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1.
Article in English | WPRIM | ID: wpr-812986

ABSTRACT

The cholinergic anti-inflammatory pathway (CAP) is a neuro-immunomodulatory pathway,in which acetylcholine (ACh) released by the interaction of vagal nerves with α7 nicotinic acetylcholine receptor (α7nAChR),which prevents the synthesis and release of pro-inflammatory cytokines and ultimately regulates the local or systemic inflammatory response in a feedback manner. It has been shown that there are many possible effective treatments for sepsis, including vagus nerve stimulation by physical therapy, drugs such as acetylcholine receptor agonist and ultrasound therapy.


Subject(s)
Acetylcholine , Humans , Inflammation , Neuroimmunomodulation , Sepsis , Vagus Nerve Stimulation , alpha7 Nicotinic Acetylcholine Receptor
2.
Rio de Janeiro; s.n; 2020. xiv, 79 p. ilus.
Thesis in Portuguese | LILACS | ID: biblio-1128725

ABSTRACT

O timo é um órgão linfoide primário responsável pelo desenvolvimento e seleção de células T. Diversos fatores podem afetar o desenvolvimento de células T, como citocinas, quimiocinas e moléculas da matriz extracelular, mas também hormônios, neuropeptídeos e neurotransmissores. O timo recebe densa inervação simpática, liberando majoritariamente noradrenalina (NA), timócitos e células tímicas não linfoides expressam receptores adrenérgicos e podem sintetizar catecolaminas, sugerindo modulação de NA por diferentes vias. Por outro lado, poucas evidências anatômicas suportam a hipótese da inervação tímica parassimpática. Entretanto, acetilcolina (ACh) parece ser endogenamente produzida no órgão, uma vez que diferentes células no timo expressam a enzima sintetizadora de ACh (ChAT) e receptores colinérgicos. Sendo assim, o objetivo deste trabalho foi determinar o papel funcional de ACh e NA sobre os componentes linfoide e microambiental do timo, e sobre as interações entre células epiteliais e timócitos. Avaliamos a expressão de receptores adrenérgicos α1A, α1D, α2C, ß2 e colinérgicos M1, M3, M5 e α7 em timócitos e TECs, através do método de PCR quantitativa. Todas as populações celulares testadas expressavam os receptores selecionados.


Além disso, buscamos caracterizar o efeito de drogas análogas aos neurotransmissores sobre a morte e a proliferação de timócitos, através da marcação com anexina-V/iodeto de propídio (IP) e CFSE respectivamente. Timócitos obtidos do timo de camundongos C57BL/6 fêmeas, foram tratados com carbacol (análogo de Ach - em concentrações variando de 10 nM a 1000 nM) ou arterenol (análogo de NA - em concentrações variando de 10 nM a 1 mM). Verificamos que apenas arterenol na concentração de 1 mM induziu a apoptose nas células tratadas. Nenhum dos análogos modulou a proliferação celular. Avaliamos ainda o efeito das drogas sobre a migração de timócitos, agindo como quimioatrente ou modulando a migração induzida por fibronectina. Nenhuma das drogas demonstrou efeito quimioatraente ou alterou a migração induzida por fibronectina. Além disso, avaliamos o efeito das drogas sobre a interação TEC/timócitos atraves de ensaios de adesão e observamos que carbacol foi capaz de diminuir a adesão de timócitos a TECs em todas as concentrações testadas. Essa diminuição é refletida no número de timócitos que aderem às TECs e parece estar associada a modulação da expressão do receptor de laminina VLA-6. Nossos dados sugerem que timócitos e as linhagens de TECs testadas expressam receptores e que neurotransmissores, em especial a ACh, podem modular a interação entre TECs e timócitos. (AU)


Subject(s)
Animals , Mice , Thymus Gland , Carbachol , Acetylcholine
3.
Braz. j. med. biol. res ; 53(2): e9304, 2020. tab, graf
Article in English | LILACS | ID: biblio-1055489

ABSTRACT

Metabolic syndrome is a multifaceted condition associated with a greater risk of various disorders (e.g., diabetes and heart disease). In a rat model of metabolic syndrome, an acute in vitro application of rosuvastatin causes relaxation of aortic rings. Since the outcome of a subchronic rosuvastatin treatment is unknown, the present study explored its effect on acetylcholine-induced vasorelaxation of aortic rings from rats with metabolic syndrome. Animals were submitted to a 16-week treatment, including a standard diet, a cafeteria-style diet (CAF-diet), or a CAF-diet with daily rosuvastatin treatment (10 mg/kg). After confirming the development of metabolic syndrome in rats, aortic segments were extracted from these animals (those treated with rosuvastatin and untreated) and the acetylcholine-induced relaxant effect on the corresponding rings was evaluated. Concentration-response curves were constructed for this effect in the presence/absence of L-NAME, ODQ, KT 5823, 4-aminopyridine (4-AP), tetraethylammonium (TEA), apamin plus charybdotoxin, glibenclamide, indomethacin, clotrimazole, and cycloheximide pretreatment. Compared to rings from control rats, acetylcholine-induced vasorelaxation decreased in rings from animals with metabolic syndrome, and was maintained at a normal level in animals with metabolic syndrome plus rosuvastatin treatment. The effect of rosuvastatin was inhibited by L-NAME, ODQ, KT 5823, TEA, apamin plus charybdotoxin, but unaffected by 4-AP, glibenclamide, indomethacin, clotrimazole, or cycloheximide. In conclusion, the subchronic administration of rosuvastatin to rats with metabolic syndrome improved the acetylcholine-induced relaxant response, involving stimulation of the NO/cGMP/PKG/Ca2+-activated K+ channel pathway.


