-
Atherosclerosis Nov 2023To understand pathophysiological mechanisms underlying migraine as a cardiovascular risk factor, we studied neuropeptide action and endothelial function as measures of...
BACKGROUND AND AIMS
To understand pathophysiological mechanisms underlying migraine as a cardiovascular risk factor, we studied neuropeptide action and endothelial function as measures of peripheral microvascular function in middle-aged women with or without migraine.
METHODS
We included women with the endocrine disorder polycystic ovary syndrome (PCOS), a population with supposed elevated cardiovascular risk, with and without comorbid migraine. In 26 women without and 23 women with migraine in the interictal phase (mean age 50.8 ± 2.9 years) local thermal hyperemia (LTH) of the skin of the volar forearm was measured cross-sectionally under control conditions, after inhibition of neuropeptide release by 5% lidocaine/prilocaine (EMLA) cream application, and after inhibition of nitric oxide formation by iontophoresis of NG-monomethyl-l-arginine (L-NMMA). Hereafter, changes in the natural logarithm of the reactive hyperemia index (lnRHI) and augmentation index (AI) during reperfusion after occlusion-derived ischemia were measured.
RESULTS
While mean values under control conditions and L-NMMA conditions were similar, migraine patients had a significantly higher mean area of the curve (AUC) of the total LTH response after EMLA application than those without (86.7 ± 26.5% versus 67.9 ± 24.2%; p = 0.014). This was also reflected by a higher median AUC of the plateau phase under similar conditions in women with migraine compared to those without (83.2% (IQR[73.2-109.5]) versus 73.2% (IQR[54.3-92.0]); p = 0.039). Mean changes in lnRHI and AI scores were similar in both groups.
CONCLUSIONS
In PCOS patients with migraine, neuropeptide action was lower compared with those without migraine. While larger studies are warranted, these findings provide a potential mechanism supporting previous findings that migraine may be independent from traditional risk factors, including atherosclerosis.
Topics: Middle Aged; Humans; Female; omega-N-Methylarginine; Polycystic Ovary Syndrome; Vasodilation; Risk Factors; Migraine Disorders
PubMed: 37400308
DOI: 10.1016/j.atherosclerosis.2023.06.078 -
European Journal of Pharmacology Dec 2023Myopia is one of the most prevalent eye diseases that seriously threaten the eyesight of children and adolescents worldwide. However, the pathogenesis is still unclear,...
Suppressive effect of nitric oxide synthase (NOS) inhibitor L-NMMA acetate on choroidal fibrosis in experimental myopic guinea pigs through the nitric oxide signaling pathway.
Myopia is one of the most prevalent eye diseases that seriously threaten the eyesight of children and adolescents worldwide. However, the pathogenesis is still unclear, and effective drugs are still scarce. In the present study, the guinea pigs were randomly divided into a normal control (NC) group, a lens-induced myopia (LIM) group, a NOS inhibitor (L-NMMA) injection group, and a NOS inhibitor solvent phosphate-buffered saline (PBS) group and the animals received relevant treatments. After 2- and 4-week different treatments, we noted that the refraction and choroidal thickness in the LIM group decreased compared with the NC group, whereas the ocular axial length increased significantly, and the choroid showed a fibrotic trend. The expression of NOS1, NOS3, TGF-β1, COLI, and α-SMA at gene and protein levels was increased significantly in the choroid (all P < 0.05). After intravitreal injection of NOS inhibitor L-NMMA, we found that compared with the LIM group, the refraction and the choroidal thickness significantly increased, whereas the axial length reduced significantly, accompanied by an increase of choroidal thickness and an improvement of choroidal fibrosis. The expression levels of choroidal NOS1, NOS3, TGF-β, COLI, and α-SMA were significantly reduced (all P < 0.05). In conclusion, the trend of choroidal fibrosis in LIM guinea pigs is positively correlated with the increase in axial length. The NOS inhibitor L-NMMA can alleviate the process of choroidal fibrosis in myopic guinea pigs by inhibiting NO signaling pathway.
Topics: Child; Guinea Pigs; Animals; Humans; Adolescent; omega-N-Methylarginine; Nitric Oxide; Myopia; Choroid; Enzyme Inhibitors; Signal Transduction; Nitric Oxide Synthase
PubMed: 37863413
DOI: 10.1016/j.ejphar.2023.176111 -
Journal of Applied Physiology... Jul 2023Ninety-million Americans suffer metabolic syndrome (MetSyn), increasing the risk of diabetes and poor brain outcomes, including neuropathology linked to lower cerebral...
