Increased Plasma Nitric Oxide Research Articles

The effect of exenatide (a GLP-1 analogue) and sitagliptin (a DPP-4 inhibitor) on asymmetric dimethylarginine (ADMA) metabolism and selected biomarkers of cardiac fibrosis in rats with fructose-induced metabolic syndrome

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis, is a risk factor for endothelial dysfunction, a common pathophysiological denominator for both atherogenesis and cardiac fibrosis.We aimed to investigate whether the cardioprotective and antifibrotic effects of incretin drugs, exenatide and sitagliptin, may be associated with their ability to affect circulating and cardiac ADMA metabolism.Normal and fructose-fed rats were treated with sitagliptin (5.0/10 mg/kg) or exenatide (5/10 µg/kg) for 4 weeks. The following methods were used: LC-MS/MS, ELISA, Real-Time-PCR, colorimetry, IHC and H&E staining, PCA and OPLS-DA projections.Eight-week fructose feeding resulted in an increase in plasma ADMA and a decrease in NO concentration. Exenatide administration into fructose-fed rats reduced the plasma ADMA level and increased NO level. In the heart of these animals exenatide administration increased NO and PRMT1 level, reduced TGF-ß1, α-SMA levels and COL1A1 expression. In the exenatide treated rats renal DDAH activity positively correlated with plasma NO level and negatively with plasma ADMA level and cardiac α-SMA concentration. Sitagliptin treatment of fructose-fed rats increased plasma NO concentration, reduced circulating SDMA level, increased renal DDAH activity and reduced myocardial DDAH activity. Both drugs attenuated the myocardial immunoexpression of Smad2/3/P and perivascular fibrosis.In the metabolic syndrome condition both sitagliptin and exenatide positively modulated cardiac fibrotic remodeling and circulating level of endogenous NOS inhibitors but had no effects on ADMA levels in the myocardium.

Dietary ARA, DHA, and Carbohydrate Ratios Affect the Immune Status of Gilthead Sea Bream Juveniles upon Bacterial Challenge.

This study aims to assess the effects of different dietary n-6/n-3 long-chain polyunsaturated fatty acid ratios and CHO content in the immune response of gilthead seabream. For that purpose, gilthead sea bream juveniles (initial body weight = 47.5 g) were fed for 84 days with four isoproteic (47% crude protein) and isolipidic (18% crude lipids) diets with high (20%) or low (5%) level of gelatinized starch (HS or LS diets, respectively) and included approximately 2.4% ARA or DHA. At the end of the trial, the DHA-enriched groups presented increased red blood cell (RBC) count, hemoglobin, plasmatic nitric oxide (NO) content, and antiprotease and alternative complement activities. The ARA groups had increased thrombocyte count, and plasmatic bactericidal activity against Vibrio anguillarum was lower in the fish fed the ARA/LS diet. After the feeding trial, the fish were challenged with an intraperitoneal injection (i.p.) of killed Photobacterium damselae subsp. piscicida (Phdp) and sampled at 4 and 24 h after the challenge. At 4 h after i.p., the ARA groups presented increased plasma total immunoglobulins (Ig) and bactericidal activity against V. anguillarum. In addition, the fish fed the ARA/LS diet presented lower white blood cell (WBC) and alternative complement activity. At 24 h after i.p., the ARA groups presented increased RBC, WBC, and thrombocyte numbers, total IG, plasma peroxidase activity, and casp3 expression in the distal intestine. The HS groups presented increased plasma NO content and bactericidal activity against Phdp and decreased protease, antiprotease activity, and bactericidal activity against V. anguillarum. In conclusion, high dietary DHA levels seemed to improve the immune status of unchallenged gilthead sea bream juveniles, while high dietary ARA levels improved the fish immune response to a bacterial challenge. The energy provided by dietary starch seems to be important to promote a fast response by the fish immune system after a challenge.

Dietary nitrate improves jaw bone remodelling in zoledronate-treated mice.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious complication that occurs in patients with osteoporosis or metastatic bone cancer treated with bisphosphonate. There is still no effective treatment and prevention strategy for BRONJ. Inorganic nitrate, which is abundant in green vegetables, has been reported to be protective in multiple diseases. To investigate the effects of dietary nitrate on BRONJ-like lesions in mice, we utilized a well-established mouse BRONJ model, in which tooth extraction was performed. Specifically, 4 mM sodium nitrate was administered in advance through drinking water to assess the short- and long-term effects on BRONJ. Zoledronate injection could induce severe healing inhibition of the tooth extraction socket, while addition of pretreating dietary nitrate could alleviate the inhibition by reducing monocyte necrosis and inflammatory cytokines production. Mechanistically, nitrate intake increased plasma nitric oxide levels, which attenuated necroptosis of monocytes by downregulating lipid and lipid-like molecule metabolism via a RIPK3 dependent pathway. Our findings revealed that dietary nitrate could inhibit monocyte necroptosis in BRONJ, regulate the bone immune microenvironment and promote bone remodelling after injury. This study contributes to the understanding of the immunopathogenesis of zoledronate and supports the feasibility of dietary nitrate for the clinical prevention of BRONJ.