Subject(s)
Animals , Male , Rats , Aorta/drug effects , Vasodilation/drug effects , Endothelium, Vascular/drug effects , Acetylcholine/pharmacology , Metabolic Syndrome/physiopathology , Rosuvastatin Calcium/pharmacology , Vasodilator Agents , Endothelium, Vascular/physiopathology , Rats, Wistar , Disease Models, Animal
4.
J. venom. anim. toxins incl. trop. dis ; 26: e20190041, 2020. graf
Article in English | ID: biblio-1056676

ABSTRACT

Here, we described the presence of a neurotoxin with phospholipase A2 activity isolated from Micrurus lemniscatus venom (Mlx-8) with affinity for muscarinic acetylcholine receptors (mAChRs). Methods: The purification, molecular mass determination, partial amino acid sequencing, phospholipase A2 activity determination, inhibition of the binding of the selective muscarinic ligand [3H]QNB and inhibition of the total [3H]inositol phosphate accumulation in rat hippocampus of the Mlx-8 were determined. Results: Thirty-one fractions were collected from HPLC chromatography, and the Mlx-8 toxin was used in this work. The molecular mass of Mlx-8 is 13.628 Da. Edman degradation yielded the following sequence: NLYQFKNMIQCTNTRSWL-DFADYG-CYCGRGGSGT. The Mlx-8 had phospholipase A2 enzymatic activity. The pKi values were determined for Mlx-8 toxin and the M1 selective muscarinic antagonist pirenzepine in hippocampus membranes via [3H]QNB competition binding assays. The pKi values obtained from the analysis of Mlx-8 and pirenzepine displacement curves were 7.32 ± 0.15, n = 4 and 5.84 ± 0.18, n = 4, respectively. These results indicate that Mlx-8 has affinity for mAChRs. There was no effect on the inhibition ability of the [3H]QNB binding in hippocampus membranes when 1 µM Mlx-8 was incubated with 200 µM DEDA, an inhibitor of phospholipase A2. This suggests that the inhibition of the phospholipase A2 activity of the venom did not alter its ability to bind to displace [3H]QNB binding. In addition, the Mlx-8 toxin caused a blockade of 43.31 ± 8.86%, n = 3 and 97.42 ± 2.02%, n = 3 for 0.1 and 1 µM Mlx-8, respectively, on the total [3H]inositol phosphate content induced by 10 µM carbachol. This suggests that Mlx-8 inhibits the intracellular signaling pathway linked to activation of mAChRs in hippocampus. Conclusion: The results of the present work show, for the first time, that muscarinic receptors are also affected by the Mlx-8 toxin, a muscarinic ligand with phospholipase A2 characteristics, obtained from the venom of the Elapidae snake Micrurus lemniscatus, since this toxin was able to compete with muscarinic ligand [3H]QNB in hippocampus of rats. In addition, Mlx-8 also blocked the accumulation of total [3H]inositol phosphate induced by muscarinic agonist carbachol. Thus, Mlx-8 may be a new pharmacological tool for examining muscarinic cholinergic function.(AU)


Subject(s)
Animals , Rats , Snakes , Elapid Venoms/adverse effects , Phospholipases A2 , Inositol Phosphates , Acetylcholine , Receptors, Muscarinic/analysis , Sequence Analysis, Protein
5.
Article in English | WPRIM | ID: wpr-787138

ABSTRACT

The purpose of this study was to characterize the genetic contribution to endothelial adaptation to exercise training. Vasoreactivity was assessed in aortas from four inbred mouse strains (129S1, B6, NON, and SJL) after 4 weeks of moderate intensity continuous exercise training (MOD), high intensity interval training (HIT) or in sedentary controls (SED). Intrinsic variations in endothelium-dependent vasorelaxation (EDR) to acetylcholine (ACh) as well as vasocontractile responses were observed across SED groups. For responses to exercise training, there was a significant interaction between mouse strain and training intensity on EDR. Exercise training had no effect on EDR in aortas from 129S1 and B6 mice. In NON, EDR was improved in aortas from MOD and HIT compared with respective SED, accompanied by diminished responses to PE in those groups. Interestingly, EDR was impaired in aorta from SJL HIT compared with SED. The transcriptional activation of endothelial genes was also influenced by the interaction between mouse strain and training intensity. The number of genes altered by HIT was greater than MOD, and there was little overlap between genes altered by HIT and MOD. HIT was associated with gene pathways for inflammatory responses. NON MOD genes showed enrichment for vessel growth pathways. These findings indicate that exercise training has non-uniform effects on endothelial function and transcriptional activation of endothelial genes depending on the interaction between genetic background and training intensity.


