Possible Role Of Nitric Oxide Research Articles

Simvastatin enhances the antihypertensive effect of ramipril in hypertensive hypercholesterolemic animals and patients. Possible role of nitric oxide, oxidative stress, and high sensitivity C‐reactive protein

In this study, the effects of simvastatin on the blood pressure and on the antihypertensive activity of ramipril in hypertensive hypercholesterolemic animals and patients were evaluated. In hypertensive hypercholesterolemic animals, repeated administration of simvastatin slightly but significantly decreased the systolic blood pressure, enhanced its progressive reductions induced by repeated administration of ramipril and corrected the compromised lipid profile. Concomitantly, repeated administration of simvastatin, ramipril or simvastatin in combination with ramipril to these animals, increased nitric oxide (NO) production and decreased the elevated serum malondialdehyde (MDA) and high sensitivity C-reactive protein (hs-CRP) levels. The effects of combined treatment were greater than those of simvastatin or ramipril alone. In hypertensive hypercholesterolemic patients, repeated administration of ramipril decreased systolic and diastolic blood pressure, increased NO production, and decreased the elevated serum MDA and hs-CRP levels. Addition of simvastatin to ramipril therapy enhanced these effects and corrected the compromised lipid profile. Simvastatin but not ramipril inhibited the contractile responses of isolated aortic rings induced by angiotensin 11. l-arginine and acetylcholine enhanced, while l-NAME inhibited effects of simvastatin, and simvastatin in combination with ramipril on these contractile responses. These findings suggest that simvastatin exerts antihypertensive effect and enhances the antihypertensive effect of ramipril in hypertensive hypercholesterolemic animals and patients. In addition to its cholesterol-lowering effect, the ability of simvastatin to ameliorate endothelial dysfunction through increasing NO bioavailability and through suppression of oxidative stress and vascular inflammation and its ability to enhance the effect of ramipril on these parameters may play a pivotal role in these effects.

Possible role of nitric oxide generated by leukocytes in the pathogenesis of hypertensive cerebral edema in stroke-prone spontaneously hypertensive rats

We investigated the mechanisms responsible for cerebral edema in stroke-prone spontaneously hypertensive rats (SHRSP), including leukocyte activation and nitric oxide (NO) generation, both in vivo and in vitro. We also investigated the effects of angiotensin II (AngII) on leukocyte function in relation to NO production. Leukocyte–endothelial cell adhesion in brain microvessels was investigated by electron tomography using ultra-high voltage electron microscopy. Electron tomography clearly showed that leukocytes had well-developed intracellular organelles and abundant microvilli that were tangled with the endothelial cells in brain microvessels. Under confocal microscopic examination, diaminofluorescein-2 (a NO indicator)-positive cells were closely localized to anti-granulocyte-positive cells. The fluorescence intensity was much stronger in SHRSP than in age-matched Wistar–Kyoto (WKY) rats, as a normotensive control. Mac-1 (leukocyte integrin, CD11b/CD18), angiotensin type 1 (AT1) receptor and inducible nitric oxide synthase (iNOS) expression was higher (or tended to be higher) in SHRSP leukocytes than in WKY leukocytes. The plasma NO metabolite content was also higher in SHRSP than in WKY rats. All of these factors were upregulated by AngII stimulation. Furthermore, NO release from leukocytes was enhanced by AngII or lipopolysaccharide through NF-κB activation, but was suppressed by an AT1 receptor blocker or s-methyl-isothiourea. The present study revealed that one of the causative factors for cerebral edema in SHRSP rats is the generation of NO radicals by iNOS activated via NF-κB in AngII-stimulated leukocytes. Thus, the pathogenesis of cerebral edema in SHRSP is likely to involve inflammatory processes mediated by AngII.