0153 Bright light exposition potentiates the vasodilation promoted by dynamic handgrip exercise

Abstract Introduction Bright light (~5000 lux) directed at human skin increases plasma nitric oxide concentration promoting vasodilation, with increased skeletal muscle blood flow (BF) and decreased blood pressure (BP). The same stimulus directed at the eyes increases sympathetic activity, promoting vasoconstriction and increased BP. If bright light potentiates or mitigates the vasodilation promoted during exercise is unknown. Therefore, this study aimed to compare the effect of different intensities of lights on vasodilation of the active skeletal muscle during dynamic handgrip exercise. Methods Eleven healthy and physically inactive adult men (29±6 years) participated of the current study. All experiments were conducted between June and July 2021, beginning at 5 PM and under constant environmental conditions. Subjects performed dynamic handgrip exercise using the dominant arm at a 90º angle in the supine position with 2 s cycles of contraction and relaxation for 6 min at 40% of maximal voluntary contraction during the three experimental condition in a randomized order: (BL) 5000 lux, Control light (CL) 500 lux, and Dim light (DL) ≤8 lux. In each condition, (BL, CL or DL), subjects remained in a rested state for 20 min before 1 min of baseline assessment followed by exercise. Conditions were always separated by 20 min of washout (under CL). Assessments comprised BF, vascular conductance (VC), and diameter of brachial artery of exercising arm (Ultrasound); BP measured in the rest arm (Photoplethysmography) and heart rate (ECG). Two-way ANOVA for repeated measures, p≤0.05. Results Baseline were not different (p>0.05). During exercise, BF and VC increased in the three conditions, however it was potentiated by BL (p < 0.0001 and p < 0.0001, respectively) compared with CL (+19% and +15%, respectively) and with DL (+12% and +11%, respectively). Arterial diameter increased similarly in the three conditions. Mean BP increased in the three conditions, however it was attenuated in the BL compared with DL (-23%) and similar to CL (<0.0001). Conclusion Bright light can potentiate skeletal muscle vasodilation during a small-mass muscle exercise attenuating the increase of BP. Support (If Any) The São Paulo Research Foundation - FAPESP 2020/11588-2.

Antihypertensive Effect of Dietary β-Conglycinin in the Spontaneously Hypertensive Rat (SHR).

Dietary β-conglycinin has been shown to increase plasma adiponectin concentration and decrease visceral adipose tissue weight in rats. Since adiponectin is one of the factors regulating blood pressure, as well as modulating lipid metabolism, we examined whether dietary β-conglycinin affects blood pressure in spontaneously hypertensive rats. The experimental diets were prepared according to the AIN-93G formula containing 20% protein, either casein (Control) or casein replaced with soy protein isolate (SOY) or β-conglycinin (β-CON) at the proportion of 50%. Male rats (SHR/Izm, 6 wk-old) were fed the diets for 7 weeks. The SOY compared with the Control significantly suppressed the blood pressure both at week 4 (p = 0.011, Control vs. SOY) and thereafter, and β-CON had even higher suppression (p = 0.0002, Control vs. β-CON). SOY and β-CON increased plasma adiponectin concentration followed by an increase in plasma nitric oxide and possibly a decreasing trend of gene expressions of angiotensinogen in the liver and renin in the kidney. The results indicated suppression by β-conglycinin of increasing blood pressure through an enhancement of plasma adiponectin, probably in combination with a regulation of the renin–angiotensin system in spontaneously hypertensive rats.