Subject(s)
Acetylcholine , Animals , Aorta , Endothelium , Gene Expression Profiling , Genetic Background , Mice , Mice, Inbred Strains , Transcriptional Activation , Vasodilation
6.
Article in English | WPRIM | ID: wpr-719635

ABSTRACT

Most diabetic patients experience diabetic mellitus (DM) urinary bladder dysfunction. A number of studies evaluate bladder smooth muscle contraction in DM. In this study, we evaluated the change of bladder smooth muscle contraction between normal rats and DM rats. Furthermore, we used pharmacological inhibitors to determine the differences in the signaling pathways between normal and DM rats. Rats in the DM group received an intraperitoneal injection of 65 mg/kg streptozotocin and measured blood glucose level after 14 days to confirm DM. Bladder smooth muscle contraction was induced using acetylcholine (ACh, 10⁻⁴ M). The materials such as, atropine (a muscarinic receptor antagonist), U73122 (a phospholipase C inhibitor), DPCPX (an adenosine A1 receptor antagonist), udenafil (a PDE5 inhibitor), prazosin (an α₁-receptor antagonist), papaverine (a smooth muscle relaxant), verapamil (a calcium channel blocker), and chelerythrine (a protein kinase C inhibitor) were pre-treated in bladder smooth muscle. We found that the DM rats had lower bladder smooth muscle contractility than normal rats. When prazosin, udenafil, verapamil, and U73122 were pre-treated, there were significant differences between normal and DM rats. Taken together, it was concluded that the change of intracellular Ca²⁺ release mediated by PLC/IP3 and PDE5 activity were responsible for decreased bladder smooth muscle contractility in DM rats.


Subject(s)
Acetylcholine , Animals , Atropine , Blood Glucose , Calcium Channels , Humans , Injections, Intraperitoneal , Muscle, Smooth , Papaverine , Prazosin , Protein Kinase C , Rats , Receptor, Adenosine A1 , Receptors, Muscarinic , Streptozocin , Type C Phospholipases , Urinary Bladder , Verapamil
7.
Article in English | WPRIM | ID: wpr-764072

ABSTRACT

BACKGROUND AND OBJECTIVES: Mesenchymal stem cells (MSCs) are used to treat autoimmune or inflammatory diseases. Our aim was to determine the immunomodulatory mechanisms elicited by MSCs during inflammation. METHODS AND RESULTS: We cocultured MSCs with peripheral blood mononuclear cells for a mixed lymphocyte reaction or stimulated them by phytohemagglutinin. Morphological changes of MSCs and secretion of acetylcholine (ACh) from MSCs were measured. The effects of an ACh antagonist and ACh agonist on lymphocyte proliferation and proinflammatory-cytokine production were determined. The inflammatory milieu created by immune-cell activation caused MSCs to adopt a neuronlike phenotype and induced them to release ACh. Additionally, nicotinic acetylcholine receptors (nAChRs) were upregulated in activated peripheral blood mononuclear cells. We observed that ACh bound to nAChR on activated immune cells and led to the inhibition of lymphocyte proliferation and of proinflammatory-cytokine production. MSC-mediated immunosuppression through ACh activity was reversed by an ACh antagonist called α-bungarotoxin, and lymphocyte proliferation was inhibited by an ACh agonist, ACh chloride. CONCLUSIONS: Our findings point to a novel immunomodulatory mechanism in which ACh secreted by MSCs under inflammatory conditions might modulate immune cells. This study may provide a novel method for the treatment of autoimmune diseases by means of MSCs.


Subject(s)
Acetylcholine , Autoimmune Diseases , Humans , Immunosuppression , Inflammation , Lymphocyte Culture Test, Mixed , Lymphocytes , Mesenchymal Stem Cells , Methods , Phenotype , Receptors, Nicotinic
8.
Article in English | WPRIM | ID: wpr-765974

ABSTRACT

Pediatric chronic intestinal pseudo-obstruction is a rare disorder characterized by a severe impairment of gastrointestinal motility leading to intestinal obstruction symptoms in the absence of mechanical causes. The diagnosis is usually clinical and diagnostic work is usually aimed to rule out mechanical obstruction and to identify any underlying diseases. Treatment is challenging and requires a multidisciplinary effort. In this manuscript we describe the youngest child successfully treated with the orally administrable, long-acting, reversible anti-cholinesterase drug, pyridostigmine. Like other drugs belonging to cholinesterase inhibitors, pyridostigmine enhances gut motility by increasing acetylcholine availability in the enteric nervous system and neuro-muscular junctions. Based on the direct evidence from the reported case, we reviewed the current literature on the use of pyridostigmine in severe pediatric dysmotility focusing on intestinal pseudo-obstruction. The overall data emerged from the few published studies suggest that pyridostigmine is an effective and usually well tolerated therapeutic options for patients with intestinal pseudo-obstruction. More specifically, the main results obtained by pyridostigmine included marked reduction of abdominal distension, reduced need of parenteral nutrition, and improvement of oral feeding. The present case and review on pyridostigmine pave the way for eagerly awaited future randomized controlled studies testing the efficacy of cholinesterase inhibitors in pediatric severe gut dysmotility.


