Increased Plasma Nitric Oxide Research Articles

Nebivolol prevents remodeling in a rat myocardial infarction model: an echocardiographic study

Ventricular remodeling (VR) which develops after myocardial infarction (MI) plays an important role in progressive left ventricular dysfunction. We aimed to investigate the role of nebivolol treatment on VR after a MI in a rat ischemia-reperfusion model. Rats were divided into 3 groups of 12 each: sham operated (sham-control), MI-induced (MI-control) and nebivolol treated (MI-nebivolol). Left ventricular (LV) diameters, volumes, and diastolic filling parameters were evaluated by echocardiography. On the 28th day, after recording the systemic and LV pressures and determining the plasma nitric oxide (NO) and peroxynitrite (ONOO-) levels , animals were sacrificed and heart, body and LV weights (HW, BW, LVW) were measured and infarct sizes were determined. Results were evaluated statistically by ANOVA for repeated measurements 3x3 factorial design with post-hoc Bonferroni test. After MI, while VR (an increase in LV diameters and volumes associated with a decrease in EF, FS and posterior wall thickness change (LWPc) was significant in MI-control rats (p<0.05 for; all comparisons) these changes were significantly less in MI-nebivolol group (p=0.08 and p=0.06 for EF and FS respectively). LV end diastolic pressure (LVEDP) was lower (p<0.005) and Delta+/- dp/dt's (p<0.05) were higher in MI-nebivolol group compared to MI-control animals. Although infarct sizes were similar in MI-induced groups (p=0.79); LVW/HW and HW/BW's were significantly greater in the MI-control group compared to sham-control (p<0.01 for all comparisons), these changes were not statistically significant in MI-nebivolol group. The increase in plasma NO and ONOO- levels were also prevented with nebivolol. Nebivolol therapy reduced the effects of VR in rats after MI. These beneficial effects were not related to its heart rate and blood pressure reducing effects. Nitric oxide regulatory action of this compound may contribute these beneficial effects on VR developed after MI.

Green Tea Catechins Improve Human Forearm Endothelial Dysfunction and Have Antiatherosclerotic Effects in Smokers

Because green tea reduces cardiovascular and cerebrovascular risk, the purpose of this study aimed to elucidate the effect of green tea catechins (GTC) on endothelial dysfunction in smokers. The 30 healthy male smokers were divided into 3 groups and given green tea beverages containing 0 mg (control group), 80 mg (medium-dose group) or 580 mg (high-dose group) of GTC daily for 2 weeks. Endothelial-dependent and- independent vasodilatation was investigated by measuring the forearm blood flow (FBF) responses to acetylcholine and sodium nitroprusside using venous occlusion strain-gauge plethysmography. The FBF response to acetylcholine significantly increased at 2 h and 1 and 2 weeks after GTC intake in the high-dose group, but no increase was observed in the other groups. FBF responses to sodium nitroprusside did not alter in any group at any time point. A significant increase in plasma nitric oxide and a decrease in asymmetrical dimethylarginine, malondealdehyde and 4-hydroxynonenal, C-reactive protein, monocyte chemotactic protein-1, and soluble CD40 ligand levels were detected after chronic consumption of high-dose GTC. GTC have antiatherosclerotic effects on dysfunctional vessels in smokers through increasing the level of nitric oxide and reducing oxidative stress.

Polaprezinc Protects Mice against Endotoxin Shock

Polaprezinc (PZ), a chelate compound consisting of zinc and l-carnosine (Car), is an anti-ulcer drug developed in Japan. In the present study, we investigated whether PZ suppresses mortality, pulmonary inflammation, and plasma nitric oxide (NO) and tumor necrosis factor (TNF)-α levels in endotoxin shock mice after peritoneal injection of lipopolysaccharide (LPS), and how PZ protects against LPS-induced endotoxin shock. PZ pretreatment inhibited the decrease in the survival rate of mice after LPS injection. PZ inhibited the increases in plasma NO as well as TNF-α after LPS. Compatibly, PZ suppressed LPS-induced inducible NO synthase mRNA transcription in the mouse lungs. PZ also improved LPS-induced lung injury. However, PZ did not enhance the induction of heat shock protein (HSP) 70 in the mouse lungs after LPS. Pretreatment of RAW264 cells with PZ suppressed the production of NO and TNF-α after LPS addition. This inhibition likely resulted from the inhibitory effect of PZ on LPS-mediated nuclear factor-κB (NF-κB) activation. Zinc sulfate, but not Car, suppressed NO production after LPS. These results indicate that PZ, in particular its zinc subcomponent, inhibits LPS-induced endotoxin shock via the inhibition of NF-κB activation and subsequent induction of proinflammatory products such as NO and TNF-α, but not HSP induction.