Poly I:C and R848 facilitate nitric oxide production via inducible nitric oxide synthase in chicks

Nitric oxide (NO) is a gaseous bioactive molecule associated with many physiological functions including vasodilation and neurotransmission. NO also plays an important role in immune responses during viral infections in mammals. However, there is a paucity of knowledge regarding the involvement of NO in viral infections in birds. Therefore, the purpose of the present study was to determine if intraperitoneal (IP) injection of poly I:C and R848 (resiquimod), which are analogues of virus component, affects NO production in chicks (Gallus gallus) as a bird model. The involvement of inducible NO synthase (iNOS) in poly I:C- and R848-induced anorexia and corticosterone release was also investigated. These virus analogues significantly increased plasma NO metabolites (NOx) concentrations. IP injection of poly I:C and R848 significantly increased iNOS mRNA expression in several organs including the liver. On the other hand, poly I:C and R848 significantly decreased mRNA expressions of endothelial NOS and neural NOS in several organs, indicating that induction of iNOS might be responsible for increased NOx levels in plasma. This finding was further confirmed by using a selective iNOS inhibitor, S-methylisothiourea sulfate (SMT), which abolished the poly I:C- and R848-induced increase in plasma NOx concentration. In addition, SMT partly attenuated the poly I:C- and R848-induced increase in plasma corticosterone concentration, suggesting that corticosterone release induced by these virus analogues may be partly mediated by iNOS. Collectively, the present results suggest that viral infections facilitate NO production by inducing iNOS. The liver would play an important role in the NO production because the response in iNOS mRNA expression to poly I:C and R848 was remarkable. The present results also suggest that NO is associated with corticosterone release in birds under viral infection.

Effect of nitrate administration on plasma nitric oxide levels in patients with peripheral arterial disease at Dr. Sardjito General Hospital, Yogyakarta

Peripheral arterial disease (PAD) is a disease involving reduction of blood flow to the inferior extremity associated with atherosclerotic lesions. In 2010, more than 200 million people with PAD were reported globally, including 54.8 million in Southeast Asia. The high prevalence of PAD causes its management become challenging for clinicians. Nitric oxide (NO) has a role in endothelial function that is associated with the appearance of symptoms in PAD patients. Exogenous nitrate is usually used as a primary vasodilator in the treatment of angina pectoris and Prinzmetal angina. However, information concerning the role of nitrate administration to improve symptomatic PAD patients is limited. This study aimed to evaluate the effectiveness of exogenous nitrates in increasing plasma NO levels and improving PAD patients. A prospective pre-post clinical trial involving PAD patients who were registered in the vascular registry at Dr. Sardjito General Hospital, Yogyakarta was conducted. Primary endpoint was the change in plasma NO levels after short term administration of nitroglycerin oral 2.5 mg once daily (4 h) and long term (7 d). Analysis of variance test with Bonferroni posttest was used for statistical hypothesis testing. Among 33 subjects who completed this study, no negative side effects, and only one hypotensive patient was reported at the first follow-up after 4 h of the nitroglycerin administration. Plasma NO levels increased in the post 4 h and in the post 7 d administration. However, no statistically significant was observed (p > 0.05). Administration of exogenous nitrates in patients with PAD increases the plasma NO levels, even though it is not statistically significant.

Galangin alleviates vascular dysfunction and remodelling through modulation of the TNF-R1, p-NF-κB and VCAM-1 pathways in hypertensive rats

Galangin is a natural flavonoid isolated from ginger, honey and propolis. Aims: To investigate the effect of galangin on blood pressure, vascular changes, sympathoexcitation, oxidative stress and inflammation in rats treated with NG-nitro-l-arginine methyl ester (l-NAME). Materials and methods: Male Wistar rats (220-250 g) were given l-NAME (0.5 mg/mL in drinking water) to induce hypertension for 5 weeks. They were treated with vehicle, galangin (30 or 60 mg/kg), or amlodipine (10 mg/kg) for the final two weeks (n = 6/group). Key findings: Galangin significantly reduced blood pressure and improved the impairment of endothelium-dependent vasodilation in hypertensive rats. Sympathoexcitation, including enhancement of contractile responses to electrical field stimulation, increases in intensity of tyrosine hydroxylase and plasma norepinephrine concentration in hypertensive rats, was attenuated by galangin treatment. Galangin also reduced systemic and vascular oxidative damage and increased plasma nitric oxide levels in the hypertensive groups. Aortic remodelling accompanied by aortic wall hypertrophy and fibrosis observed in hypertensive rats were alleviated by galangin treatment. Furthermore, galangin exhibited an anti-inflammatory effect by suppressing the upregulation of tumour necrosis factor receptor 1 (TNF-R1), phospho-nuclear factor kappa B (p-NF-κB) and vascular cell adhesion protein 1 (VCAM-1) in aortic tissue and reducing plasma tumour necrosis factor alpha (TNF-α) in l-NAME rats. In conclusion, galangin had antihypertensive effects that were relevant to attenuating endothelial dysfunction, sympathoexcitation and vascular remodelling. These effects might be contributed by antioxidant and anti-inflammatory capacities and modulation of the TNF-R1, p-NF-κB and VCAM-1 pathways in hypertensive rats.

