Novel mechanism for impaired nitrergic relaxation in achalasia.
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ABSTRACT:
SUBMITTER: Boeckxstaens GE
PROVIDER: S-EPMC1856096 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHuman gastric fundus relaxation is mediated by intrinsic inhibitory pathway. We investigated the roles of nitrergic and purinergic pathways, two known inhibitory factors in gastric motility, on spontaneous and nerve-evoked contractions in human gastric fundus muscles.MethodsGastric fundus muscle strips (12 circular and 13 longitudinal) were obtained from patients without previous gastrointestinal motility disorder who underwent gastrectomy for stomach cancer. Using these specimens, we examined basal tone, peak, amplitude, and frequency of spontaneous contractions, and peak and nadir values under electrical field stimulation (EFS, 150 V, 0.3 ms, 10 Hz, 20 s). To examine responses to purinergic and nitrergic inhibition without cholinergic innervation, atropine (muscarinic antagonist, 1 μM), MRS2500 (a purinergic P2Y1 receptor antagonist, 1 μM), and N-nitro-L-arginine (L-NNA, a nitric oxide synthase inhibitor, 100 μM) were added sequentially for spontaneous and electrically-stimulated contractions. Tetrodotoxin was used to confirm any neuronal involvement.ResultsIn spontaneous contraction, L-NNA increased basal tone and peak in both muscle layers, while amplitude and frequency were unaffected. EFS (up to 10 Hz) uniformly induced initial contraction and subsequent relaxation in a frequency-dependent manner. Atropine abolished initial on-contraction and induced only relaxation during EFS. While MRS2500 showed no additional influence, L-NNA reversed relaxation (p = 0.012 in circular muscle, and p = 0.006 in longitudinal muscle). Tetrodotoxin abolished any EFS-induced motor response.ConclusionsThe relaxation of human gastric fundus muscle is reduced by nitrergic inhibition. Hence, nitrergic pathway appears to be the main mechanism for the human gastric fundus relaxation.
| S-EPMC5010257 | biostudies-literature
Project description:Electrical field stimulation (EFS)-induced non-adrenergic non-cholinergic (NANC) relaxation responses in the rabbit vaginal wall were investigated. These NANC responses were partially inhibited with the nitric oxide synthase (NOS) inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME; 500 microM), N(G)-nitro-L-arginine (300 microM) or N-iminoethyl-L-ornithine (500 microM) or the selective soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 10 microM). Application of L-NAME and ODQ concomitantly did not increase the degree of inhibition. L-NAME or ODQ were observed to be more effective at low frequencies. The resistant part of the responses was more pronounced at higher frequencies and was completely inhibited by tetrodotoxin (1 microM). Exogenous application of the peptides vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide (PACAP-27 and PACAP-38), peptide histidine methionine (PHM), peptide histidine valine (PHV), helospectin-I or -II induced a relaxation response. Calcitonin gene-related peptide or substance P did not cause any relaxation. The peptidase alpha-chymotrypsin (type II; 2 units ml(-1)) did not affect non-nitrergic NANC responses, although it did inhibit relaxation responses elicited by exogenous VIP, PACAP-27, PACAP-38, PHM, PHV, helospectin-I or -II. K(+) channel inhibitors apamin (1 microM) or charybdotoxin (100 nM) when used alone or in conjunction did not affect non-nitrergic NANC responses. The non-nitrergic NANC responses were not associated with any increase in intracellular cyclic adenosine-3', 5'-monophosphate (cyclic AMP) or cyclic guanosine-3', 5'-monophosphate (cyclic GMP) concentrations. The peptide-induced relaxations were all associated with increases in cyclic AMP concentrations. These results suggest that a neuronal factor elicits non-nitrergic NANC responses in the rabbit vaginal wall. The identity of this factor remains to be established.