Subject(s)
Acetylcholine , Child , Cholinesterase Inhibitors , Diagnosis , Enteric Nervous System , Female , Gastrointestinal Motility , Humans , Intestinal Obstruction , Intestinal Pseudo-Obstruction , Parenteral Nutrition , Pyridostigmine Bromide
9.
Article in English | WPRIM | ID: wpr-765110

ABSTRACT

BACKGROUND: Apart from its blood pressure-lowering effect by blocking the renin-angiotensin-aldosterone system, telmisartan, an angiotensin II type 1 receptor blocker (ARB), exhibits various ancillary effects including cardiovascular protective effects in vitro. Nonetheless, the protective effects of telmisartan in cerebrocardiovascular diseases are somewhat variable in large-scale clinical trials. Dysregulation of endothelial nitric oxide (NO) synthase (eNOS)-derived NO contributes to the developments of various vascular diseases. Nevertheless, the direct effects of telmisartan on endothelial functions including NO production and vessel relaxation, and its action mechanism have not been fully elucidated. Here, we investigated the mechanism by which telmisartan regulates NO production and vessel relaxation in vitro and in vivo. METHODS: We measured nitrite levels in culture medium and mouse serum, and performed inhibitor studies and western blot analyses using bovine aortic endothelial cells (BAECs) and a hyperglycemic mouse model. To assess vessel reactivity, we performed acetylcholine (ACh)-induced vessel relaxation assay on isolated rat aortas. RESULTS: Telmisartan decreased NO production in normoglycemic and hyperglycemic BAECs, which was accompanied by reduced phosphorylation of eNOS at Ser¹¹⁷⁹ (p-eNOS-Ser¹¹⁷⁹). Telmisartan increased the expression of protein phosphatase 2A catalytic subunit (PP2Ac) and co-treatment with okadaic acid completely restored telmisartan-inhibited NO production and p-eNOS-Ser¹¹⁷⁹ levels. Of the ARBs tested (including losartan and fimasartan), only telmisartan decreased NO production and p-eNOS-Ser¹¹⁷⁹ levels, and enhanced PP2Ac expression. Co-treatment with GW9662 had no effect on telmisartan-induced changes. In line with in vitro observations, telmisartan reduced serum nitrite and p-eNOS-Ser¹¹⁷⁹ levels, and increased PP2Ac expression in high fat diet-fed mice. Furthermore, telmisartan attenuated ACh-induced rat aorta relaxation. CONCLUSION: We demonstrated that telmisartan inhibited NO production and vessel relaxation at least in part by PP2A-mediated eNOS-Ser¹¹⁷⁹ dephosphorylation in a peroxisome proliferator-activated receptor γ-independent manner. These results may provide a mechanism that explains the inconsistent cerebrocardiovascular protective effects of telmisartan.


Subject(s)
Acetylcholine , Animals , Aorta , Blotting, Western , Catalytic Domain , Endothelial Cells , In Vitro Techniques , Losartan , Mice , Mice, Obese , Nitric Oxide Synthase Type III , Nitric Oxide , Okadaic Acid , Peroxisomes , Phosphorylation , Protein Phosphatase 2 , Rats , Receptor, Angiotensin, Type 1 , Relaxation , Renin-Angiotensin System , Vascular Diseases
10.
Article in English | WPRIM | ID: wpr-764979

ABSTRACT

BACKGROUND: Patients with acute myocardial infarction (AMI) have worse clinical outcomes than those with stable coronary artery disease despite revascularization. Non-culprit lesions of AMI also involve more adverse cardiovascular events. This study aimed to investigate the influence of AMI on endothelial function, neointimal progression, and inflammation in target and non-target vessels. METHODS: In castrated male pigs, AMI was induced by balloon occlusion and reperfusion into the left anterior descending artery (LAD). Everolimus-eluting stents (EES) were implanted in the LAD and left circumflex (LCX) artery 2 days after AMI induction. In the control group, EES were implanted in the LAD and LCX in a similar fashion without AMI induction. Endothelial function was assessed using acetylcholine infusion before enrollment, after the AMI or sham operation, and at 1 month follow-up. A histological examination was conducted 1 month after stenting. RESULTS: A total of 10 pigs implanted with 20 EES in the LAD and LCX were included. Significant paradoxical vasoconstriction was assessed after acetylcholine challenge in the AMI group compared with the control group. In the histologic analysis, the AMI group showed a larger neointimal area and larger area of stenosis than the control group after EES implantation. Peri-strut inflammation and fibrin formation were significant in the AMI group without differences in injury score. The non-target vessel of the AMI also showed similar findings to the target vessel compared with the control group. CONCLUSION: In the pig model, AMI events induced endothelial dysfunction, inflammation, and neointimal progression in the target and non-target vessels.


Subject(s)
Acetylcholine , Arteries , Balloon Occlusion , Constriction, Pathologic , Coronary Artery Disease , Drug-Eluting Stents , Endothelium , Fibrin , Follow-Up Studies , Humans , Inflammation , Male , Myocardial Infarction , Reperfusion , Stents , Swine , Vasoconstriction
11.
Experimental Neurobiology ; : 320-328, 2019.
Article in English | WPRIM | ID: wpr-763772

ABSTRACT

The basolateral amygdala (BLA) receives dense projections from cholinergic neurons of the basal forebrain. Acetylcholine can contributes to amygdala-dependent behaviors: formation and extinction of fear memory and appetitive instrumental learning. However, the cholinergic mechanism at the circuit level has not been defined yet. We demonstrated that cholinergic-induced di-synaptic inhibition of BLA pyramidal neurons exhibits a retrograde form of short-term synaptic inhibition, depolarization-induced suppression of inhibition (DSI). Activation of nicotinic receptors was sufficient to evoke action potentials in cholecystokinin (CCK)-positive inhibitory neurons, which strongly inhibit pyramidal neurons through their perisomatic synapses. Our cell type-specific monosynaptic retrograde tracing also revealed that CCK neurons are innervated by basal forebrain cholinergic neurons. Therefore, our data indicated that CCK inhibitory neurons mediate the cholinergic-induced di-synaptic inhibition of BLA pyramidal neurons.