Plasma nitrate/nitrite levels are unchanged after long-term aerobic exercise training in older adults

Reduced nitric oxide (NO) production and bioactivity is a major contributor to endothelial dysfunction. Animal data suggest that improvements in endothelial function in response to aerobic exercise training may depend on the duration of the training program. However, no studies have examined changes in NO (as assessed by the major NO metabolites, nitrate and nitrite, NO x ) after long-term training in humans. In addition, aging may impair the ability of the vasculature to increase NO with exercise. Thus, we determined whether 24 weeks of aerobic exercise training increases plasma NO x levels in sedentary older adults. We also examined changes in forearm blood flow (FBF) at rest and during reactive hyperemia as a measure of vasomotor function. Plasma NO x levels were measured in 82 men and women using a modified Griess assay. FBF was assessed in a subset of individuals ( n = 15) using venous occlusion plethysmography. After 24 weeks of exercise training, there were significant improvements in maximum oxygen consumption, HDL cholesterol, triglycerides, and body fat. Changes in plasma NO x levels ranged from −14.83 to +16.69 μmol/L; however, the mean change overall was not significant (−0.33 ± 6.30 μmol/L, p = 0.64). Changes in plasma NO x levels were not associated with age, gender, race, HDL cholesterol, triglycerides, body weight, body fat, or maximal oxygen consumption. There were also no significant changes in basal FBF, peak FBF, hyperemic response, total hyperemic flow, or minimum forearm vascular resistance with exercise training. In conclusion, improvements in plasma NO x levels and FBF are not evident after long-term training in older adults.

EFFECTS OF 1400W AND/OR NITROGLYCERIN ON RENAL OXYGENATION AND KIDNEY FUNCTION DURING ENDOTOXAEMIA IN ANAESTHETIZED RATS

1. The pathogenesis of acute renal failure (ARF) in sepsis is multifactorial. The role of nitric oxide (NO) in septic ARF has been a source of controversy. We hypothesized that endotoxaemia-induced exacerbation of inducible nitric oxide synthase (iNOS)-related NO release impairs renal oxygenation and contributes to ARF in anaesthetized rats. 2. In the present study, rats received lipopolysaccharide (2.5 mg/kg) for 30 min. Two hours later, fluid resuscitation was started (HES130; 5 mL/kg per h after a 5 mL/kg bolus) supplemented either by the NO donor nitroglycerin (NTG; 0.5 µg/kg per min after a 2 µg/kg bolus), the selective iNOS inhibitor 1400 W (3 mg/kg per h after a 3 mg/kg bolus) or both. Systemic haemodynamics and renal microvascular Po2 (µPo(2)) were recorded continuously. Furthermore, creatinine clearance, plasma NO(x) (nitrate + nitrite + S-nitrosothiols) levels and the expression of iNOS mRNA were measured. 3. Endotoxaemia reduced renal blood flow, decreased mean arterial pressure, resulted in anuria and was associated with an increase in plasma NO(x) levels and renal iNOS expression. Renal µPo2 deteriorated gradually during endotoxaemia and there was a significant decrease in renal O(2) delivery and consumption. Manipulation of NO levels had no beneficial effect on systemic haemodynamics, renal µPo(2) or creatinine clearance over standard fluid resuscitation. The application of 1400 W+NTG significantly reduced plasma NO(x) levels compared with fluid resuscitation and NTG alone. 4. Neither iNOS inhibition, NO donation nor a combination of both showed beneficial effects on systemic haemodynamics, renal oxygenation and renal function compared with fluid resuscitation alone. Our results question the proposed key role of NO in the pathogenesis of septic ARF in rats.