| S-EPMC1573144 | biostudies-other
Project description:BackgroundElevated arginase (Arg) activity is reported to be involved in diabetes-induced vascular endothelial dysfunction. It can reduce L-arginine availability to nitric oxide (NO) synthase (NOS) and NO production. Akita mice, a genetic non-obese type 1 diabetes model, recapitulate human diabetes. We determined the role of Arg in a time-course of diabetes-associated endothelial dysfunction in aorta and corpora cavernosa (CC) from Akita mice.Methods and resultsEndothelium-dependent relaxation, Arg and NOS activity, and protein expression levels of Arg and constitutive NOS were assessed in aortas and CC from Akita and non-diabetic wild type (WT) mice at 4, 12 and 24 wks of age. Systolic blood pressure (SBP) was assessed by tail cuff. In aorta and CC, Akita mice exhibited a progressive impairment of vascular endothelial and nitrergic function increased Arg activity and expression (Arg1 in aorta and both Arg1 and Arg2 in CC) compared with that of age-matched WT mice. Treatment of aorta and CC from Akita mice with an Arg inhibitor (BEC or ABH) reduced diabetes-induced elevation of Arg activity and restored endothelial and nitrergic function. Reduced levels of phospho-eNOS at Ser(1177) (in aorta and CC) and nNOS expression (in CC) were observed in Akita mice at 12 and 24 wks. Akita mice also had decreased NOS activity in aorta and CC at 12 and 24 wks that was restored by BEC treatment. Further, Akita mice exhibited moderately increased SBP at 24 wks and increased sensitivity to PE-induced contractions in aorta and sympathetic nerve stimulation in CC at 12 and 24 wks.ConclusionsOver 24 wks of diabetes in Akita mice, both aortic and cavernosal tissues exhibited increased Arg activity/expression, contributing to impaired endothelial and nitrergic function and reduced NO production. Our findings demonstrate involvement of Arg activity in diabetes-induced impairment of vascular function in Akita mouse.
| S-EPMC3747112 | biostudies-literature
Project description:Left ventricular diastolic dysfunction is associated with mortality outcomes in severe sepsis and septic shock. There are ongoing issues with diagnosing diastolic dysfunction in this cohort, partly owing to the poor applicability of traditional parameters in the hyperdynamic circulation. In this feasibility study, we sought to assess the utility of a novel parameter (septal e'/s') to identify diastolic dysfunction in patients with severe sepsis and septic shock who had normal systolic function against the 2016 American Society Echocardiography and European Association of Cardiovascular Imaging (ASE/EACI) guidelines on diastolic dysfunction.In this prospective observational pilot study, patients identified as having severe sepsis and septic shock underwent transthoracic echocardiography on day 1 and day 3 of their intensive care unit admission. In patients with normal systolic function, septal e'/s' was calculated using the peak modal velocity of the s' compared with the e' from the septal annulus tissue Doppler imaging and compared with their diastolic grade according to the 2016 ASE/EACI guidelines on diastolic dysfunction.On day 1 of admission, 44 of 62 patients with severe sepsis and septic shock had normal systolic function. There was a strong association of those with diastolic dysfunction having a reduced septal e'/s' compared with patients with normal diastolic function (AUC 0.91). A similar relationship was seen with patients who had indeterminate diastolic dysfunction. On day 3, 37 patients had normal systolic function. Again, there was a strong association of those with diastolic dysfunction and a reduced septal e'/s' (AUC 0.95).A reduction in septal e'/s' may indicate diastolic dysfunction in patients with severe sepsis and septic shock who have normal systolic function. As opposed to limited traditional measures of diastolic dysfunction, it is applicable in those with hyperdynamic systolic function.