Captopril versus enalapril in the protection of the gastric mucosa against NSAID induced gastric mucosal injury in rats

Background: Different mechanisms have been suggested for the development of nonsteroidal antiinflammatory drugs (NSAIDs) induced gastropathy. Angiotensin converting enzyme inhibitors have been suggested to have gastroprotective effects. This study investigates the gastroprotective effects of Angiotensin converting enzyme inhibitors, captopril and enalapril on indomethacin induced gastric mucosal damage in rats .Materials and methods: The study was conducted on 50 adult male albino rats, divided into 5 groups, the first served as a control received the vehicle , the second received indomethacin orally of 60mg/kg. The third and fourth groups were pretreated orally 30 minute prior indomethacin with either captopril or enalapril. In order to study the possible role of nitric oxide (NO) in the gastroprotective effect of captopril; intraperitoneal NG-L-Arginine Methyl Ester (L-NAME) a nitric oxide synthase inhibitor was given 30 minutes prior to captopril administration followed by indomethacin and this served as fifth group. The rats were then sacrificed after 4 hours and their stomachs were isolated and submitted to macroscopical assessment and for the measurement of the gastric prostaglandinE2 (PGE2), and myeloperoxidase (MPO).Results: Captopril in a dose of 15 mg/kg produced a significant reduction (p <0.05) in the gastric damage score .These protective effects were associated with a significant increase (p <0.05) in gastric PGE2 levels and marked decrease (p <0.05) in MPO activity, L-NAME pretreatment didn't abrogate the effects of captopril. Enalapril pretreatment failed to show the gastroprotective effects of captopril.Conclusions: The prophylactic use of captopril in this study prevented indomethacin induced gastropathy .This protective effect was associated with PGE2 upregulation and decreased oxyradical generation reflected by a decrease in MPO activity .Enalapril failed to produce the gastroprotective effects of captopril.

The Acute Effect of Ethanol on Adrenal Cortex in Female Rats—Possible Role of Nitric Oxide

The present study was designed to investigate a possible role of endogenous nitric oxide (NO) in the adrenal response to an acute alcohol administration in female rats. To this end, N(ω)-nitro-L-arginine-methyl ester (L-NAME), a competitive inhibitor of all isoforms of NO synthase, was used. Adult female Wistar rats showing diestrus Day 1 were treated with: (a) ethanol (2 or 4 g/kg, intraperitoneally); (b) L-NAME (30 or 50 mg/kg, subcutaneously) followed by either ethanol or saline 3 h later. Untreated and saline-injected rats were used as controls. The animals were killed 30 min after last injection. Adrenal cortex was analyzed morphometrically, and plasma levels of adrenocorticotropic hormone (ACTH) and serum concentrations of corticosterone were determined. Acute ethanol treatment enhanced the levels of ACTH and corticosterone in a dose-dependent manner. Stereological analysis revealed that acute alcohol administration induced a significant increase in absolute volume of the cortex and the zona fasciculata (ZF). In addition, ethanol at a dose of 4 g/kg increased volume density and length of the capillaries in the ZF. However, other stereological parameters were unaffected by alcohol exposure. Pretreatment with both doses of L-NAME had no effect on ethanol-induced changes. Obtained findings indicate that acute ethanol treatment stimulates the activity of the adrenal cortex and that this effect is not mediated by endogenous NO in female rats under these experimental conditions.

N-nitro-l-arginine, a nitric oxide synthase inhibitor, aggravates iminodipropionitrile-induced neurobehavioral and vestibular toxicities in rats

Exposure of iminodipropionitrile (IDPN) to rodents produces permanent behavioral syndrome characterized by repetitive head movements, circling and back walking. Other synthetic nitriles of industrial importance such as crotonitrile and allylnitrile are also able to produce similar motor deficits in experimental animals. However, due to the well-defined behavioral deficits and their easy quantification, IDPN-induced behavioral syndrome is a preferential animal model to test the interaction of various agents with synthetic nitriles. This study reports the effect of non-specific nitric oxide synthase inhibitor, N-nitro-L-arginine (NARG) on IDPN-induced neurobehavioral toxicity in adult male Wistar rats. Four groups of animals were given i.p. injections of IDPN (100 mg/kg) for 6 days. These rats were treated with oral administration of NARG in the doses of 0 (IDPN alone group), 50, 150 and 300 mg/kg, 60 min before IDPN, respectively. Control rats received vehicle only, whereas another group was treated with 300 mg/kg of NARG alone (without IDPN). The results showed that NARG significantly exacerbated the incidence and intensity of IDPN-induced dyskinetic head movements, circling and back walking. The histology of inner ear showed massive degeneration of the sensory hair cells in the crista ampullaris of rats receiving the combined treatment with IDPN and NARG, suggesting a possible role of nitric oxide in IDPN-induced neurobehavioral syndrome in rats.

