myocardium (P < 0.003), irrespective of E(2) status. This study demonstrates a differential regulation of NOS expression and activity in response to pressure overload and E(2) status, the former being mainly involved in the induction of NOS1, whereas the latter regulated NOS3 activity and in turn cardiac function.

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Sex-specific vascular responses of the rat aorta: effects of moderate term (intermediate stage) streptozotocin-induced diabetes

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2015-0272 ◽

2016 ◽

Vol 94 (4) ◽

pp. 408-415 ◽

Cited By ~ 3

Author(s):

Xiaoyuan Han ◽

Sonali Shaligram ◽

Rui Zhang ◽

Leigh Anderson ◽

Roshanak Rahimian

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Mrna Expression ◽

Intermediate Stage ◽

Diabetic Rats ◽

Female Rats ◽

Diabetic Rat ◽

Male And Female ◽

Male And Female Rats ◽

Oxide Synthase

Hyperglycemia affects male and female vascular beds differently. We have previously shown that 1 week after the induction of diabetes with streptozotocin (STZ), male and female rats exhibit differences in aortic endothelial function. To examine this phenomenon further, aortic responses were studied in male and female rats 8 weeks after the induction of diabetes (intermediate stage). Endothelium-dependent vasodilation (EDV) to acetylcholine (ACh) was measured in phenylephrine (PE) pre-contracted rat aortic rings. Concentration response curves to PE were generated before and after L-NAME, a nitric oxide synthase (NOS) inhibitor. Furthermore, mRNA expression of endothelial nitric oxide synthase (eNOS) and NADPH oxidase subunit (Nox1) were determined. At 8 weeks, diabetes impaired EDV to a greater extent in female than male aortae. Furthermore, the responsiveness to PE was significantly enhanced only in female diabetic rats, and basal NO, as indicated by the potentiation of the response to PE after L-NAME, was reduced in female diabetic rat aortae to the same levels as in males. In addition, eNOS mRNA expression was decreased, while the Nox1 expression was significantly enhanced in diabetic female rats. These results suggest that aortic function in female diabetic rats after 8 weeks exhibits a more prominent impairment and that NO may be involved.

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Abstract 15295: Molecular Mechanism of Chronic Sildenafil-Caused Regression of Heart Failure: Effects on the Express of Cardiac SR Ca2+-ATPase, Subtype of β-Adrenergic Receptors and Nitric Oxide Synthase Isoforms

Circulation ◽

10.1161/circ.130.suppl_2.15295 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Heng-Jie Cheng ◽

Tiankai Li ◽

Che Ping Cheng

Keyword(s):

Nitric Oxide ◽

Heart Failure ◽

Nitric Oxide Synthase ◽

Adrenergic Receptors ◽

Left Ventricular ◽

Male Rats ◽

Protein Levels ◽

Myocyte Function ◽

Oxide Synthase ◽

Β Adrenergic Receptors

Background: Sildenafil (SIL), a selective inhibitor of PDE5 has been shown to exert profound beneficial effects in heart failure (HF). Recently we further found that SIL caused regression of cardiac dysfunction in a rat model with isoproterenol (ISO)-induced progressive HF. However, the molecular basis is unclear. We hypothesized that reversal of HF-induced detrimental alterations on the expressions of cardiac SR Ca 2+ -ATPase (SERCA2a), β-adrenergic receptors (AR) and nitric oxide synthase (NOS) isoforms by SIL may play a key role for its salutary role in HF. Methods: Left ventricular (LV) and myocyte function and the protein levels of myocyte β 1 - and β 3 - AR, SERCA2a, phospholamban (PLB) and three NOS were simultaneously evaluated in 3 groups of male rats (6/group): HF , 3 months (M) after receiving ISO (170 mg/kg sq for 2 days); HF/SIL , 2 M after receiving ISO, SIL (70 μg/kg/day sq via mini pump) was initiated and given for 1 M; and Controls (C). Results: Compared with controls, ISO-treated rats progressed to severe HF at 3 M after ISO followed by significantly decreased LV contractility (E ES , HF: 0.7 vs C: 1.2 mmHg/μl) and slowed LV relaxation, reductions in the peak velocity of myocyte shortening (77 vs 136 μm/sec), relengthening (62 vs 104 μm/sec) and [Ca 2+ ] iT (0.15 vs 0.24) accompanied by a diminished myocyte inotropic response to β-AR agonist, ISO (10 -8 M). These abnormalities were associated with concomitant significant decreases in myocyte protein levels of β 1 -AR (0.23 vs 0.64), SERCA2a (0.46 vs 0.80), PLB Ser16 /PLB ratio (0.24 vs 0.40) and eNOS (0.28 vs 0.46), but significantly increases in protein levels of β 3 -AR (0.29 vs 0.10) and iNOS (0.18 vs 0.08) with relatively unchanged nNOS. Chronic SIL prevented the HF-induced decreases in LV and myocyte contraction, relaxation, peak [Ca 2+ ] iT , and restored normal myocyte contractile response to ISO stimulation. With SIL, protein levels of myocyte β 1 - and β 3 -AR, SERCA2a were restored close to control values, but eNOS was significantly elevated than controls (0.77). Conclusions: Chronic SIL prevents HF-caused downregulation of cardiac β 1 -AR and reverse contrast changes between iNOS and β 3 -AR with SERCA 2a and eNOS expression, leading to the preservation of LV and myocyte function, [Ca 2+ ] iT , and β-adrenergic reserve.

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EFFECT OF RATE CORROSION OF Mg AND Mg ALLOY ON RENAL NITRIC OXIDE SYNTHASE ACTIVITY IN MALE AND FEMALE RATS

Pathophysiology ◽

10.1016/j.pathophys.2018.07.181 ◽

2018 ◽

Vol 25 (3) ◽

pp. 246 ◽

Cited By ~ 1

Author(s):

Juraj Laco ◽

Andrej Barta ◽

Marina Cebová ◽

Miroslav Čavojský ◽

František Simančík ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Female Rats ◽

Mg Alloy ◽

Male And Female ◽

Male And Female Rats ◽

Oxide Synthase ◽

Nitric Oxide Synthase Activity

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Nitric oxide synthase 2 and pressure-overload-induced left ventricular remodelling in mice

Experimental Physiology ◽

10.1113/expphysiol.2005.033068 ◽

2006 ◽

Vol 91 (3) ◽

pp. 633-639 ◽

Cited By ~ 11

Author(s):

Ryuji Hataishi ◽

Ana Clara Rodrigues ◽

John G. Morgan ◽

Fumito Ichinose ◽

Geneviève Derumeaux ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Pressure Overload ◽

Left Ventricular ◽

Ventricular Remodelling ◽

Left Ventricular Remodelling ◽

Nitric Oxide Synthase 2 ◽

Oxide Synthase

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Different responses of nitric oxide synthase inhibition on morphine-induced antinociception in male and female rats

Pathophysiology ◽

10.1016/j.pathophys.2010.05.004 ◽

2011 ◽

Vol 18 (2) ◽

pp. 143-149 ◽

Cited By ~ 5

Author(s):

Mahmoud Hosseini ◽

Zahra Taiarani ◽

Mosa Al-Reza Hadjzadeh ◽

Soodabeh Salehabadi ◽

Maryam Tehranipour ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Female Rats ◽

Male And Female ◽

Male And Female Rats ◽

Oxide Synthase

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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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