| S-EPMC5512826 | biostudies-other
Project description:IntroductionIn stroke models, Inducible Nitric Oxide Synthase (iNOS) expression initiates cellular toxicity due to excessive Nitric Oxide (NO) generation. Anchusa italica is a medicinal herb with anti-inflammatory, antioxidant and neuroprotective properties. This study evaluated the antioxidant activity and NOS mRNA expression of the Hydroalcoholic Extract Of Anchusa Italica (HEAI) in an experimental stroke model in rats.MethodsThe stroke model was induced by bilateral occlusion of both common carotid arteries for 60 min. Twenty-four hours after surgery, HEAI (50 and 100 mg/kg i.p.) was injected daily for 10 consecutive days. mRNA expression levels of NOS subtypes and hippocampal Brain-Derived Neurotrophic Factor (BDNF) were studied using real-time PCR. Besides, hippocampal tissue plus serum concentrations of NO and Malondialdehyde (MDA) were measured.ResultsHEAI decreased MDA in both serum and hippocampal tissue and also reduced serum NO levels. Additionally, in the HEAI-treated groups, a down-regulation of iNOS mRNA expression, and an up-regulation of BDNF mRNA expression were observed.ConclusionThe results indicated that the administration of HEAI even after the onset of ischemia protects the brain from free radical injury and inflammation via a down-regulation of iNOS expression inhibiting NO production and an up-regulation of BDNF mRNA.
| S-EPMC7502191 | biostudies-literature
Project description:Developmental dyslexia is characterised as an inability to read fluently. Apart from literacy problems, dyslexics have other language difficulties including inefficient speech encoding and deficient novel word learning. Yet, the neural mechanisms underlying these impairments are largely unknown. We tracked online formation of neural memory traces for a novel spoken word-form in dyslexic and normal-reading children by recording the brain's electrophysiological response dynamics in a passive perceptual exposure session. Crucially, no meaning was assigned to the new word-form nor was there any task related to the stimulus, enabling us to explore the memory-trace formation of a purely phonological form in the absence of any short-term or working memory demands. Similar to previously established neural index of rapid word learning in adults, the control children demonstrated an early brain response enhancement within minutes of exposure to the novel word-form that originated in frontal cortices. Dyslexic children, however, lacked this neural enhancement over the entire course of exposure. Furthermore, the magnitude of the rapid neural enhancement for the novel word-form was positively associated with reading and writing fluency. This suggests that the rapid neural learning mechanism for online acquisition of novel speech material is associated with reading skills. Furthermore, the deficient online learning of novel words in dyslexia, consistent with poor rapid adaptation to familiar stimuli, may underlie the difficulty of learning to read.
| S-EPMC6109122 | biostudies-literature
Project description:Magnetic relaxation switching (MRSw) assays that employ target-induced aggregation (or disaggregation) of magnetic nanoparticles (MNPs) can be used to detect a wide range of biomolecules. The precise working mechanisms, however, remain poorly understood, often leading to confounding interpretation. We herein present a systematic and comprehensive characterization of MRSw sensing. By using different types of MNPs with varying physical properties, we analyzed the nature and transverse relaxation modes for MRSw detection. The study found that clustered MNPs are universally in a diffusion-limited fractal state (dimension of ~2.4). Importantly, a new model for transverse relaxation was constructed that accurately recapitulates observed MRSw phenomena and predicts the MRSw detection sensitivities and dynamic ranges.
| S-EPMC3429660 | biostudies-literature
Project description:Postsynaptic density (PSD) proteins in excitatory synapses are relatively immobile components, while there is a structured organization of mobile scaffolding proteins lying beneath the PSDs. For example, shank proteins are located further away from the membrane in the cytosolic faces of the PSDs, facing the actin cytoskeleton. The rationale of this organization may be related to important roles of these proteins as "exchange hubs" for the signaling proteins for their migration from the subcortical cytosol to the membrane. Notably, PSD95 have also been demonstrated in prejunctional nerve terminals of nitrergic neuronal varicosities traversing the gastrointestinal smooth muscles. It has been recently reported that motor proteins like myosin Va play important role in transcytosis of nNOS. In this review, the hypothesis is forwarded that nNOS delivered to subcortical cytoskeleton requires interactions with scaffolding proteins prior to docking at the membrane. This may involve significant role of "shank," named for SRC-homology (SH3) and multiple ankyrin repeat domains, in nitric oxide synthesis. Dynein light chain LC8-nNOS from acto-myosin Va is possibly exchanged with shank, which thereafter facilitates transposition of nNOS for binding with palmitoyl-PSD95 at the nerve terminal membrane. Shank knockout mice, which present with features of autism spectrum disorders, may help delineate the role of shank in enteric nitrergic neuromuscular transmission. Deletion of shank3 in humans is a monogenic cause of autism called Phelan-McDermid syndrome. One fourth of these patients present with cyclical vomiting, which may be explained by junctionopathy resulting from shank deficit in enteric nitrergic nerve terminals.
