Pharmacology最新文献

{"title":"Melatonin Supports the Survival of Cholinergic Neurons in Organotypic Brain Slices of the Basal Nucleus of Meynert.","authors":"Grazia Ilaria Caruso,&nbsp;Dhwani S Korde,&nbsp;Christian Humpel","doi":"10.1159/000527887","DOIUrl":"https://doi.org/10.1159/000527887","url":null,"abstract":"<p><p>The nucleus basalis of Meynert (nBM) is the major source of cholinergic neurons in the basal forebrain, which require nerve growth factor (NGF) for their survival. Melatonin, a pleiotropic hormone, has been shown to exert neuroprotection in several experimental models, but its effect on nBM neurons is not well known. Thus, the aim of this study is to evaluate the effect of melatonin in organotypic brain slices of the nBM. Organotypic nBM slices were incubated for 2 weeks without (control) or with 100 ng/mL NGF, 1 μM melatonin, or a combination of both. Cholinergic neurons were immunohistochemically stained for choline acetyltransferase (ChAT) and subjected to a co-localization study with silent information regulator 1 (SIRT1) and melatonin receptor 1A (MT1A), both potentially involved in melatonin neuroprotection. Counting of ChAT-positive neurons in nBM slices showed that melatonin and NGF significantly increased the number of ChAT-positive neurons compared to the control in a dose-dependent manner (1-10 μM). In co-treatment with NGF, melatonin did not potentiate the maximal NGF-mediated effect. Immunohistochemical analysis proved that cholinergic nBM neurons co-localized with SIRT1 and MT1A receptor. Our data show that melatonin improves the survival of cholinergic nBM neurons and confirm that they express SIRT1 and MT1A.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":"108 2","pages":"204-212"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9391733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral Administration of Artemisia argyi Polysaccharide Increases Estrogen Level and Maintains Blood Lipid Homeostasis in Ovariectomized Rats.","authors":"Pengfei Zhang,&nbsp;Huimin Sun,&nbsp;Dexin Yang,&nbsp;Yuanyuan Wang,&nbsp;Jiejuan Cheng,&nbsp;Changchun Zeng","doi":"10.1159/000527465","DOIUrl":"https://doi.org/10.1159/000527465","url":null,"abstract":"<p><strong>Introduction: </strong>Artemisia argyi polysaccharide (AAP) has a beneficial effect on menstruation-related symptoms and the potential regulation of lipid metabolism. It is expected to be a safe and effective ingredient for estrogen deficiency and lipid metabolic disorders. Here, we investigate the effect of AAP on body weight gain, estrogen level, and blood lipid changes in ovariectomized (OVX) rats.</p><p><strong>Methods: </strong>Thirty-six female Wistar rats were randomly divided into six treatment groups, including a sham-operated (Sham) group, OVX group, estrogen replacement (OVX + E2) group, and AAP treatment (OVX + 125, 250, 500 mg/kg AAP) group. The body weight and feed intake were recorded every week. The level of estrogen and blood lipid was determined. The gene expressions and protein expressions of estrogen receptors (ERs), fatty acid synthetase (FAS), acetyl CoA carboxylase 2 (ACC2), and 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) were determined.</p><p><strong>Results: </strong>AAP treatment significantly decreased the body weight gain and average daily food intake of rats in the OVX group. Treatment with AAP significantly increased the relative weight of the uterus, plasma estrogen level, and the gene expression and protein expression of ER-α in the uterus. For blood lipids, plasma levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol were significantly reduced by AAP treatment in OVX rats. AAP treatment decreased the expression of FAS and HMGR in the liver of OVX rats. Furthermore, AAP treatment significantly increased the gene expression of ACC2, the protein expression of P-ACC2, and the ratio of P-ACC2/ACC2.</p><p><strong>Conclusion: </strong>In summary, AAP treatment exerts beneficial effects on body weight gain and lipid metabolism disorder induced by ovariectomy through increasing estrogen levels, inhibiting FAS, and promoting fatty acid oxidation.