Ninety-million Americans suffer metabolic syndrome (MetSyn), increasing the risk of diabetes and poor brain outcomes, including neuropathology linked to lower cerebral blood flow (CBF), predominantly in anterior regions. We tested the hypothesis that total and regional CBF is lower in MetSyn more so in the anterior brain and explored three potential mechanisms. Thirty-four controls (25 ± 5 yr) and 19 MetSyn (30 ± 9 yr), with no history of cardiovascular disease/medications, underwent four-dimensional flow magnetic resonance imaging (MRI) to quantify macrovascular CBF, whereas arterial spin labeling quantified brain perfusion in a subset ( = 38/53). Contributions of cyclooxygenase (COX; = 14), nitric oxide synthase (NOS, = 17), or endothelin receptor A signaling ( = 13) were tested with indomethacin, -monomethyl-L-arginine (L-NMMA), and Ambrisentan, respectively. Total CBF was 20 ± 16% lower in MetSyn (725 ± 116 vs. 582 ± 119 mL/min, < 0.001). Anterior and posterior brain regions were 17 ± 18% and 30 ± 24% lower in MetSyn; reductions were not different between regions ( = 0.112). Global perfusion was 16 ± 14% lower in MetSyn (44 ± 7 vs. 36 ± 5 mL/100 g/min, = 0.002) and regionally in frontal, occipital, parietal, and temporal lobes (range 15-22%). The decrease in CBF with L-NMMA ( = 0.004) was not different between groups ( = 0.244, = 14, 3), and Ambrisentan had no effect on either group ( = 0.165, = 9, 4). Interestingly, indomethacin reduced CBF more in Controls in the anterior brain ( = 0.041), but CBF decrease in posterior was not different between groups ( = 0.151, = 8, 6). These data indicate that adults with MetSyn exhibit substantially reduced brain perfusion without regional differences. Moreover, this reduction is not due to loss of NOS or gain of ET-1 signaling but rather a loss of COX vasodilation. We tested the impact of insulin resistance (IR) on resting cerebral blood flow (CBF) in adults with metabolic syndrome (MetSyn). Using MRI and research pharmaceuticals to study the role of NOS, ET-1, or COX signaling, we found that adults with MetSyn exhibit substantially lower CBF that is not explained by changes in NOS or ET-1 signaling. Interestingly, adults with MetSyn show a loss of COX-mediated vasodilation in the anterior but not posterior circulation.
Topics: Humans; Young Adult; omega-N-Methylarginine; Metabolic Syndrome; Indomethacin; Cerebrovascular Circulation
PubMed: 37199780
DOI: 10.1152/japplphysiol.00688.2022 -
American Journal of Physiology.... Dec 2023Animal data indicate that insulin triggers a robust nitric oxide synthase (NOS)-mediated dilation in cerebral arteries similar to the peripheral tissue vasodilation...
Animal data indicate that insulin triggers a robust nitric oxide synthase (NOS)-mediated dilation in cerebral arteries similar to the peripheral tissue vasodilation observed in healthy adults. Insulin's role in regulating cerebral blood flow (CBF) in humans remains unclear but may be important for understanding the links between insulin resistance, diminished CBF, and poor brain health outcomes. We tested the hypothesis that an oral glucose challenge (oral glucose tolerance test, OGTT), which increases systemic insulin and glucose, would acutely increase CBF in healthy adults due to NOS-mediated vasodilation, and that changes in CBF would be greater in anterior regions where NOS expression or activity may be greater. In a randomized, single-blind approach, 18 young healthy adults (24 ± 5 yr) underwent magnetic resonance imaging (MRI) with a placebo before and after an OGTT (75 g glucose), and 11 of these adults also completed an -monomethyl-l-arginine (l-NMMA) visit. Four-dimensional (4-D) flow MRI quantified macrovascular CBF and arterial spin labeling (ASL) quantified microvascular perfusion. Subjects completed baseline imaging with a placebo (or l-NMMA), then consumed an OGTT followed by MRI scans and blood sampling every 10-15 min for 90 min. Contrary to our hypothesis, total CBF ( = 0.17) and global perfusion ( > 0.05) did not change at any time point up to 60 min after the OGTT, and no regional changes were detected. l-NMMA did not mediate any effect of OGTT on CBF. These data suggest that insulin-glucose challenge does not acutely alter CBF in healthy adults.
Topics: Adult; Animals; Humans; omega-N-Methylarginine; Glucose Tolerance Test; Enzyme Inhibitors; Single-Blind Method; Nitric Oxide Synthase; Cerebrovascular Circulation; Glucose; Insulin
PubMed: 37842740
DOI: 10.1152/ajpregu.00169.2022 -
Microbial Pathogenesis Oct 2023The CXCL8/CXCR1 axis in conjoint with the free radicals and anti-oxidants dictates the severity of inflammation caused by the bacteria, Staphylococcus aureus. S.aureus...
Pyrrolidine dithiocarbamate in combination with L-N-monomethyl arginine alleviates Staphylococcus aureus infection via regulation of CXCL8/CXCR1 axis in peritoneal macrophages in vitro.