Subject(s)
Acetylcholine , Action Potentials , Basal Forebrain , Basolateral Nuclear Complex , Cholecystokinin , Cholinergic Neurons , Conditioning, Operant , Iontophoresis , Memory , Neurons , Pyramidal Cells , Receptors, Nicotinic , Synapses
12.
Article in English | WPRIM | ID: wpr-759012

ABSTRACT

The autonomic nervous system plays critical roles in maintaining homeostasis in humans, directly regulating inflammation by altering the activity of the immune system. The cholinergic anti-inflammatory pathway is a well-studied neuroimmune interaction involving the vagus nerve. CD4-positive T cells expressing β2 adrenergic receptors and macrophages expressing the alpha 7 subunit of the nicotinic acetylcholine receptor in the spleen receive neurotransmitters such as norepinephrine and acetylcholine and are key mediators of the cholinergic anti-inflammatory pathway. Recent studies have demonstrated that vagus nerve stimulation, ultrasound, and restraint stress elicit protective effects against renal ischemia-reperfusion injury. These protective effects are induced primarily via activation of the cholinergic anti-inflammatory pathway. In addition to these immunological roles, nervous systems are directly related to homeostasis of renal physiology. Whole-kidney three-dimensional visualization using the tissue clearing technique CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) has illustrated that renal sympathetic nerves are primarily distributed around arteries in the kidneys and denervated after ischemia-reperfusion injury. In contrast, artificial renal sympathetic denervation has a protective effect against kidney disease progression in murine models. Further studies are needed to elucidate how neural networks are involved in progression of kidney disease.


Subject(s)
Acetylcholine , Arteries , Autonomic Nervous System , Cholinergic Neurons , Homeostasis , Humans , Immune System , Inflammation , Kidney Diseases , Kidney , Macrophages , Nervous System , Neurotransmitter Agents , Norepinephrine , Optogenetics , Physiology , Receptors, Adrenergic , Receptors, Nicotinic , Reperfusion Injury , Spleen , Sympathectomy , Sympathetic Nervous System , T-Lymphocytes , Ultrasonography , Vagus Nerve , Vagus Nerve Stimulation
13.
Einstein (Säo Paulo) ; 17(3): eAO4600, 2019. graf
Article in English | LILACS | ID: biblio-1011991

ABSTRACT

ABSTRACT Objective: To characterize the calcium influx pathways implicated in the sustained elevation of endothelial intracellular calcium concentration, required for the synthesis and release of relaxing factors. Methods: We evaluated the effect of the newly synthesized pyrazole derivatives, described as selective inhibitors for ORAI (BTP2/Pyr2 and Pyr6) and TRPC3 (Pyr3 and Pyr10) channels, upon endothelium- and extracellular calcium-dependent relaxations stimulated by acetylcholine and thapsigargin, in pre-constricted rat thoracic aortic rings. Results: Acetylcholine and thapsigargin responses were completely reverted by Pyr2 and Pyr6 (1 to 3μM). Pyr3 (0.3 to 3μM) caused a rapid reversal of acetylcholine (6.2±0.08mg.s−1) and thapsigargin (3.9±0.25mg.s−1) relaxations, whereas the more selective TRPC3 blocker Pyr10 (1 to 3μM) had no effect. The recently described TRPC4/5 selective blocker, ML204 (1 to 3μM), reverted completely acetylcholine relaxations, but minimally thapsigargin induced ones. Noteworthy, relaxations elicited by GSK1016790A (TRPV4 agonist) were unaffected by pyrazole compounds or ML204. After Pyr2 and Pyr6 pre-incubation, acetylcholine and thapsigargin evoked transient relaxations similar in magnitude and kinetics to those observed in the absence of extracellular calcium. Sodium nitroprusside relaxations as well as phenylephrine-induced contractions (denuded aorta) were not affected by any of pyrazole compounds (1 to 3μM). Conclusion: These observations revealed a previously unrecognized complexity in rat aorta endothelial calcium influx pathways, which result in production and release of nitric oxide. Pharmacologically distinguishable pathways mediate acetylcholine (ORAI/TRPC other than TRPC3/TRPC4 calcium-permeable channels) and thapsigargin (TRPC4 not required) induced calcium influx.