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":"108 2","pages":"147-156"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9407527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lafutidine Ameliorates Indomethacin-Induced Small Intestinal Damage in Rats by Modifying the Intestinal Mucosal Barrier, Inflammation, and Microbiota.","authors":"Lanping Zhu,&nbsp;Junyi Guo,&nbsp;Qinlingfei Liu,&nbsp;Yang Luo,&nbsp;Jing Zhao,&nbsp;Weilong Zhong,&nbsp;Siyuan Sun,&nbsp;Xiuxiu Xu,&nbsp;Huixi Liang,&nbsp;Chenxi Lou,&nbsp;Chongfei Song,&nbsp;Jihua Chen,&nbsp;Jingwen Zhao,&nbsp;Bangmao Wang,&nbsp;Xin Chen","doi":"10.1159/000529879","DOIUrl":"https://doi.org/10.1159/000529879","url":null,"abstract":"<p><strong>Introduction: </strong>Nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal damage is a serious and escalating clinical problem without effective treatment. Lafutidine (LAF) is a novel histamine H2 receptor antagonist with a mucosal protective action. This study aimed to investigate the protective effect of LAF on indomethacin (IND)-induced enteropathy in rats.</p><p><strong>Methods: </strong>Rats were treated with LAF for 10 days with concomitant IND treatment on the final 5 days. Changes in metabolism and hematological and biochemical parameters were measured, and intestinal damage was blindly scored. Intestinal mucosal tissue and luminal contents were collected for transcriptome and microbiota sequencing. Intestinal inflammation and barrier function were also evaluated.</p><p><strong>Results: </strong>LAF treatment prevented anorexia and weight loss in rats and ameliorated reductions in hemoglobin, hematocrit, total protein, and albumin levels. LAF reduced the severity of IND-induced intestinal damage including macroscopic and histopathological damage score. Transcriptome sequencing results indicated that LAF might have positive effects on intestinal inflammation and the intestinal mucosal barrier. Further research revealed that LAF decreased neutrophil infiltration, and IL-1β and TNF-α expression in intestinal tissue. Besides, the treatment increased mucus secretion, MUC2, Occludin, and ZO-1 expression, and decreased serum D-lactate levels. LAF treatment also ameliorates microbial dysbiosis in small intestine induced by IND and increased the abundance of Lactobacillus acidophilus.</p><p><strong>Conclusion: </strong>LAF may protect against NSAID enteropathy via enhancing the intestinal mucosal barrier, inhibiting inflammation, and regulating microbiota.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":"108 3","pages":"286-300"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9528683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Normal and Overweight Pregnancy in GLUT4 and Glucose-Dependent Vascular Contractility.","authors":"Esther Juarez Cortés, Gustavo López Y López, Eduardo I Perez Muñoz, Betzabel Rodriguez Reyes, Damian A Madrigal-Aguilar, Rosa A Bobadilla-Lugo","doi":"10.1159/000533344","DOIUrl":"10.1159/000533344","url":null,"abstract":"<p><strong>Introduction: </strong>Obesity during pregnancy can contribute to hypertensive complications through changes in glucose utilization. We investigated the impact of vascular glucose uptake, GLUT4 density, and endothelium on agonist-induced vasoconstriction in the aortas of overweight pregnant rats.</p><p><strong>Methods: </strong>Isolated aortic rings with or without endothelium from pregnant or nonpregnant rats fed a standard (SD) or hypercaloric diet (HD) were contracted with phenylephrine or serotonin (10-9 to 10-4<sc>M</sc>) using standard (11 m<sc>m</sc>) or without (0 m<sc>m</sc>) glucose Krebs solution. GLUT4 density in the aortas was measured using the en face method.</p><p><strong>Results: </strong>Aortas from overweight pregnant animals (PHD) showed increased Phe-induced vasoconstriction (p &lt; 0.05 vs. pregnant standard diet [PSD]), which was endothelium-independent. The contraction decreased significantly in the absence of glucose. In contrast, vessels from pregnant SD rats maintained their contraction in glucose-free Krebs solution. 5-HT increases PHD aortic contraction only in the absence of glucose. The fetal aortas from PHD mothers showed blunted vasoconstriction. Overweight significantly reduced GLUT4 expression in maternal and fetal aortas (p &lt; 0.05 vs. PSD).