Role of Nitric Oxide in Motor Control: Implications for Parkinson's Disease Pathophysiology and Treatment

According to classical thinking about Parkinson's disease, loss of dopaminergic input from the substantia nigra pars compacta leads to overactivity and underactivity of the indirect and direct output pathways, respectively, in the basal ganglia. Administration of the dopamine precursor L-DOPA (l-3, 4-dihydroxyphenylalanine) is proposed to induce changes in the opposite directions. L-DOPA is the most used drug to treat Parkinson`s disease symptoms. After repeated treatment with this compound, however, disabling secondary effects such as the abnormal involuntary movements usually appear. Nitric oxide is a free radical that can also act as an atypical neurotransmitter and influences dopamine-mediated neurotransmission. In this paper we will briefly review the role of nitric oxide on motor control and in Parkinson's disease, particularly a possible role of nitric oxide in L-DOPA induced dyskinesia in rodents. Recent results show that nitric oxide synthase inhibition reduces L-DOPA-induced dyskinesia in rats and mice. The effect is dose-dependent, does not suffer tolerance nor interferes with L-DOPA positive motor effects. These preclinical findings suggest that nitric oxide is a promising therapeutic target for the reduction of L-DOPA-induced dyskinesia.

Nitric oxide in the ventral tegmental area is involved in retrieval of inhibitory avoidance memory by nicotine

In the present study, the possible involvement of nitric oxide systems in the ventral tegmental area (VTA) in nicotine's effect on morphine-induced amnesia and morphine state-dependent memory in adult male Wistar rats was investigated. Step-through type inhibitory avoidance task was used to test memory retrieval. Post-training administration of morphine (5 and 7.5 mg/kg) induced amnesia. The response induced by post-training morphine was significantly reversed by pre-test administration of the drug. Pre-test injection of nicotine (0.4 and 0.8 mg/kg s.c.) alone and nicotine (0.1, 0.4 and 0.8 mg/kg s.c.) plus an ineffective dose of morphine also significantly reversed the amnesia induced by morphine. Morphine amnesia was also prevented by pre-test administration of l-arginine (1 and 3 μg/rat, intra-VTA), a nitric oxide (NO) precursor. Interestingly, an ineffective dose of nicotine (0.1 mg/kg s.c.) in combination with low dose of l-arginine (0.3 μg/rat, intra-VTA) synergistically improved memory performance impaired by morphine given after training. In contrast, pre-test administration of NG nitro-l-arginine methyl ester hydrochloride (l-NAME), a nitric oxide synthase (NOS) inhibitor (2 μg/rat, intra-VTA) prevented the nicotine reversal of morphine effect on memory. The results suggest a possible role for nitric oxide of ventral tegmental area in the improving effect of nicotine on the morphine-induced amnesia.

Structural, Histochemical and Immunocytochemical Study of the Forestomach Mucosa in Domestic Ruminants

The forestomach plays an important role in the digestion physiology of ruminants. The aim of this study is to clarify the morpho-functional role of the mucosa in each of the three compartments of the forestomach in three domestic ruminants species, viz cattle, buffalo and sheep, by means of structural, histochemical and immunocytochemical methods, including transmission electron microscopy, light microscopy and scanning electron microscopy. These methods were chosen to demonstrate the indirect evidence for the presence of nitric oxide (NO) employing NADPHd and nitric oxide synthase I (NOS I). The various cell layers of the forestomach epithelium are described and illustrated in detail. An intense NADPHd staining was observed in the granulosa, spinosa and basal layers of the epithelium, in particular in the cytoplasm over the nucleus. NOS I immunoreactivity was found in all specimens of the forestomach mucosa. The results of this study might reflect a possible role of NO in delaying the onset of cellular apoptosis in the forestomach mucosa of the domestic ruminants, by playing a role in the production of cell energy.