The effect of coenzyme Q10 on blood plasma nitric oxide and total antioxidant capacity levels in hypothyroidism-induced rats

In this study, the effect of coenzyme Q10 (CoQ10) on nitric oxide (NO) and total antioxidant (TAS) capacity in rats for which experimentally hypothyroidism was induced through PTU was investigated. A total of 32 healthy male Wistar Albino rats weighing 300-350g, approximately 12 weeks old, were used as animal material in the study. . Rats were divided into 4 experimental groups as control (K), Coenzyme Q10 (C), Hypothyroidism (H), and Coenzyme Q10 + Hypothyroidism (CH). During the trial period of three weeks, 3mg CoQ10 (10mg/kg/day) was dissolved in 0.3 ml of maize oil and intraperitoneally administered for each animal in group C. In group H, PTU has added to drinking water daily at a weight/volume (w/v) ratio of %0.05. In the HC group, coenzyme Q10 was administered intraperitoneally and PTU was administered with drinking water at a rate of %0.05. TT4, TT3, and TSH levels were determined in serum samples and NO and TAS levels in plasma samples. In the present study; the highest plasma NO level among the groups was determined in group H (p<0.05) and there was no significant difference between other groups (H, C, HC) (p>0.05). The plasma TAS value of group H was found to be significantly higher than the same value in the K, C and HC groups (p<0.05). The plasma TAS level in group C had no difference from the same value in the HC group (p>0.05), although it was higher than the same value of group K (p<0.05). As a result, it was found to cause oxidative stress in hypothyroidism-induced rats with a particular increase in plasma NO levels, and CoQ10 was found to be effective in normalizing the increased plasma NO level due to hypothyroidism.

Extract of varieties of guava (Psidium guajava L.) leaf modulate angiotensin-1-converting enzyme gene expression in cyclosporine-induced hypertensive rats

BackgroundHypertension has become a serious health problem with which people have to live day by day, it sometimes results in severe organ damage with a dead end. Management with Psidium guajava L. (guava) leaf extract through modulation of angiotensin-converting enzyme (ACE) mRNA expression would give succor to patients with hypertension. However, there are several reports on medicinal efficacy of guava leaf with dearth of information on its varieties. HypothesisElevation of the ACE mRNA level in the kidney plays a primary role in the acceleration of local angiotensin II formation and thus sustain hypertension. Studies have shown the significance of investigating the molecular mechanism of ACE activities in pathophysiological states, this work sought to investigate the modulatory effect of aqueous extract of leaf from different varieties of guava on ACE mRNA gene expression in cyclosporine-induced hypertensive rats. MethodsHypertension was induced via intraperitoneal (i.p) administration of cyclosporine (25mg/kg/day); an aqueous extract of leaves from white, red, and pink guava was prepared, 250 and 500mg/kg body weight of the extracts were administered to the rats by oral gavage for 7 days. The systolic (SBP) and diastolic (DBP) blood pressure was measured, ACE mRNA expression level was determined using RT-qPCR, with kidney function markers in plasma (creatinine, urea, and uric acid), plasma nitric oxide level, the kidney histopathology, as well as phenolic characterization of the guava leaves. ResultsThe results showed a significant (p<0.05) increase in SBP, DBP, plasma creatinine, urea, and uric acid concentration, as well as nitric oxide level with up-regulation of ACE gene expression in the rats' kidneys with severe glomerular damage, necrosis, and capillary collapse. However, a significant (p<0.05) down-regulation of ACE mRNA expression level, reduced serum creatinine, urea, and uric acid concentration with mild-moderate kidney damage was observed in the treated rats. The leaves extract characterization and quantification revealed chlorogenic acid, rutin, vanillic acid, and quercetin as the most abundant phenolic compounds in the leaves. ConclusionsThe oral administration of the aqueous extract of different varieties of guava leaf (rich in phenolics), reduced SBP, DBP, kidney function markers concentration in the plasma, with increased plasma nitric oxide level, ameliorate kidney damage, and down-regulate renal ACE gene expression with no significant (p>0.05) difference in activities of extracts from different varieties of guava leaves used for this study. This could be a useful therapeutic measure for the treatment/management of hypertension.

Effects of Dietary N-carbamylglutamate on Growth Performance, Apparent Digestibility, Nitrogen Metabolism and Plasma Metabolites of Fattening Holstein Bulls.