| S-EPMC4335390 | biostudies-literature
Project description:The aim of this study was to examine the relationship between physical activity level and impaired left ventricular (LV) relaxation in a large sample of apparently healthy men and women. We conducted a cross-sectional study in 57,449 adults who underwent echocardiography as part of a comprehensive health examination between March 2011 and December 2014. Physical activity level was assessed using the Korean version of the International Physical Activity Questionnaire Short Form. The presence of impaired LV relaxation was determined based on echocardiographic findings. Physical activity levels were inversely associated with the prevalence of impaired LV relaxation. The multivariable-adjusted odds ratios (95% confidence interval) for impaired LV relaxation comparing minimally active and health-enhancing physically active groups to the inactive group were 0.84 (0.77-0.91) and 0.64 (0.58-0.72), respectively (P for trend < 0.001). These associations were modified by sex (p for interaction <0.001), with the inverse association observed in men, but not in women. This study demonstrated an inverse linear association between physical activity level and impaired LV relaxation in a large sample of middle-aged Koreans independent of potential confounders. Our findings suggest that increasing physical activity may be independently important in reducing the risk of impaired LV relaxation.
| S-EPMC6102302 | biostudies-literature
Project description:Vagal preganglionic neurons innervate myenteric ganglia. These autonomic efferents are distributed so densely within the ganglia that it has been impractical to track individual vagal axons through the myenteric plexus with tracer labeling. To evaluate whether vagal efferent axons evidence selectivity, particularly for nitrergic or non-nitrergic myenteric neurons within the plexus, we limited the numbers and volumes of brainstem dextran biotin tracer injections per animal. Reduced labeling and the use of immunohistochemistry generated cases in which some individual axons could be distinguished and traced in three dimensions (Neurolucida) within and among successive (up to 46) myenteric ganglia. In the myenteric plexus of all stomach regions, the majority (∼86%) of vagal efferents were organized into two distinct subtypes. One subtype (∼24% of dextran-labeled efferents, designated "primarily nitrergic") selectively contacted and linked-both within and between ganglia-nitric oxide synthase positive (nNOS+) neurons into presumptive motor modules. A second subtype (∼62% of efferents, designated "primarily non-nitrergic") appeared to selectively contact and link-both within and between ganglia-non-nitrergic enteric neurons into a second type of effector ensemble. A third candidate type (∼14% of labeled preganglionics), appeared to lack "nitrergic selectivity" and to contact both nNOS+ and nNOS- enteric neurons. In addition to the quantitative assessment of the efferent axons in stomach, qualitative observations of the proximal duodenum indicated similar selective vagal efferent projections, in proportions comparable with those evaluated in the stomach. Limited injections of tracer, three-dimensional (3-D) tracing of individual axons, and histochemistry of myenteric neurons might distinguish additional efferent phenotypes.NEW & NOTEWORTHY The present study highlights the following: 1) one type of vagal efferent axon selectively innervates nitrergic upper gastrointestinal myenteric neurons; 2) a second type of vagal efferent selectively innervates non-nitrergic gastrointestinal myenteric neurons; and 3) the two types of vagal efferents might modulate peristalsis reciprocally and cooperatively.
| S-EPMC9942884 | biostudies-literature