Two Hypomorphic Alleles of Mouse Ass1 as a New Animal Model of Citrullinemia Type I and Other Hyperammonemic Syndromes

Citrullinemia type I (CTLN1, OMIM# 215700) is an inherited urea cycle disorder that is caused by an argininosuccinate synthetase (ASS) enzyme deficiency. In this report, we describe two spontaneous hypomorphic alleles of the mouse Ass1 gene that serve as an animal model of CTLN1. These two independent mouse mutant alleles, also described in patients affected with CTLN1, interact to produce a range of phenotypes. While some mutant mice died within the first week after birth, others survived but showed severe retardation during postnatal development as well as alopecia, lethargy, and ataxia. Notable pathological findings were similar to findings in human CTLN1 patients and included citrullinemia and hyperammonemia along with delayed cerebellar development, epidermal hyperkeratosis, and follicular dystrophy. Standard treatments for CTLN1 were effective in rescuing the phenotype of these mutant mice. Based on our studies, we propose that defective cerebellar granule cell migration secondary to disorganization of Bergmann glial cell fibers cause cerebellar developmental delay in the hyperammonemic and citrullinemic brain, pointing to a possible role for nitric oxide in these processes. These mouse mutations constitute a suitable model for both mechanistic and preclinical studies of CTLN1 and other hyperammonemic encephalopathies and, at the same time, underscore the importance of complementing knockout mutations with hypomorphic mutations for the generation of animal models of human genetic diseases.

Effect of Rectal Distention on Lower Urinary Tract Function in Children

We investigated the effect of rectal distention on lower urinary tract function. Children were assigned to a constipation and lower urinary tract symptoms group or to a lower urinary tract symptoms only group. The definition of constipation was based on pediatric Rome III criteria. Standard urodynamics were done initially and repeated during simultaneous barostat pressure controlled rectal balloon distention and after balloon deflation. We evaluated the effects of rectal balloon inflation and deflation on urodynamic parameters. Colonic transit time measurement, anorectal manometry and the Parenting Rating Scale of child behavior were also used. We studied 7 boys and 13 girls with a median age of 7.5 years who had constipation and lower urinary tract symptoms, and 3 boys and 3 girls with a median age of 7.5 years who had lower urinary tract symptoms only. Urodynamic patterns of response to rectal distention were inhibitory in 6 children and stimulatory in 12, and did not change in 8. In 54% of the cases balloon deflation reversed balloon inflation changes while in 46% balloon inflation changes persisted or progressed. No significant differences were noted in children with vs without constipation and no clinical symptom or diagnostic study predicted the occurrence, direction or degree of bladder responses. In almost 70% of children with lower urinary tract symptoms rectal distention significantly but unpredictably affected bladder capacity, sensation and overactivity regardless of whether the children had constipation, and independent of clinical features and baseline urodynamic findings. Urodynamics and management protocols for lower urinary tract symptoms that fail to recognize the effects of rectal distention may lead to unpredictable outcomes.

Role of nitric oxide on purinergic signalling in the cochlea

In the inner ear, there is considerable evidence that extracellular adenosine 5'-triphosphate (ATP) plays an important role in auditory neurotransmission as a neurotransmitter or a neuromodulator, although the potential role of adenosine signalling in the modulation of auditory neurotransmission has also been reported. The activation of ligand-gated ionotropic P2X receptors and G protein-coupled metabotropic P2Y receptors has been reported to induce an increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) in inner hair cells (IHCs), outer hair cells (OHCs), spiral ganglion neurons (SGNs), and supporting cells in the cochlea. ATP may participate in auditory neurotransmission by modulating [Ca(2+)](i) in the cochlear cells. Recent studies showed that extracellular ATP induced nitric oxide (NO) production in IHCs, OHCs, and SGNs, which affects the ATP-induced Ca(2+) response via the NO-cGMP-PKG pathway in those cells by a feedback mechanism. A cross-talk between NO and ATP may therefore exist in the auditory signal transduction. In the present article, I review the role of NO on the ATP-induced Ca(2+) signalling in IHCs and OHCs. I also consider the possible role of NO in the ATP-induced Ca(2+) signalling in SGNs and supporting cells.