Simple SummaryIt is critical to find an effective and safe feed additive to improve the utilization of nitrogen by ruminants. N-carbamylglutamate (NCG), a structural analogue of N-acetylglutamate, may have the potential to improve the utilization of nitrogen by bulls. Therefore, the effects of adding different levels of NCG on the growth performance, nutrient digestibility, nitrogen metabolism and plasma metabolites of fattening Holstein bulls were investigated in this study. The addition of NCG increased concentrations of plasma Arg, Ile, Val, total essential amino acid and total nonessential amino acid, which in turn resulted in higher N utilization and CP digestibility for growth and, therefore, higher average daily gain in NCG-fed bulls.N-carbamylglutamate (NCG), a structural analog of N-acetylglutamate, improves nitrogen utilization in dairy cows. However, the effects of NCG on bulls are unknown. The purpose of the current research was to investigate the effects of adding different amounts of NCG on growth performance, nutrient digestibility, nitrogen metabolism and plasma metabolites of fattening Holstein bulls. Twenty-four Holstein bulls with similar body weights (BW, 408 ± 21.9 kg) and ages (450 ± 6.1 d; all mean ± SD) were selected for the feeding trial. After 2 weeks of adaptation, bulls were blocked by BW and age and subsequently randomly assigned to 1 of 4 groups: (1) CON group (control diet), (2) L group (supplementation with 20 mg/kg BW NCG), (3) M group (supplementation with 40 mg/kg BW NCG), or (4) H group (supplementation with 80 mg/kg BW NCG). The addition of NCG linearly and quadratically increased the average daily gain (CON vs. L vs. M vs. H = 1.03 vs. 1.19 vs. 1.40 vs. 1.26 kg/d) (p < 0.05), feed conversion ratio (CON vs. L vs. M vs. H = 11.92 vs. 9.22 vs. 7.76 vs. 8.62) (p < 0.05), crude protein digestibility (CON vs. L vs. M vs. H = 64.3 vs. 63.8 vs. 67.7 vs. 65.8%) (0.05 < p < 0.10), N retention (p < 0.05) and N utilization (p < 0.05) of bulls, whereas the contents of fecal N (0.05 < p < 0.10) and urinary N (0.05 < p < 0.10) in NCG-fed bulls linearly decreased compared with those in CON bulls. Bulls fed NCG showed a quadratic increased plasma nitric oxide (p < 0.05) concentration. Furthermore, Arg (p < 0.05), Ile (p < 0.05), Val (p < 0.05), Ala (p < 0.05), Glu (p < 0.05), Ser (p < 0.05), total essential amino acid (p < 0.05) and total nonessential amino acid (p < 0.05) concentrations linearly and quadratically increased with increasing doses of NCG. In contrast, plasma urea (p < 0.05) and ammonia (p < 0.05) concentration linearly and quadratically decreased with increasing doses of NCG. Overall, the addition of NCG increased plasma Arg, Ile, Val, TEAA and TNEAA concentration, which in turn resulted in a higher N utilization and, therefore, higher average daily gain in NCG-fed bulls, providing baseline data for the widespread application of NCG in beef cattle production.

L-Citrulline Supplementation Increases Plasma Nitric Oxide Levels and Reduces Arginase Activity in Patients With Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) is becoming a major contributor to cardiovascular disease. One of the early signs of T2DM associated cardiovascular events is the development of vascular dysfunction. This dysfunction has been implicated in increasing the morbidity and mortality of T2DM patients. One of the important characteristics of vascular dysfunction is the impaired ability of endothelial cells to produce nitric oxide (NO). Additionally, decreases in the availability of NO is also a major contributor of this pathology. NO is produced by the activity of endothelial NO synthase (eNOS) on its substrate, L-arginine. Reduced availability of L-arginine to eNOS has been implicated in vascular dysfunction in diabetes. Arginase, which metabolizes L-arginine to urea and ornithine, competes directly with NOS for L-arginine. Hence, increases in arginase activity can decrease arginine levels, reducing its availability to eNOS and decreasing NO production. Diabetes has been linked to elevated arginase and associated vascular endothelial dysfunction. We aimed to determine levels of plasma NO and arginase activity in (T2DM) patients and the effects of L-citrulline supplementation, a natural arginase inhibitor, on inhibiting arginase activity in these patients. Levels of arginase correlated with HbA1c levels in diabetic patients. Twenty-five patients received L-citrulline supplements (2000 mg/day) for 1 month. Arginase activity decreased by 21% in T2DM patients after taking L-citrulline supplements. Additionally, plasma NO levels increased by 38%. There was a modest improvement on H1Ac levels in these patients, though not statistically significant. The effect of L-citrulline on arginase activity was also studied in bovine aortic endothelial cells (BAECs) grown in high glucose (HG) conditions. HG (25 mM, 72 h) caused a 2-fold increase in arginase activity in BAECs and decreased NO production by 30%. L-citrulline (2.5 mM) completely prevented the increase in arginase activity and restored NO production levels. These data indicate that L-citrulline can have therapeutic benefits in diabetic patients through increasing NO levels and thus maintaining vascular function possibly through an arginase inhibition related pathway.