Abstract: P699 EVIDENCE OF A ROLE OF T REGULATORY CELLS MEDIATING ATHEROPROTECTION BY APO B 100 PEPTIDE IMMUNIZATION

The estrogen in the prevention of atherosclerosis trial (EPAT) was a 2-year randomized controlled trial in which unopposed 17β-estradiol reduced subclinical atherosclerosis progression, measured as change in carotid intima-media thickness (CIMT). This study was conducted to determine whether long-term 17β-estradiol 1 mg daily increased plasma nitric oxide (NO) levels and whether this accounted for atheroprotection in EPAT. Although the on-trial serum estradiol level was significantly higher in the estradiol-treated group (n = 91 subjects) than the placebo group (n = 89 subjects) (mean (S.D.) = 59.0 (31.7) pg/ml versus 14.3 (10.4) pg/ml, p < 0.0001), there was no significant difference in the on-trial plasma NO levels, 18.5 (8.2) μM versus 20.1 (9.3) μM. Correlation between on-trial estradiol level and NO change was −0.22 (p = 0.003) in the total sample (placebo- and estradiol-treated subjects) and −0.21 (p = 0.049) in the estradiol-treated group. Change in NO levels was inversely correlated to change in LDL-cholesterol in the estradiol group (r = −0.23, p = 0.03). An NO response to 17β-estradiol according to age, time since menopause and baseline CIMT was not found arguing against a possible NO effect in healthy versus diseased endothelium. NO levels were not related to CIMT progression. In this study, we found no evidence for an estrogen-induced effect on plasma total NO levels which unlikely accounted for the mechanism underlying the 17β-estradiol atheroprotective effect on subclinical atherosclerosis progression.

Increased plasma nitric oxide, L‐arginine, and arginase‐1 in cirrhotic patients with progressive renal dysfunction

Increased levels of nitric oxide (NO) are hypothesized to contribute to renal dysfunction in patients with decompensated cirrhosis. In this study, we examined whether splanchnic and/or peripheral NO levels and L-arginine (L-Arg) correlate with progressive renal dysfunction in cirrhotics. Serum NO metabolites (NOx) and L-Arg were measured in: controls (n = 10); organ donors (n = 12); compensated cirrhotics (n = 17), cirrhotics with ascites (n = 25), refractory ascites (n = 11) or hepatorenal syndrome type II (HRS) (n = 11) and chronic renal failure patients (n = 18). Plasma NOx and L-Arg levels rose progressively with worsening renal function in decompensated cirrhotics. Both NOx and L-Arg levels were highest in patients with HRS (P < 0.001 and P < 0.025, respectively). While there were no differences in NOx levels related to the site of sampling, L-Arg levels were lowest in hepatic venous blood. There were significant relationships of NOx and L-Arg with Model for End-Stage Liver Disease score and Child-Pugh scores (P < 0.04 and P < 0.01, respectively). Multivariate analysis showed a significant relationship between NOx, L-Arg and HRS. Worsening renal function in decompensated cirrhosis is accompanied by progressive elevation in plasma NOx and L-Arg. These findings support the hypothesis that NO-mediated vasodilation is probably linked with the mechanism of progressive renal failure in decompensated cirrhotics.

Metformin Prevents Progression of Heart Failure in Dogs

Some studies have shown that metformin activates AMP-activated protein kinase (AMPK) and has a potent cardioprotective effect against ischemia/reperfusion injury. Because AMPK also is activated in animal models of heart failure, we investigated whether metformin decreases cardiomyocyte apoptosis and attenuates the progression of heart failure in dogs. Treatment with metformin (10 micromol/L) protected cultured cardiomyocytes from cell death during exposure to H2O2 (50 micromol/L) via AMPK activation, as shown by the MTT assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and flow cytometry. Continuous rapid ventricular pacing (230 bpm for 4 weeks) caused typical heart failure in dogs. Both left ventricular fractional shortening and left ventricular end-diastolic pressure were significantly improved in dogs treated with oral metformin at 100 mg x kg(-1) x d(-1) (n=8) (18.6+/-1.8% and 11.8+/-1.1 mm Hg, respectively) compared with dogs receiving vehicle (n=8) (9.6+/-0.7% and 22+/-0.9 mm Hg, respectively). Metformin also promoted phosphorylation of both AMPK and endothelial nitric oxide synthase, increased plasma nitric oxide levels, and improved insulin resistance. As a result of these effects, metformin decreased apoptosis and improved cardiac function in failing canine hearts. Interestingly, another AMPK activator (AICAR) had effects equivalent to those of metformin, suggesting the primary role of AMPK activation in reducing apoptosis and preventing heart failure. Metformin attenuated oxidative stress-induced cardiomyocyte apoptosis and prevented the progression of heart failure in dogs, along with activation of AMPK. Therefore, metformin may be a potential new therapy for heart failure.