Role of nitric oxide in young patients with vasovagal syncope

Nitric oxide (NO) formed in the vascular endothelium produces, among other effects, a strong vasodilation. In order to evaluate the possible role of NO in hypotension induced by head-up tilt test (HUT), we measured plasma levels of its metabolites, nitrites and nitrates (NOx), during the test. Twelve patients with vasovagal syncope and positive HUT [HUT(+)] (mean age: 23+/-5 years) and 13 healthy volunteers with negative HUT (controls) (mean age: 24+/-5 years) were included. Venous blood samples were obtained during the baseline stage for biochemical measurements. Plasma values of NOx were obtained under baseline conditions (T0), at the end of the HUT (T1), and 15 min after the end of the HUT (T2). The baseline biochemical values as well as haemodynamic parameters were similar in HUT(+) patients and controls. NOx plasma values (in micromol/L) were as follows [HUT(+) vs. controls]: T0: 5.7+/-1.6 vs. 8.8+/-4.7 (P=0.05), T1: 6.1+/-3.2 vs. 8.5+/-3.6 (P=NS), and T2: 6.1+/-3 vs. 10.2+/-8.9 (P=NS). The NOx levels were directly correlated with the insulin levels (Spearman's R=0.53, P=0.008). Baseline plasma levels of NOx were significantly lower in HUT(+) patients than in controls. However, since the expected increase in NOx values during HUT-induced syncope was not observed, the possible role of NO in vasovagal hypotension is uncertain.

Expression pattern of thermogenesis-related factors in interscapular brown adipose tissue of alloxan-treated rats: Beneficial effect of l-arginine

Metabolic abnormalities underlying diabetes can be abrogated by l-arginine. Here we examined the molecular basis of disturbed interscapular brown adipose tissue (IBAT) thermogenesis and the possible role of nitric oxide (NO) in the IBAT of diabetic rats. To induce diabetes, adult Mill Hill hybrid hooded male rats were given a single alloxan dose (120 mg/kg). Both non-diabetic and diabetic groups were further divided into three subgroups receiving: (i) l-arginine·HCl (2.25%) or (ii) N ω-nitro- l-arginine methyl ester ( l-NAME·HCl, 0.01%) for 12 days in drinking water and (iii) untreated controls. Treatment of the diabetic animals started after diabetes induction (glucose level ⩾12 mmol/L). Diabetes led to a decrease in the mRNA levels of uncoupling protein 1 (UCP1), peroxisomal proliferator activator receptor gamma (PPARγ) and endothelial NO synthase (eNOS) as revealed by RT-PCR. The diabetic rats had reduced eNOS and inducible NOS (iNOS) protein contents accompanied by low tissue vascularization, a parameter directly related to tissue thermogenic state. Downregulation of glutathione peroxidase (GSH-Px) and catalase (CAT) transcripts were also observed in diabetes. In contrast, the expression level of PPARγ coactivator-1α (PGC-1α) mRNA was elevated. Supplementation with l-arginine not only restored diabetes-induced changes in the expressions of these molecules important for IBAT regulation, but also increased the vascularity. Interestingly, l-NAME induced similar patterns of changes in vascularity and PGC-1α mRNA level as did l-arginine. In summary, our results provide insight into the molecular basis underlying diabetes-induced metabolic and functional disturbances in the IBAT and suggest a beneficial role for the l-arginine–NO production pathway.

Cholestasis induces apoptosis in mice cardiac cells: the possible role of nitric oxide and oxidative stress

Acute cholestasis is associated with cardiovascular complications. The purpose of the present study was to investigate the effect of cholestasis on heart apoptosis and the involvement of nitric oxide (NO) and oxidative stress in the possible altered apoptosis of cholestatic hearts. Cholestasis was induced by bile duct-ligation, and sham-operated mice served as controls. Three days after the surgery, heart tissues were evaluated for apoptosis and the level of malondialdehyde (MDA), and the activities of catalase (CAT), glutathione peroxidase (GSHPx) and superoxide dismutase (SOD) have been studied in cardiac tissues. The role of treatment with l-NAME, a non-selective inhibitor of NO synthase, or with d-NAME, an inactive isomer of l-NAME, on cholestatic and sham cardiac apoptosis, level of MDA and CAT, SOD and GSHPx activities was also investigated. The content of NO in cardiac tissue was also determined. Cholestatic hearts showed structural abnormalities and increased apoptosis compared with sham hearts. Treatment with l-NAME, but not d-NAME, improved both structural abnormalities and enhanced apoptosis of cholestatic hearts. Cholestatic hearts also had an increased level of MDA and decreased activities of CAT and GSHPx, which were not modified by d-NAME treatment. By l-NAME treatment, the level of MDA decreased and activities of CAT, GSHPx and SOD increased in BDL mice. The content of NO was higher in cholestatic cardiac tissue, which was decreased by l-NAME treatment. In conclusion, apoptosis in cholestatic heart might have occurred because of NO overproduction, which could induce oxidative stress in the heart of cholestatic mice.