RESUMO Objetivo: Caracterizar as vias do influxo de cálcio envolvidas no aumento sustentado da concentração intracelular de cálcio na célula endotelial, essencial para a síntese e a liberação de fatores relaxantes. Métodos: Analisamos o efeito de derivados pirazólicos sintetizados recentemente, descritos como inibidores seletivos para canais ORAI (BTP2/Pyr2 e Pyr6) e TRPC3 (Pyr3 e Pyr10), nos relaxamentos dependentes de endotélio e cálcio extracelular, produzidos por acetilcolina e tapsigargina, em anéis pré-contraídos da aorta torácica de rato. Resultados: As respostas de acetilcolina e tapsigargina foram completamente revertidas por Pyr2 e Pyr6 (1 a 3μM). Pyr3 (0,3 a 3μM) produziu reversão rápida dos relaxamentos de acetilcolina (6,2±0,08mg.s−1) e tapsigargina (3,9±0,25mg.s−1), enquanto o bloqueador mais seletivo para TRPC3, Pyr10 (1 a 3μM), não apresentou efeito. ML204 (1 a 3μM), bloqueador seletivo de TRPC4, descrito há pouco tempo, reverteu os relaxamentos induzidos por acetilcolina de forma completa, mas afetou minimamente aqueles produzidos por tapsigargina. Os derivados pirazólicos ou ML204 não afetaram os relaxamentos estimulados com GSK1016790A (TRPV4-agonista). Ainda, após pré-incubação com Pyr2 e Pyr6, acetilcolina e tapsigargina provocaram relaxamentos transitórios semelhantes em magnitude e cinética àqueles observados na ausência de cálcio extracelular. Os relaxamentos do nitroprussiato de sódio e as contrações induzidas pela fenilefrina (aorta sem endotélio) não foram afetados pelos compostos pirazólicos (1 a 3μM). Conclusão: Essas observações revelaram uma complexidade desconhecida das vias de influxo de cálcio no endotélio da aorta de rato, que resultam na produção e na liberação de óxido nítrico. Vias distinguíveis farmacologicamente medeiam o influxo estimulado por acetilcolina (ORAI TRPC, diferentes de TRPC3 TRPC4) e tapsigargina (TRPC4 não requerido).


Subject(s)
Animals , Male , Acetylcholine/pharmacology , Calcium/pharmacology , Thapsigargin/pharmacology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Endothelium-Dependent Relaxing Factors/metabolism , Nitric Oxide/metabolism , Aorta, Thoracic/drug effects , Time Factors , Vasodilator Agents/pharmacology , Rats, Wistar , TRPC Cation Channels/metabolism , TRPV Cation Channels/drug effects , TRPV Cation Channels/metabolism , Calcium Release Activated Calcium Channels/metabolism
14.
Article in Chinese | WPRIM | ID: wpr-776529

ABSTRACT

OBJECTIVE@#To investigate the effects of Xiaotan Huayu Liqiao formula (the Chinese Medicine) on mesenteric artery function in rats exposed to chronic intermittent hypoxia (CIH), and to explore the related mechanism.@*METHODS@#Forty-eight male SD rats were randomly divided into four groups as Normoxia, CIH, Formula+CIH and formula group. Rats were exposed to normoxia in the Normoxia and Formula group, or intermittent hypoxia in CIH or Formula+CIH group. Xiaotan Huayu Liqiao formula was given at 24g/kg by intragastric administration before intermittent hypoxia exposure. The pathological changes of mesenteric artery were determined by HE staining, and the relaxation of mesenteric artery (induced by acetylcholine(ACh) and L-arginine(L-Arg)) was recorded by microvascular ring technique. Serums of all rats were collected (0 d and 21 d) and the content of NO was detected by ELISA. The levels of endothelial nitric oxide synthase (eNOS) and p-eNOS were measured by Western blot.@*RESULTS@#Compared with Normoxia group, the mesenteric arterial endothelial injury and media thickening were observed and the relaxation of mesenteric artery was significantly reduced in rats exposed to CIH. The level of NO in serum and the ratio of p-eNOS/eNOS were also decreased in the CIH group. Xiaotan Huayu Liqiao formula administration improved the pathologic changes and dilatation function of mesenteric artery, increased the levels of NO and p-eNOS. Compared with Normoxia group,all the results were not observed significant difference in Formula group.@*CONCLUSION@#Xiaotan Huayu Liqiao formula increased the bioavailability of NO, and ameliorated the CIH induced mesenteric artery function injury.


Subject(s)
Acetylcholine , Animals , Drugs, Chinese Herbal , Pharmacology , Hypoxia , Pathology , Male , Mesenteric Arteries , Pathology , Nitric Oxide , Metabolism , Nitric Oxide Synthase Type III , Metabolism , Random Allocation , Rats , Rats, Sprague-Dawley
15.
Neuroscience Bulletin ; (6): 156-166, 2019.
Article in English | WPRIM | ID: wpr-775475

ABSTRACT

Cardiovascular diseases are life-threatening illnesses with high morbidity and mortality. Suppressed vagal (parasympathetic) activity and increased sympathetic activity are involved in these diseases. Currently, pharmacological interventions primarily aim to inhibit over-excitation of sympathetic nerves, while vagal modulation has been largely neglected. Many studies have demonstrated that increased vagal activity reduces cardiovascular risk factors in both animal models and human patients. Therefore, the improvement of vagal activity may be an alternate approach for the treatment of cardiovascular diseases. However, drugs used for vagus nerve activation in cardiovascular diseases are limited in the clinic. In this review, we provide an overview of the potential drug targets for modulating vagal nerve activation, including muscarinic, and β-adrenergic receptors. In addition, vagomimetic drugs (such as choline, acetylcholine, and pyridostigmine) and the mechanism underlying their cardiovascular protective effects are also discussed.