Thermoregulation and Vasopressin Secretion during Polymicrobial Sepsis

Objective: We investigated the time course of thermoregulation, nitric oxide (NO) formation and hydroelectrolytic alterations, as well as mean arterial pressure and arginine vasopressin (AVP) secretion, in experimental sepsis induced by cecal ligation and puncture (CLP). Methods: Male Wistar rats submitted to CLP or a sham operation were divided into 4 groups, as follows: group 1, for survival rate evaluation for 24 h; group 2, for body temperature (Tb) analysis; group 3, for mean arterial pressure registration, and group 4, for blood collection and processing of the neurohypophysis and hypothalamic nuclei 0, 2, 4, 6 and 24 h after surgery. AVP levels and content were measured in plasma, neurohypophysis and the hypothalamic paraventricular and supraoptic nuclei. Results: Animals which underwent CLP showed high mortality, a progressive decrease in mean arterial pressure and an increase in plasma NO. Tb dropped during the first 4 h and showed a progressive increase 6 h after surgery. Plasma AVP levels increased immediately after CLP surgery and again at 6 h, before returning to basal levels at 24 h. This was followed by a depletion of neurohypophyseal AVP content at 4 h that continued until 24 h. AVP content in the supraoptic nucleus was elevated 24 h after CLP surgery, while in the paraventricular nucleus, an increase was observed at 6 h and 24 h. Conclusions: In the present study, laparotomy and hypotension may have been responsible for the increase in plasma AVP in the initial phase of polymicrobial sepsis, and this may have contributed to the observed hypothermia. Moreover, an apparently impaired replenishment of AVP content in the neurohypophysis, possibly due to increased NO formation, may explain the impaired AVP secretion in the late phase of severe sepsis.

Mechanisms responsible for pulmonary hypertension

Mechanisms responsible for pulmonary hypertension

Lack of evidence for contribution of intron4a/b polymorphism of endothelial nitric oxide synthase (NOS3) gene to plasma nitric oxide levels

Objective — Nitric oxide (NO) is synthesized from L-arginine by endothelium nitric oxide synthase (NOS3). It has been shown that reduced NO synthesis in endothelial cells has been implicated in the development of coronary atherosclerosis.We hypothesized that polymorphisms of NOS3 gene might be associated with increased susceptibility of coronary artery disease (CAD) and plasma NO concentrations.Methods and results — We studied the NOS3 intron4 gene polymorphism in 141 unrelated CAD patients with positive coronary angiograms in the Shahid Rajaee Heart Hospital and 159 age-matched control subjects without a history of symptomatic CAD.The NOS3 gene polymorphism was analysed by polymerase chain reaction. Plasma NO was also determined. The genotype frequencies for NOS34a/b polymorphism differed significantly between CAD patients and controls (P = 0.041). Mean plasma NOx concentration was significantly higher (P = 0.0009) in CAD patients (87.5 μM) than in controls (62.7 μM). Mean plasma NOx concentrations in the subjects with 4a allele and in the subjects without 4a allele were not significantly different. Plasma lipids, except HDL-C were also remarkably increased in the CAD group.Conclusions — The present study provides evidence that the intron4a/b polymorphism of the NOS3 gene is associated with CAD. Mean plasma NO was higher in CAD patients than in control subjects. The NOS34a/b polymorphism was not associated with increased plasma NO.

Is nitric oxide involved in the pathophysiology of essential hyperhidrosis?