The role of nitric oxide in airway responsiveness in diabetic-antigen sensitized guinea pigs in vitro.

Clinical asthma and airway responsiveness appear to be less severe when diabetes is superimposed. The aim of the present study was to determine the possible role of Nitric Oxide (NO) in the airway reactivity under diabetic and diabetic-allergic conditions. Twenty-five male guinea-pigs were divided into five groups of five each as follows: diabetic, antigen sensitized, diabetic- antigen sensitized, insulin-treated diabetic- antigen ovalbumin sensitized and control animals. Tracheal rings of all groups were mounted in an organ bath system for isometric contraction measurements. Tissues were pre-incubated with either of the following chemicals: L-NAME, L-arginine or methylene blue. Cumulative concentration response curve was made with histamine. Decrease in the airway reactivity in diabetic and diabetic- antigen sensitized animals were shown compared to the antigen sensitized animals. pEC(50) values of histamine in the presence of L-Arg showed increase in diabetic and diabetic- antigen sensitized animals compared to the controls. In the presence of methylene blue, these values showed an increase in diabetic and diabetic- antigen sensitized animals compared to the controls. However, incubation with L-NAME did not change the airway responsiveness to histamine in diabetic and diabetic- antigen sensitized animals compared to the controls. Experimental diabetes causes were found to decrease the responsiveness of tracheal rings in the presence or absence of allergy. Findings of this research work showed that NO had no role in hypo-responsiveness of airway in diabetic and diabetic- antigen sensitized animals.

Altered expression of neuronal nitric oxide synthase in weaver mutant mice

The weaver mouse represents the only genetic animal model of gradual nigrostriatal dopaminergic neurodegeneration which is proposed as a pathophysiological phenotype of Parkinson's disease. The aim of the present study was to analyze the nitric oxide and dopaminergic systems in selected brain regions of homozygous weaver mice at different postnatal ages corresponding to specific stages of the dopamine loss. Structural deficits were evaluated by quantification of tyrosine hydroxylase and neuronal nitric oxide synthase-immunostaining in the cortex, striatum, accumbens nuclei, subthalamic nuclei, ventral tegmental area, and substantia nigra compacta of 10-day, 1- and 2-month-old wild-type and weaver mutant mice. The results confirmed the progressive loss of dopamine during the postnatal development in the adult weaver mainly affecting the substantia nigra pars compacta, striatum, and subthalamic nucleus and slightly affecting the accumbens nuclei and ventral tegmental area. A general decrease in neuronal nitric oxide synthase-immunostaining with age was revealed in both the weaver and wild-type mice, with the decrease being most pronounced in the weaver. In contrast, there was an increase in the substantia nigra pars compacta nitric oxide synthase-immunostaining and a decrease mainly in the subthalamic and accumbens nuclei of the 2-month-old weaver mutant. The decrease in the expression of nNOS may bear functional significance related to the process of aging. DA neurons from the substantia nigra directly modulate the activity of subthalamic nucleus neurons, and their loss may contribute to the abnormal activity of subthalamic nucleus neurons. Although the functional significance of these changes is not clear, it may represent plastic compensating adjustments resulting from the loss of dopamine innervation, highlighting a possible role of nitric oxide in this process.