Subject(s)
Acetylcholine , Pharmacology , Animals , Cardiovascular Diseases , Drug Therapy , Cholinergic Agents , Therapeutic Uses , Humans , Receptors, Muscarinic , Sympathetic Nervous System , Vagus Nerve
16.
Neuroscience Bulletin ; (6): 67-78, 2019.
Article in English | WPRIM | ID: wpr-775464

ABSTRACT

The rostral ventrolateral medulla (RVLM) is a key region in cardiovascular regulation. It has been demonstrated that cholinergic synaptic transmission in the RVLM is enhanced in hypertensive rats. Angiotensin-converting enzyme 2 (ACE2) in the brain plays beneficial roles in cardiovascular function in hypertension. The purpose of this study was to determine the effect of ACE2 overexpression in the RVLM on cholinergic synaptic transmission in spontaneously hypertensive rats (SHRs). Four weeks after injecting lentiviral particles containing enhanced green fluorescent protein and ACE2 bilaterally into the RVLM, the blood pressure and heart rate were notably decreased. ACE2 overexpression significantly reduced the concentration of acetylcholine in microdialysis fluid from the RVLM and blunted the decrease in blood pressure evoked by bilateral injection of atropine into the RVLM in SHRs. In conclusion, we suggest that ACE2 overexpression in the RVLM attenuates the enhanced cholinergic synaptic transmission in SHRs.


Subject(s)
Acetylcholine , Metabolism , Animals , Blood Pressure , Physiology , Cardiovascular System , Metabolism , Cholinergic Neurons , Metabolism , Hypertension , Metabolism , Male , Peptidyl-Dipeptidase A , Metabolism , Rats , Rats, Inbred SHR , Metabolism
17.
Kosin Medical Journal ; : 1-14, 2019.
Article in English | WPRIM | ID: wpr-760468

ABSTRACT

OBJECTIVES: Intracoronary injection of acetylcholine (Ach) has been shown to induce significant coronary artery spasm (CAS) in patients with vasospastic angina. Clinical significance and angiographic characteristics of patients with ischemic electrocardiogram (ECG) changes during the Ach provocation test are not clarified yet. METHODS: A total 4,418 consecutive patients underwent coronary angiography with Ach provocation tests from 2004 to 2012 were enrolled. Ischemic ECG changes were defined as transient ST-segment depression or elevation ( > 1 mm) and T inversion with/without chest pain. Finally, a total 2,293 patients (28.5% of total subjects) proven CAS were enrolled for this study. RESULTS: A total 119 patients (5.2%) showed ECG changes during Ach provocation tests. The baseline clinical and procedural characteristics are well balanced between the two groups. Ischemic ECG change group showed more frequent chest pain, higher incidence of baseline spasm, severe vasospasm, multi-vessel involvement, and more diffuse spasm ( > 30 mm) than those without ischemic ECG changes. At 5 years, the incidences of death, major adverse cardiac events (MACE) and major adverse cardiac and cerebral events (MACCE) were higher in the ischemic ECG change group despite of optimal medical therapy. CONCLUSIONS: The patients with ischemic ECG changes during Ach provocation tests were associated with more frequent chest pain, baseline spasm, diffuse, severe and multi-vessel spasm than patients without ischemic ECG changes. At 5-years, the incidences of death, MACE and MACCE were higher in the ischemic ECG change group, suggesting more intensive medical therapy with close clinical follow up will be required.


Subject(s)
Acetylcholine , Chest Pain , Coronary Angiography , Coronary Vessels , Depression , Electrocardiography , Follow-Up Studies , Humans , Incidence , Spasm
18.
Psiquiatr. salud ment ; 35(1/2): 9-16, ene.-jun. 2018.
Article in Spanish | LILACS | ID: biblio-998636

ABSTRACT

El síndrome metabólico (SM) corresponde a un conjunto de factores de riesgo derivados de la obesidad visceral e insulinoresistencia. 35.3% de la población adulta chilena presentó SM en el período 2009 - 2010, con diferencia significativa entre hombres y mujeres (41.6% vs 30.9%, respectivamente). En Estados Unidos se ha calculado que la media de años potencialmente perdidos en pacientes con enfermedades mentales va de 25 a 30, comparada con la población general. La principal causa de muerte es la enfermedad coronaria. La mayoría de los pacientes en tratamiento neuroléptico en hospitales psiquiátricos no reciben control de factores de riesgo metabólicos. La evidencia señala que los pacientes esquizofrénicos no son adecuadamente pesquisados ni tratados por Dislipidemia (hasta un 88% de estos pacientes siguen sin tratamiento) ni por hipertensión (hasta un 62%). El objetivo de este trabajo es evaluar factores de riesgo cardiovascular en varones hospitalizados en unidad de corta estadía psiquiátrica del Instituto Psiquiátrico Dr. José Horwitz Barak. Se evaluó a 35 pacientes varones, de los cuales un 37% presentó SM, un 45.3% presentó sobrepeso.