The Effects of Mat Pilates Training on Vascular Function and Body Fatness in Obese Young Women With Elevated Blood Pressure.

Effective nonpharmacological interventions targeting the enhancement of vascular function and decline of body fatness (BF) in obese individuals are indispensable for the prevention of hypertension and cardiovascular events in young adults. Mat Pilates training (MPT) has gained significant popularity worldwide, yet its effects on vascular function and body composition are understudied. We examined the effects of MPT on vascular function and BF in young obese women with elevated blood pressure (BP). Twenty-eight young obese women with elevated BP were randomized to an MPT (n = 14) or a nonexercising control (CON, n = 14) group for 12 weeks. Systemic arterial stiffness (brachial-ankle pulse wave velocity (baPWV)), brachial and aortic BP, wave reflection (augmentation index (AIx)), plasma nitric oxide (NO) levels, and BF percentage (BF%) were assessed before and after 12 weeks. MPT significantly reduced (P ˂ 0.05) baPWV (-0.7 ± 0.2 m/s), AIx (-4 ± 1%), brachial systolic BP (-5 ± 1 mm Hg), aortic systolic BP (-6 ± 1 mm Hg), and BF% (-2 ± 1%), while significantly increasing plasma NO (6 ± 2 µM) (P ˂ 0.05) compared with CON. MPT improved systemic arterial stiffness, aortic BP, wave reflection, circulating plasma NO, and BF% in young obese women with elevated BP. MPT may be an effective intervention for the improvement of vascular function and BF in young obese women with elevated BP, a population at risk for hypertension and early vascular complications. Trial Number NCT03907384.

The impact of pulsed electromagnetic field therapy on blood pressure and circulating nitric oxide levels: a double blind, randomized study in subjects with metabolic syndrome

Purpose: Regulation of blood pressure (BP) is important in reducing the risk for cardiovascular disease. There is growing interest in non-pharmacological methods to treat BP including a novel approach using pulsed electromagnetic field therapy (PEMF). PEMF therapy has been proposed to impact physiological function at the cellular and tissue level and one possible mechanism is through an impact on endothelial function and nitric oxide (NO) related pathways. The focus of the present study was to evaluate the effect of PEMF on BP and NO in subjects with mild to moderate metabolic syndrome.Materials and methods: For 12 weeks, 23 subjects underwent PEMF therapy and 21 subjects underwent sham therapy. BP was measured at rest and near the end of submaximal exercise pre- and 12 week post-therapy. Additionally, plasma NO was measured at similar time points.Results: The PEMF demonstrated an increase in NO after therapy (p = .04) but SHAM did not (p = .37). For resting BP, there were no differences in systolic BP (SBP), diastolic BP (DBP) or mean arterial pressure (MAP) between groups (p > .05). During exercise, PEMF had a reduction in peak SBP (p = .04), but not SHAM (p = .57). PEMF demonstrated significant relationships between baseline SBP and change in SBP following therapy (r = −0.71, p < .01) and between MAP and change in MAP following therapy (r = −0.60, p < .01), but no such relationships were found in SHAM. Subjects with resting hypertension (SBP ≥140 mmHg) in PEMF (n = 11) had significant reductions in SBP, DBP and MAP when compared to SHAM with hypertension (n = 9) (p < .05). In this sub-group analysis, PEMF demonstrated lowered peak SBP (p = .04) at a given exercise load (p = .40) but SHAM did not (p > .05).Conclusion: PEMF may increase plasma NO availability and improve BP at rest and during exercise. However, this beneficial effect appears to be more pronounced in subjects with existing hypertension.

Consumption of Aged White Wine under a Veil of Flor Reduces Blood Pressure-Increasing Plasma Nitric Oxide in Men at High Cardiovascular Risk.