</p><p><strong>Conclusions: </strong>Aortic contractility is independent of glucose uptake during healthy pregnancy. In contrast, overweight pregnancy increases contractility. This increase depends directly on smooth muscle glucose uptake and inversely on GLUT-4 density. The increased contraction observed in the vasculature of overweight mothers was inverted in the fetal aortas.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"521-529"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10169381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effects of Novel Triazolopyrimidine Derivatives on H2S Production in Lung and Vascular Tonus in Aorta.","authors":"Emine Nur Ozbek, Huseyin Istanbullu, Umran Kızrak, Elif Alan Albayrak, Gülnur Sevin, Gunay Yetik-Anacak","doi":"10.1159/000533419","DOIUrl":"10.1159/000533419","url":null,"abstract":"<p><strong>Introduction: </strong>Hydrogen sulfide (H2S), known as a third gasotransmitter, is a signaling molecule that plays a regulatory role in physiological and pathophysiological processes. Decreased H2S levels were reported in inflammatory respiratory diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary hypertension. H2S donors or drugs that increase H2S have emerged as novel treatments for inflammatory respiratory diseases. We previously showed that resveratrol (RVT) causes vascular relaxation and antioxidant effects by inducing H2S production. In the current study, we synthesized a new molecule Cpd2, as an RVT analog. We examined the effect of Cpd2 and its precursor chalcone compound (Cpd1) on H2S formation under both healthy and oxidative stress conditions in the lung, as well as vascular relaxation in the aorta.</p><p><strong>Methods: </strong>Cpd2 synthesized from Cpd1 with microwaved in basic conditions. H2S formation was measured by H2S biosensor in the mice lungs under both healthy and pyrogallol-induced oxidative stress conditions in the presence/absence of H2S synthesis inhibitor aminooxyacetic acid (AOAA). The effect of compounds on vascular tonus is investigated in mice aorta by DMT myograph.</p><p><strong>Results: </strong>RVT and Cpd2 significantly increased <sc>l</sc>-cysteine (<sc>l</sc>-cys) induced-H2S formation in the lung homogenates of healthy mice, but Cpd1 did not. Superoxide anion generator pyrogallol caused a decrease in H2S levels in mice lungs and Cpd2 restored it. Inhibition of Cpd2-induced H2S formation by AOAA confirmed that Cpd2 increases endogenous H2S formation in both healthy and oxidative stress conditions. Furthermore, we found that both Cpd1 and Cpd2 (10-8-10-4 M) caused vascular relaxation in mice aorta.</p><p><strong>Discussion and conclusion: </strong>We found that Cpd2, a newly synthesized RVT analog, is an H2S-inducing molecule and vasorelaxant similar to RVT. Since H2S has antioxidant and anti-inflammatory effects, Cpd2 has a potential for the treatment of respiratory diseases where oxidative stress and decreased H2S levels are present.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"530-539"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10267310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High On-Treatment Platelet Reactivity: Aspirin versus Clopidogrel.","authors":"René M'Pembele,&nbsp;Samantha Ahlbrecht,&nbsp;Carolin Helten,&nbsp;Philipp Mourikis,&nbsp;David Naguib,&nbsp;Saif Zako,&nbsp;Kajetan Trojovsky,&nbsp;Ragnar Huhn,&nbsp;Tobias Petzold,&nbsp;Thomas Hohlfeld,&nbsp;Tobias Zeus,&nbsp;Malte Kelm,&nbsp;Lisa Dannenberg,&nbsp;Amin Polzin","doi":"10.1159/000527816","DOIUrl":"https://doi.org/10.1159/000527816","url":null,"abstract":"<p><strong>Background: </strong>Antithrombotic regimen in patients on oral anticoagulation (OAC) post-percutaneous coronary intervention (PCI) is challenging. At least, one antiplatelet agent in combination with OAC is recommended after PCI for 6-12 months. Clopidogrel is used most frequently in this setting. However, data comparing P2Y12 inhibition with clopidogrel versus cyclooxygenase inhibition by acetylsalicylic acid (ASA, aspirin) is missing. It is well known that the antiplatelet effects of ASA and clopidogrel are frequently impaired (high on-treatment platelet reactivity [HTPR]). In this pilot investigation, we compared the antiplatelet effects of clopidogrel versus ASA.