The CXCL8/CXCR1 axis in conjoint with the free radicals and anti-oxidants dictates the severity of inflammation caused by the bacteria, Staphylococcus aureus. S.aureus mediated inflammatory processes is regulated by NF-κB and its product, iNOS. The objective of this study was to examine the effects of inhibition of NF-κB and iNOS on CXCL8/CXCR1, alteration in M1/M2 polarization of macrophages and associated inflammatory responses during S.aureus infection in vitro. For this, the murine peritoneal macrophages were pretreated with NF-κB inhibitor, Pyrrolidine dithiocarbamate (PDTC) and iNOS inhibitor, L-N-monomethyl arginine (LNMMA), either alone or in combination, followed by time-dependent S.aureus infection. The chemotactic migrations of macrophages were determined by the agarose spot assay. The iNOS, NF-κB and CXCR1 protein expressions were evaluated. The ROS level (superoxide, HO, NO) and antioxidant activities (SOD, CAT, GSH, arginase) were measured. The intra-macrophage phagoctyic activity had been analyzed by confocal microscopy. S.aureus activated macrophages showed increased iNOS expression that symbolizes M1 characterization of macrophages. The results suggest that the combination treatment of LNMMA + PDTC was effective in diminution of CXCL8 production and CXCR1 expression through downregulation of NF-κB and iNOS signaling pathway. Consequently, there was decrement in macrophage migration, reduced ROS generation, elevated antioxidant enzyme activity as well as bacterial phagocytosis at 90 min post bacterial infection. The increased arginase activity further proves the switch from pro-inflammatory M1 to anti-inflammatory M2 polarization of macrophages. Concludingly, the combination of PDTC + LNMMA could resolve S.aureus mediated inflammation through mitigation of CXCL8/CXCR1 pathway switching from M1 to M2 polarization.
Topics: Mice; Animals; Macrophages, Peritoneal; Staphylococcus aureus; omega-N-Methylarginine; Antioxidants; Reactive Oxygen Species; NF-kappa B; Hydrogen Peroxide; Arginase; Cytokines; Staphylococcal Infections; Receptors, Interleukin-8A; Inflammation
PubMed: 37567327
DOI: 10.1016/j.micpath.2023.106294 -
Nutrients Jun 2023Changes in serum concentration of methylarginines and amino acids after exercise are well documented, whereas the effects of exercise applied together with fasting are...
Changes in serum concentration of methylarginines and amino acids after exercise are well documented, whereas the effects of exercise applied together with fasting are still debated and not thoroughly studied. Thus, we hypothesised that alterations in methylarginines such as ADMA, SDMA and L-NMMA might be responsible for decreased exercise performance after 8 days of fasting. Additionally, we propose that conditions in which the human body is exposed to prolonged fasting for more than a week elicit a distinctly different response to exercise than after overnight fasting. A group of 10 healthy men with previous fasting experience participated in the study. The exercise test was performed until exhaustion with a gradually increasing intensity before and after the 8-day fast. Blood samples were collected before and immediately after exercise. ADMA, SDMA, L-NMMA, dimethylamine and amino acids were analysed in serum samples by ID-LC-MS/MS. SDMA, L-NMMA and dimethylamine significantly decreased after 8 days of fasting, whereas ADMA did not change. BCAA, Phe, alanine and some other amino acids increased after fasting. Exercise-induced changes in amino acids were distinct after an 8-day fast compared to overnight fasting. A decrease in physical performance accompanied all of these alterations. In conclusion, our data indicate that neither methyl-arginine changes nor the Trp/BCAA ratio can explain exercise-induced fatigue after fasting. However, the observed decrease in hArg concentration suggests the limited synthesis of creatine, possibly contributing to reduced physical performance.
Topics: Male; Humans; Amino Acids; omega-N-Methylarginine; Chromatography, Liquid; Tandem Mass Spectrometry; Arginine
PubMed: 37447307
DOI: 10.3390/nu15132981 -
Toxicology and Industrial Health 2024This toxicology study was conducted to assess the impact of formaldehyde, a common air pollutant found in Chinese gymnasiums, on the brain function of athletes. In this...
This toxicology study was conducted to assess the impact of formaldehyde, a common air pollutant found in Chinese gymnasiums, on the brain function of athletes. In this research, a total of 24 Balb/c male mice of SPF-grade were divided into four groups, each consisting of six mice. The mice were exposed to formaldehyde at different concentrations, including 0 mg/m, 0.5 mg/m, 3.0 mg/m, and 3.0 mg/m in combination with an injection of L-NMMA (N-monomethyl-L-arginine), which is a nitric oxide synthase antagonist. Following a one-week test period (8 h per day, over 7 days), measurements of biomarkers related to the nitric oxide (NO)/cGMP-cAMP signaling pathway were carried out on the experimental animals post-treatment. The study found that: (1) Exposure to formaldehyde can lead to brain cell apoptosis and neurotoxicity; (2) Additionally, formaldehyde exposure was found to alter the biomarkers of the NO/cGMP-cAMP signaling pathway, with some changes being statistically significant ( < 0.05 or < 0.01); (3) The use of L-NMMA, an antagonist of the NO/cGMP-cAMP signaling pathway, was found to prevent these biomarker changes and had a protective effect on brain cells. The study suggests that the negative impact of formaldehyde on the brain function of mice is linked to the regulation of the NO/cGMP-cAMP signaling pathway.
Topics: Humans; Male; Mice; Animals; omega-N-Methylarginine; Nitric Oxide; Mice, Inbred BALB C; Cyclic GMP; Formaldehyde; Signal Transduction; Brain; Biomarkers; Respiratory Hypersensitivity
PubMed: 37921628
DOI: 10.1177/07482337231210942