Background: Hypertension remains the largest attributable risk factor of cardiovascular disease (CVD), and a reduction of cardiovascular events is linked to diminished elevated blood pressure (BP) values. High alcohol intake is a common cause of hypertension, but some studies have suggested that moderate wine consumption may reduce BP and increase plasma nitric oxide (NO) due to its polyphenol content. Objective: The aim of the present study was to compare the effects of Andalusian aged white wine (AWW) under a veil of flor, an alcoholic beverage with a moderate polyphenol content, with those of gin, an alcoholic beverage without polyphenols, on BP and plasma NO in men at high cardiovascular risk. Methods: This study was designed as an open, randomized crossover-controlled trial in which 38 high-risk male volunteers, aged 55 to 80, received 30 g of ethanol daily in the form of AWW or gin. This was carried out over the course of three weeks, after a two-week washout period. At baseline and after each intervention period, BP, anthropometric parameters, and plasma NO were measured; food intake was also recorded, and physical activity was monitored. Results: Compared to gin, AWW significantly reduced systolic and diastolic BP (p ≤ 0.033; both) and increased plasma NO levels (p = 0.013). Additionally, changes in BP values observed after AWW significantly correlated with increases in plasma NO. No changes in food intake, physical activity, body weight, or waist were observed between the two intervention periods. Conclusions: Moderate daily consumption of AWW may be useful to reduce elevated BP due to an increase of NO synthesis. This effect could be attributed to grape-derived compounds in AWW, such as polyphenols, which are not present in gin.

Central serotonin prevents hypotension and hypothermia and reduces plasma and spleen cytokine levels during systemic inflammation

An exceptionally high mortality rate is observed in sepsis and septic shock. Systemic administration of lipopolysaccharide (LPS) has been used as an experimental model for sepsis resulting in an exacerbated immune response, brain neurochemistry adjustments, hypotension, and hypothermia followed by fever. Central serotonergic pathways not only modulate systemic inflammation (SI) but also are affected by SI, including in the anteroventral region of the hypothalamus (AVPO), which is the hierarchically most important region for body temperature (Tb) control. In this study, we sought to determine if central serotonin (5-HT) plays a role in SI induced by intravenous administration of LPS (1.5 mg/kg) in male Wistar rats (280–350 g) by assessing 5-HT levels in the AVPO, mean arterial pressure, heart rate, and Tb up to 300 min after LPS administration, as well as assessing plasma and spleen cytokine levels, nitric oxide (NO) plasma levels, and prostaglandin (PG) E2 levels in the AVPO at 75 min and 300 min after LPS administration. We observed reduced AVPO 5-HT levels, hypotension, tachycardia, hypothermia followed by fever, as well as observing increased plasma NO, plasma and spleen cytokines and AVPO PGE2 levels in SI. Intracerebroventricular (icv) administration of 5-HT 30 min before LPS administration prevented hypotension and hypothermia, which were accompanied by reduced plasma NO, as well as plasma TNF-α, IL-1β, IL-6, and IL-10 and spleen TNF-α and IL-10 levels. We suggest that SI reduced 5-HT levels in the AVPO favor an increased pro-inflammatory status both centrally and peripherally that converge to hypotension and hypothermia. Moreover, our results are consistent with the notion that exogenous 5-HT given icv prevents hypotension and hypothermia probably activating the splenic anti-inflammatory pathway.

Carthamus Tinctorius L. extract attenuates cardiac remodeling in L-NAME-induced hypertensive rats by inhibiting the NADPH oxidase-mediated TGF-β1 and MMP-9 pathway

Carthamus tinctorius L. (CT) has been widely used in Asian countries as a beverage and a folk medicine. The current study investigates the effect of CT extract on cardiac remodeling and possible mechanisms involved in Nw-nitro-l-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats were administrated with L-NAME (40mg/kg/day) for five weeks to induce hypertension. Hypertensive rats were treated with CT extract (300mg/kg/day) or captopril (5mg/kg/day) or vehicle for a further two weeks. Treatment of hypertensive rats with CT extract or captopril significantly decreased systolic blood pressure, left ventricular (LV) hypertrophy and fibrosis, small intramyocardial coronary artery remodeling, and cardiac weight index. CT extract or captopril increased plasma nitric oxide metabolite (NOx) levels and reduced plasma transforming growth factor β1 (TGF-β1) level, together with downregulation of cardiac TGF-β1 and matrix metalloproteinases-9 (MMP-9) expression. In addition, decreased plasma malondialdehyde (MDA) levels, consistent with downregulation of NADPH oxidase subunit gp91phox expression in heart tissue, was also observed after CT extract or captopril treatment. These findings suggest that CT extract alleviates cardiac remodeling in L-NAME-induced hypertensive rats, which is possibly related to inhibition of the NADPH oxidase-mediated TGF-β1-MMP-9 pathway.

The Effects of Magnesium and Vitamin E Co-Supplementation on Hormonal Status and Biomarkers of Inflammation and Oxidative Stress in Women with Polycystic Ovary Syndrome.