</p><p><strong>Methods: </strong>In this retrospective single-center database analysis, we investigated platelet reactivity by light transmission aggregometry in patients under different antiplatelet regimes. Results were presented as maximum of aggregation (MoA). HTPR to ASA and to clopidogrel were assessed.</p><p><strong>Results: </strong>755 patients were enrolled. 677 were on ASA, 521 were on clopidogrel, and 198 had OAC. Overall mean age was 73 ± 13.4 years, and 458 (60.7%) were male. HTPR to ASA occurred in 94/677 patients (13.9%), and mean arachidonic acid-induced MoA was 14.15 ± 19.04%. HTPR to clopidogrel occurred in 241/521 patients (46.3%), and mean adenosine diphosphate-induced MoA was 50.06 ± 20.42%. HTPR to clopidogrel was significantly more frequent than HTPR to ASA; single antiplatelet therapy (SAPT)-mono ASA: 27/199 (13.6%) versus mono clopidogrel: 6/18 (33.3%); p = 0.037; SAPT with OAC-OAC with ASA: 8/35 (22.9%) versus OAC with clopidogrel: 27/60 (45%); p = 0.046. Same difference in HTPR contingency could be shown in subgroups of dual antiplatelet therapy and ASA + clopidogrel + OAC therapy.</p><p><strong>Conclusion: </strong>Impaired pharmacodynamic response to clopidogrel was more frequent as HTPR to ASA. Hence, ASA should be tested in combination with OAC post-PCI.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":"108 1","pages":"83-89"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10488441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety of Tigecycline in Patients on Antithrombotic Therapy: A Single-Center Retrospective Study.","authors":"Chuwen Lin, Miaoqin Tan, Dongmei Wang, Chunping Gu, Yongming Wu, Shengnan Wang","doi":"10.1159/000532001","DOIUrl":"10.1159/000532001","url":null,"abstract":"<p><strong>Introduction: </strong>The aims of the study were to investigate the risk factors of tigecycline-induced hypofibrinogenemia and to evaluate the safety of tigecycline with concomitant antithrombotic drugs.</p><p><strong>Methods: </strong>We performed a retrospective analysis of patients who received tigecycline for more than 3 days between January 2015 and June 2019. Clinical and laboratory data were collected including fibrinogen concertation, tigecycline dose, duration of treatment, disease severity, complete blood count, indicators of infection, liver and renal function. Risk factors of hypofibrinogenemia were analyzed by univariate and multivariate analysis. To evaluate the safety of tigecycline and concomitant antithrombotic drugs, bleeding events were assessed by comparing the decline in hemoglobin and the amount of red blood cell transfusion in patients with antithrombotic drugs and those without.</p><p><strong>Results: </strong>This study included a total of 68 cases, 20 of which experienced hypofibrinogenemia while receiving tigecycline treatment. Duration of treatment, cefoperazone/sulbactam combination therapy, and fibrinogen levels prior to initiation of tigecycline were risk factors associated with tigecycline-induced hypofibrinogenemia. There were 26 recorded bleeding incidents, 25 of which happened before the start of tigecycline. Antithrombotic and non-antithrombotic patients did not differ in their hemoglobin decline or need for red blood cell transfusions while taking tigecycline.</p><p><strong>Conclusion: </strong>A longer treatment duration, cefoperazone/sulbactam combination therapy, and a lower level of fibrinogen before tigecycline were associated with an increased risk of tigecycline-induced hypofibrinogenemia. A combination of antithrombotic drugs and tigecycline did not aggravate the bleeding events during tigecycline treatment.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"540-549"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41147729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin's Role in Hyperlactatemia and Lactic Acidosis in ICU Patients: A Systematic Review.","authors":"Livia Mueller,&nbsp;Michel Moser,&nbsp;Josef Prazak,&nbsp;Daniel G Fuster,&nbsp;Joerg C Schefold,&nbsp;Patrick Zuercher","doi":"10.1159/000528252","DOIUrl":"https://doi.org/10.1159/000528252","url":null,"abstract":"<p><strong>Introduction: </strong>Metformin-treated patients may experience severe hyperlactatemia or lactic acidosis (LA). LA often requires intensive-care-unit (ICU) treatment, and mortality rates are high. Here, we investigate the impact of renal dysfunction and renal replacement therapy (RRT) on the outcomes of critically ill patients with metformin-associated LA (MALA). Furthermore, we assessed associations between mortality and metformin dose, metformin plasma/serum concentrations, lactate level, and arterial pH. Finally, we investigated whether the recommended classification in MALA, metformin-unrelated LA, metformin-induced LA, and LA in metformin therapy appears useful in this regard.