Essential hyperhidrosis (EH) is a disorder of excessive, bilateral, and relatively symmetric sweating occurring in the axillae, palms, soles, or craniofacial region without obvious etiology. The expression of endothelial nitric oxide synthase (eNOS) in eccrine clear cells, reported by an immunohistochemical technique, has suggested that nitric oxide (NO) may play a role in the physiology of production and/or excretion of sweat in the human skin eccrine gland. To determine plasma NO levels in patients with EH and healthy controls. We assessed the levels of plasma NO in patients with EH (n = 31) in comparison with those in age- and sex-matched healthy controls (n = 28). Total nitrite (nitrite + nitrate) was measured by a spectrophotometer at 545 nm after the conversion of nitrate to nitrite by copperized cadmium granules. Plasma NO levels were found to be significantly increased in EH patients in comparison with the control group (P = 0.0001). These findings indicate a possible role of increased plasma NO levels in the pathophysiology of EH.

Does hormone treatment alter arterial properties in postmenopausal women?

Arterial elastic properties and wave reflections constitute left ventricular pulsatile afterload and are directly related to cardiovascular morbidity and mortality. During the aging process, elastic arteries stiffen and increase pulse wave velocity, causing the reflected pressure wave to arrive at the heart during systole, and augment systolic and pulse blood pressure, resulting in left ventricular hypertrophy. The incidence of cardiovascular disease is much greater in men aged 30–50 years compared with women of a similar age. Among women, the incidence of cardiovascular disease increases dramatically after menopause, which occurs at an average age of 52 years. This observation has lead to the belief that sex hormones produced premenopausally impede or delay the progression of cardiovascular disease. Therefore, it appears logical that the administration of female sex hormones, hormone treatment (HT), estrogen alone or with progesterone should provide some degree of cardiovascular protection. This idea was supported by experiments in animals and isolated arterial segments demonstrating that HT increases plasma nitric oxide, decreases endothelin-1 levels and causes smooth muscle relaxation. Also, 17β-estradiol administration decreases collagen and increases elastin in the aortic wall of rats. These experimental studies suggest an improvement in both elastic and muscular artery properties and favorabe modifications of arterial wave reflection characteristics. Furthermore, HT improves lipoprotein metabolism and reduces coronary artery plaque formation in animal models. Unfortunately, observational and interventional studies in postmenopausal women that have evaluated the impact of HT on cardiovascular changes have produced inconsistent and inconclusive results. Most studies agree that arterial stiffness increases after menopause, partly due to advancing age and reduced estrogen production. Results from most studies that were designed to investigate the effects of HT on arterial properties have shown a selective decrease in elastic artery stiffness with little effect on muscular arteries. This beneficial effect was observed only if estrogen alone was administered. The main objective of this review is to discuss the ill effects of arterial stiffness in general and attempt to translate information from previous experimental studies to those in postmenopausal women and explain the beneficial effects of HT on arterial stiffness and improvement in left ventricular afterload.

Enhanced erythro-phagocytosis in polycythemic mice overexpressing erythropoietin

AbstractAdaptive mechanisms to hematocrit levels of 0.9 in our erythropoietin-overexpressing mice (tg6) include increased plasma nitric oxide levels and erythrocyte flexibility. Doubled reticulocyte counts in tg6 suggest an increased erythrocyte turnover. Here we show that compared with wild-type (wt) animals, erythrocyte lifespan in tg6 is 70% lower in tg6 mice. Transgenic mice have a younger erythrocyte population as indicated by higher intercellular water and potassium content, higher flexibility, decreased density, increased surface to volume ratio, and decreased osmotic fragility. Interestingly, despite being younger, the tg6 erythrocyte population also harbors characteristics of accelerated aging such as an increased band 4.1a to 4.1b ratio, signs of oxidative stress, or decreased surface CD47 and sialic acids. In tg6, in vivo tracking of PKH26-labeled erythrocytes revealed dramatically increased erythrocyte incorporation by their liver macrophages. In vitro experiments showed that tg6 macrophages are more active than wt macrophages and that tg6 erythrocytes are more attractive for macrophages than wt ones. In conclusion, in tg6 mice erythrocyte aging is accelerated, which results, together with an increased number and activity of their macrophages, in enhanced erythrocyte clearance. Our data points toward a new mechanism down-regulating red cell mass in excessive erythrocytosis in mice.