Synergistic approach of magnesium and vitamin E may benefit clinical symptoms of patients with polycystic ovary syndrome (PCOS) through improving their metabolic profiles and reducing oxidative stress and inflammation. This study was designed to determine the effects of magnesium and vitamin E co-supplementation on hormonal status and biomarkers of inflammation and oxidative stress in women with PCOS. This randomized, double-blind, placebo-controlled trial was conducted among 60 women with PCOS, aged 18-40years old. Participants were randomly divided into two groups to take 250mg/day magnesium plus 400mg/day vitamin E supplements or placebo (n = 30 each group) for 12weeks. Fasting blood samples were taken at baseline and after the 12-week intervention to quantify related variables. Magnesium and vitamin E co-supplementation resulted in a significant reduction in hirsutism (β - 0.37; 95% CI, - 0.70, - 0.05; P = 0.02) and serum high-sensitivity C-reactive protein (hs-CRP) (β - 0.67mg/L; 95% CI, - 1.20, - 0.14; P = 0.01), and a significant increase in plasma nitric oxide (NO) (β 3.40μmol/L; 95% CI, 1.46, 5.35; P = 0.001) and total antioxidant capacity (TAC) levels (β 66.32mmol/L; 95% CI, 43.80, 88.84; P < 0.001). Overall, magnesium and vitamin E co-supplementation for 12weeks may benefit women with PCOS on hirsutism, serum hs-CRP, plasma NO, and TAC levels. Clinical trial registration number http://www.irct.ir : IRCT2017082733941N8.

Nitrate-Rich Fruit and Vegetable Supplement Reduces Blood Pressure in Normotensive Healthy Young Males without Significantly Altering Flow-Mediated Vasodilation: A Randomized, Double-Blinded, Controlled Trial.

Nitric oxide (NO) is a primary vasodilatory factor released from endothelial cells of the peripheral vasculature. NO production is stimulated through enzymatic-dependent mechanisms via NO synthase and from dietary intake of nitrate-containing foods or supplements. We evaluated the efficacy of a nitrate-rich fruit and vegetable liquid supplement (FVS, AMPED NOx, Isagenix International LLC) versus a juice low in nitrates (prune juice, PRU) on circulating nitrates/nitrites as well as cardiovascular parameters in 45 healthy normotensive men (18–40 y). Blood pressure, flow-mediated dilation (FMD), and plasma nitrates and nitrites were measured at baseline and after two weeks of supplementation (2 oz/d). Subjects also completed questionnaires on sleep quality and mood since these measures have been associated with endothelial function. In contrast to PRU, FVS significantly increased plasma nitrates and nitrites (+67%, p < 0.001) and decreased diastolic blood pressure (−9%, p=0.029) after two weeks. The change in FMD for FVS supplementation versus PRU supplementation was not significant (+2% vs. −9%, respectively, p=0.145). Changes in sleep quality or total mood state did not differ between groups after the 2-week study. Thus, the nitrate-rich FVS supplement increased plasma NO and reduced diastolic blood pressure in young normotensive men, but increased plasma NO was not associated with improvements in FMD, mood, or sleep. This trial is registered with ClinicalTrials.gov NCT03486145.

Pitavastatin Upregulates Nitric Oxide Synthases in the Kidney of Spontaneously Hypertensive Rats and Wistar–Kyoto Rats

Clinical trials show potent renoprotective effects of pitavastatin (PTV), although the precise mechanism for these renoprotective effects is not fully clarified. The aim of this study was to examine the antihypertensive and renoprotective effects of PTV, focusing on the nitric oxide (NO) system. Male, 6-week-old, spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were randomized to receive vehicle or PTV (2 mg/kg bodyweight) for 8 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks. After 8 weeks, plasma biochemical parameters and renal histology were examined. NO synthase isoform (neuronal, nNOS; inducible, iNOS; and endothelial, eNOS) expression and eNOS phosphorylation were examined by western blotting. PTV attenuated hypertension and albuminuria development in SHR. PTV decreased glomerular desmin expression and medullary interstitial fibrosis in SHR. PTV tended to increase plasma NO in both strains but significantly increased urinary NO excretion only in WKY. PTV significantly increased nNOS and eNOS expression, enhanced eNOS phosphorylation at serine1177, and inhibited eNOS phosphorylation at threonine495 in the kidney of both strains. PTV treatment led to increased renal NOS expression and upregulated eNOS activity in both SHR and WKY. The antihypertensive and renoprotective effects of PTV may be related to upregulation of the NO system.