The metabolic syndrome (MS) corresponds to a set of risk factors derived from visceral obesity and insulin resistance. 35.3% of the Chilean adult population had MS in the 2009-2010 period, with a significant difference between men and women (41.6% vs 30.9%, respectively). In the United States, it has been estimated that the average number of years potentially lost in patients with mental illness ranges from 25 to 30, compared with the general population. The main cause of death is coronary heart disease. Most patients on neuroleptic treatment in psychiatric hospitals do not receive control of metabolic risk factors. The evidence indicates that schizophrenic patients are not adequately researched or treated for dyslipidemia (up to 88% of these patients remain untreated) or hypertension (up to 62%). OBJECTIVE: To evaluate cardiovascular risk factors in hospitalized men in a short stay psychiatric unit of the Psychiatric Institute Dr. José Horwitz Barak. Thirty-five male patients were evaluated, of which 37% had MS, and 45.3% were overweight.


Subject(s)
Humans , Male , Adolescent , Adult , Middle Aged , Aged , Young Adult , Antipsychotic Agents/adverse effects , Metabolic Syndrome/complications , Metabolic Syndrome/chemically induced , Heart Disease Risk Factors , Psychiatric Department, Hospital , Signal Transduction/drug effects , Acetylcholine , Norepinephrine , Nutritional Status , Risk Factors , Age Distribution , Risk Assessment , Metabolic Syndrome/diagnosis , Diabetes Mellitus/chemically induced , Dyslipidemias/chemically induced , Overweight , Hospitalization
19.
Article in English | WPRIM | ID: wpr-691344

ABSTRACT

<p><b>OBJECTIVE</b>To examine the effect of icariin (ICA) on the cognitive impairment induced by traumatic brain injury (TBI) in mice and the underlying mechanisms related to changes in hippocampal acetylation level.</p><p><b>METHODS</b>The modifified free-fall method was used to establish the TBI mouse model. Mice with post-TBI cognitive impairment were randomly divided into 3 groups using the randomised block method (n=7): TBI (vehicle-treated), low-dose (75 mg/kg) and high-dose (150 mg/kg) of ICA groups. An additional sham-operated group (vehicle-treated) was employed. The vehicle or ICA was administrated by gavage for 28 consecutive days. The Morris water maze (MWM) test was conducted. Acetylcholine (ACh) content, mRNA and protein levels of choline acetyltransferase (ChAT), and protein levels of acetylated H3 (Ac-H3) and Ac-H4 were detected in the hippocampus.</p><p><b>RESULTS</b>Compared with the sham-operated group, the MWM performance, hippocampal ACh content, mRNA and protein levels of ChAT, and protein levels of Ac-H3 and Ac-H4 were signifificantly decreased in the TBI group (P<0.05). High-dose of ICA signifificantly ameliorated the TBI-induced weak MWM performance, increased hippocampal ACh content, and mRNA and protein levels of ChAT, as well as Ac-H3 protein level compared with the TBI group (P<0.05).</p><p><b>CONCLUSION</b>ICA improved post-TBI cognitive impairment in mice by enhancing hippocampal acetylation, which improved hippocampal cholinergic function and ultimately improved cognition.</p>


Subject(s)
Acetylation , Acetylcholine , Metabolism , Animals , Brain Injuries, Traumatic , Choline O-Acetyltransferase , Genetics , Metabolism , Cognitive Dysfunction , Drug Therapy , Flavonoids , Chemistry , Pharmacology , Therapeutic Uses , Hippocampus , Pathology , Histones , Metabolism , Homeostasis , Male , Maze Learning , Mice , RNA, Messenger , Genetics , Metabolism
20.
Article in English | WPRIM | ID: wpr-713481

ABSTRACT

This study was performed to investigate the effect of a concentrate of fermented wild ginseng root culture (HLJG0701) on memory improvement in the scopolamine (SPL)-induced memory-deficient mouse model. Eight-week-old male ICR mice were used to evaluate the protective effect of HLJG0701 against the SPL-induced memory loss animal model. The Morris water maze test, which measures hippocampus-dependent learning ability, and the Y-maze test, a short-term memory assessment test, were performed and related markers were analyzed. HLJG0701-treated groups displayed significantly reduced acetylcholinesterase activity and increased acetylcholine level compared with the SPL-administered group (SPL-G) (P < 0.05). In the Y-maze test, the spontaneous alternation in al HLJG0711-treated groups was significantly increased compared with that in SPL-G (P < 0.05). In the Morris water maze test, the escape latency and time spent in the target quadrant in all HLJG0701-treated groups were significantly decreased and increased, respectively, compared with those in SPL-G (P < 0.05). In addition, the brain-derived neurotrophic factor level in groups treated with HLJG0701 300 and 600 mg/kg body weight was significantly increased compared with that in SPL-G (P < 0.05). These results suggest that the HLJG0701 may protect against memory loss by inhibiting acetylcholinesterase activity and preventing acetylcholine deficiency.


Subject(s)
Acetylcholine , Acetylcholinesterase , Animals , Body Weight , Brain-Derived Neurotrophic Factor , Ginsenosides , Humans , Learning , Male , Memory Disorders , Memory , Memory, Short-Term , Mice , Mice, Inbred ICR , Models, Animal , Panax , Scopolamine , United Nations , Water
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