Soy Consumption, Markers of Inflammation, and Endothelial Function

To determine the effects of soy consumption on markers of inflammation and endothelial function in postmenopausal women with the metabolic syndrome. This randomized cross-over clinical trial included 42 postmenopausal women with the metabolic syndrome. Participants were randomly assigned to consume a control diet (Dietary Approaches to Stop Hypertension [DASH]), soy protein diet, or soy nut diet, each for 8 weeks. Red meat in the DASH diet (one serving/day) was replaced by soy protein in the soy protein diet and by soy nut in the soy nut diet. For nitric oxide levels, the difference from the control diet was 9.8% (P < 0.01) on the soy nut and -1.7% (P = 0.10) on the soy protein diets. The difference from the control diet for serum E-selectin was -11.4% (P < 0.01) on the soy nut consumption and -4.7% (P = 0.19) on the soy protein diet. Soy nut consumption reduced interleukin-18 compared with the control diet (difference from the control diet: -9.2%, P < 0.01), but soy protein did not (difference from the control diet: -4.6%, P = 0.14). For C-reactive protein, the difference from the control diet was -8.9% (P < 0.01) on the soy nut diet and -1.6% (P < 0.01) on the soy protein diet. Short-term soy nut consumption reduced some markers of inflammation and increased plasma nitric oxide levels in postmenopausal women with the metabolic syndrome.

Relation Between Plasma Nitric Oxide Levels and Diabetic Retinopathy

Nitric oxide (NO) plays an important role in homeostatic vasodilation and the regulation of blood flow. On the other hand, excess release of NO causes various vascular complications. There are only a few reports on the relationship between plasma NO levels and microvascular complications, especially diabetic retinopathy (DR) in patients with type 2 diabetes. The purpose of this study was to determine the relationship between plasma NO levels and DR. In a prospective study, blood samples were obtained from 36 patients with diabetes and no diabetic retinopathy (NDR), 43 patients with nonproliferative diabetic retinopathy (NPDR), 18 patients with proliferative diabetic retinopathy (PDR), and 40 subjects without diabetes mellitus, who served as controls. The levels of plasma NOx (nitrite and nitrate), the stable metabolites of NO, were measured by high-performance liquid chromatography with the Griess method. The plasma NOx levels were 92.8 +/- 16.0, 70.2 +/- 6.8, 90.3 +/- 9.1, and 53.8 +/- 6.1 micromol/l in patients with NDR, NPDR, or PDR, and in the controls, respectively. The plasma NOx levels in the three diabetic groups were significantly higher than those in the control group (P < 0.05 in each case). The increased plasma NO levels in patients with type 2 diabetes indicate that NO may be associated with the pathogenesis of DR.

Increased Plasma Nitric Oxide Metabolites in Suicide Attempters

Objective: To evaluate any correlation between plasma levels of nitric oxide metabolites (NO_x) and suicide attempt. Method: Plasma NO_x levels were measured in 53 patients who had recently attempted suicide, 58 nonsuicidal psychiatric patients, and 75 normal controls. The severity of suicidal behaviors was evaluated using Weisman and Worden’s Risk-Rescue Rating Scale. Results: Plasma NO_x levels were significantly higher in suicidal patients than nonsuicidal psychiatric patients or normal control subjects (F = 11.029, d.f. = 2, 183, p < 0.001). Among the patients with a diagnosis of major depression, suicidal depressive patients had significantly higher plasma NO_x levels than nonsuicidal depressive patients (t = –3.090, d.f. = 84, p = 0.003). Conclusion: Our study suggests that increased NO production in plasma is associated with suicide attempt, especially in depressive patients.