Serum nitric oxide levels in patients with Crimean-Congo haemorrhagic fever

Crimean-Congo haemorrhagic fever (CCHF) is an acute disease affecting multiple organ systems and is characterized by fever and haemorrhages. The pathogenesis of CCHF has not been well described. Nitric oxide (NO) is an important regulator of a number of different biological processes and can participate in antimicrobial defence. In this study, we measured the level of NO in the serum of patients with CCHF and healthy controls to define the possible role of NO in the control of infection. Sixty-two patients with CCHF and 31 controls were included in the study. NO levels in CCHF patients and the control group were found to be a mean of 40.49 microM (standard deviation (SD) 23.00) and 14.89 microM (SD 7.94), respectively. NO levels were significantly higher in CCHF patients with respect to controls (p < 0.001). NO levels in the patients with non-fatal CCHF and fatal CCHF were compared and found to be a mean of 43.57 microM (SD 22.70) and 26.23 microM (SD 19.43), respectively; this difference was statistically significant (p=0.009). In conclusion, elevated levels of NO may play a protective role in CCHF.

Protective effect of hesperidin and naringin against 3 nitropropionic acid induced Huntingtons like symptoms in rats possible role of nitric oxide

Protective effect of hesperidin and naringin against 3 nitropropionic acid induced Huntingtons like symptoms in rats possible role of nitric oxide

Leptin Inhibits the Proliferation of Vascular Smooth Muscle Cells Induced by Angiotensin II through Nitric Oxide-Dependent Mechanisms

Objective. This study was designed to investigate whether leptin modifies angiotensin (Ang) II-induced proliferation of aortic vascular smooth muscle cells (VSMCs) from 10-week-old male Wistar and spontaneously hypertensive rats (SHR), and the possible role of nitric oxide (NO). Methods. NO and NO synthase (NOS) activity were assessed by the Griess and 3H-arginine/citrulline conversion assays, respectively. Inducible NOS (iNOS) and NADPH oxidase subutnit Nox2 expression was determined by Western-blot. The proliferative responses to Ang II were evaluated through enzymatic methods. Results. Leptin inhibited the Ang II-induced proliferative response of VSMCs from control rats. This inhibitory effect of leptin was abolished by NOS inhibitor, NMMA, and iNOS selective inhibitor, L-NIL, and was not observed in leptin receptor-deficient fa/fa rats. SHR showed increased serum leptin concentrations and lipid peroxidation. Despite a similar leptin-induced iNOS up-regulation, VSMCs from SHR showed an impaired NOS activity and NO production induced by leptin, and an increased basal Nox2 expression. The inhibitory effect of leptin on Ang II-induced VSMC proliferation was attenuated. Conclusion. Leptin blocks the proliferative response to Ang II through NO-dependent mechanisms. The attenuation of this inhibitory effect of leptin in spontaneous hypertension appears to be due to a reduced NO bioavailability in VSMCs.

Promoter polymorphisms of the NOS3 gene are associated with hypnotizability-dependent vascular response to nociceptive stimulation

Hypnotizability is associated with a few physiological characteristics also in the normal awake state. Differences in flow-mediated dilation (FMD) have been observed in subjects with high (Highs) or low (Lows) hypnotizability during nociceptive stimulation. FMD is largely due to the nitric oxide (NO) produced by vascular endothelium through the activity of NO synthase (eNOS). Endothelial NOS is encoded by the NOS3 locus. Aim of this pilot study was to investigate the association between genetic polymorphisms of NOS3 involved in NO blood levels and hypnotizability. Nine single nucleotide polymorphisms (SNPs) of the NOS3 gene were analyzed in the DNA of 24 Highs, 22 Lows, and 61 newborns. Two SNPs, rs1800783 (−1474 T/A) and rs2070744 (−786 T/C), located in the upstream and promoter region of the gene, respectively, showed significant differences between Highs and Lows in allele frequency. Haplotype analysis showed that the newborns were in linkage equilibrium for these SNPs, whereas both Highs and Lows showed linkage disequilibrium. The A-C haplotype (associated with lower NO availability in the general population) was more frequent in Highs, and the T-T haplotype was more frequent in Lows. Thus, the lower FMD reduction observed in Highs during nociceptive stimulation, which is indicative of higher NO availability, should be due to greater efficacy of shear stress-related transcriptional factors and/or to lower effects of NOS inhibitory controls. A consequent theoretical proposal concerns the possible role of NO in the brain vessels where, in stimulation conditions, NO diffusion to the extracellular compartment might be involved in hypnotic responding.