Increased plasma nitric oxide level associated with suicide attempt in depressive patients

Background Nitric oxide (NO) is known to influence cerebral monoaminergic activity, including the activity of serotonin. We evaluated plasma NO metabolite (NO x ) levels in depressive patients with and without a recent history of suicide attempt. Method Plasma NO x levels were measured in 39 depressive patients who had recently attempted suicide, 44 non-suicidal depressed patients, and 70 normal controls. The severity of depression was measured with the Hamilton's Depression Rating Scale. The lethality of the suicide attempt was scored using Weisman and Worden's risk-rescue rating scale and Lethality Suicide Attempt Rating Scale. Results Plasma NO x levels were significantly higher in suicidal depressive patients than non-suicidal depressive patients or normal control subjects ( Z = − 2.472, p = 0.013). However, higher plasma NO x levels in suicidal depressive patients were significantly related to a lower lethality of suicide attempts and lower severity of depression. Conclusions Our study suggests that increased plasma NO x level is associated with suicide attempts in depressive patients. Moreover, higher plasma NO x level is related with suicide attempts in mild depressed patients. However, further studies are required to understand the role of NO system in depression and suicidal behavior.

Changes in pulmonary arteriole protein kinase cα expression associated with supplemental L-arginine in broilers during cool temperature exposure

1. The present study was conducted to examine the effect of supplemental L-arginine on pulmonary arteriole protein kinase Cα (PKCα) expression in broilers exposed to cool temperature, to investigate further the molecular mechanisms of supplemental L-arginine on modulating pulmonary vascular functions in hypertensive broilers. 2. Broilers were subjected to sub-thermoneutral (cool) temperature to induce pulmonary hypertension syndrome (PHS), and an additional 10 g/kg L-arginine was added to the basal diet to evaluate the effects of supplemental L-arginine on PHS mortality, plasma nitric oxide (NO) production and pulmonary arterioles PKCα expression. 3. Supplemental L-arginine reduced PHS mortality but did not affect right/total ventricle (RV/TV) ratios in clinically healthy birds. Birds fed additional L-arginine had increased plasma NO and decreased PKCα protein expression in pulmonary arterioles; NO production was negatively correlated with PKCα expression. 4. These results demonstrated that supplemental L-arginine diminished PKCα expression in birds exposed to cool temperature. It is suggested that NO-induced loss of PKCα expression might be partially responsible for its effects on dilating pulmonary vasculature and inhibiting pulmonary vascular remodelling in vivo.

Lipopolysaccharide‐induced oxidative stress is not potentiated by knockout of GPX1 and SOD1 in mice

Our lab has previously found that knockout of cellular glutathione peroxidase (GPX1) and copper, zinc-superoxide dismutase (SOD1) attenuated protein nitration mediated by peroxynitrite. Because bacterial endotoxin lipopolysaccharide (LPS) triggers inflammatory responses involving the release of cytokines, nitric oxide (NO) and superoxide in targeted organs such as liver, we used GPX1 knockout (GPX1−/−), SOD1 knockout (SOD1−/−), GPX1 and SOD1 double-knockout (DKO) and their wild-type (WT) mice to investigate the role of these two antioxidant enzymes in LPS-induced oxidative injury in liver. Mice of the four genotypes (2-month old, Se-adequate) were killed at 0, 3, 6 or 12 h after an ip injection of saline or 5 mg LPS/kg body weight. The LPS injection caused similar increase in plasma alanine aminotransferase (P < 0.05) among the four genotypes. Hepatic total glutathione (GSH) was decreased (P < 0.05) compared with the initial values by the LPS injection at all time points in the WT mice, but only at 6 and 12 h in the other three genotypes. The GSH level in the DKO mice was higher (P < 0.05) than in the WT at 6 h. Although the LPS injection resulted in substantial increases in plasma NO in a time-dependent manner in all genotypes, the NO level in the DKO mice was lower (P < 0.05) at 3, 6, and 12 h than in the WT. The level in the GPX1−/− and SOD1−/− mice was also lower (P < 0.05) than in the WT at 3 h. The LPS-mediated hepatic protein nitration was detected in the WT, GPX1−/− and DKO mice at 3, 6 or 12 h, but not in the SOD1−/−. In conclusion, knockout of GPX1 and (or) SOD1 did not potentiate the LPS-induced liver injury, but delayed the induced hepatic GSH depletion and plasma NO production. [NIH DK53108 to XGL]