</p><p><strong>Methods: </strong>We performed a retrospective analysis based on a systematic PubMed search for publications on hyperlactatemia/LA in metformin-treated ICU patients from January 1995 to February 2020. Case-level data including demographics and clinical conditions were extracted, and logistic regression analyses were performed.</p><p><strong>Results: </strong>A total of 92 ICU patients were reported. Two of these patients had no comorbidities interfering with lactate metabolism. In the overall group, arterial pH, lactate levels, and metformin plasma/serum concentrations were similar in survivors versus non-survivors. Ingested daily metformin doses and plasma/serum creatinine levels were significantly higher in survivors versus non-survivors (p = 0.007 vs. p = 0.024, respectively). Higher plasma/serum creatinine levels, higher lactate levels, and lower arterial pH were all associated with patients receiving RRT (all p < 0.05). Overall mortality was 22% (20 out of 92 patients) and did not differ between the RRT and non-RRT groups.</p><p><strong>Conclusion: </strong>Mortality is high in ICU patients with metformin-associated hyperlactatemia/LA. Unexpectedly, higher ingested metformin dose and plasma/serum creatinine were associated with a better outcome. Survival was similar in patients with or without need for RRT.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":"108 3","pages":"213-223"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10233707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9919054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Etomidate Depresses Spontaneous Complex Spikes Activity of Cerebellar Purkinje Cells via Cannabinoid 1 Receptor in vivo in Mice.","authors":"Wen Pan,&nbsp;Chun-Ping Chu,&nbsp;De-Lai Qiu","doi":"10.1159/000531680","DOIUrl":"10.1159/000531680","url":null,"abstract":"<p><strong>Introduction: </strong>Complex spikes (CSs) activity of cerebellar Purkinje cells plays critical roles in motor coordination and motor learning by transferring information to cerebellar cortex, which is an accessible and useful model for neurophysiological investigation. Etomidate is an ultrashort-acting nonbarbiturate intravenous anesthetic, which inhibits the spontaneous activity of cerebellar Purkinje cells through activation of GABAA and glycine receptors in vivo in mice. However, the effect of etomidate on the spontaneous CSs activity of cerebellar Purkinje cells in living mouse is not clear.</p><p><strong>Methods: </strong>We here investigated the effects of etomidate on spontaneous CSs activity of cerebellar Purkinje cell in urethane-anesthetized mice by electrophysiology recording technique and pharmacological methods.</p><p><strong>Results: </strong>Our results showed that cerebellar surface perfusion of etomidate significantly depressed the activity of spontaneous CSs, which exhibited decreases in the number of spikelets and the area under curve (AUC) of the CSs. The etomidate-produced inhibition of CSs activity was persisted in the presence of GABAA and glycine receptors antagonists. However, application of cannabinoid 1 (CB1) receptor antagonist, AM-251, completely blocked the etomidate-induced inhibition of CSs. Furthermore, application of the CB1 receptor agonist, WIN55212-2, induced a decrease of CSs. Moreover, in the presence of a specific protein kinase A (PKA) inhibitor, KT5720, etomidate failed to produce decreases in the spikelets number and the AUC of the spontaneous CSs.</p><p><strong>Conclusion: </strong>These results indicate that cerebellar surface application of etomidate facilitates CB1 receptor activity resulting in a depression of spontaneous CSs activity of Purkinje cells via PKA signaling pathway in mouse cerebellar cortex. Our present results suggest that the etomidate administration may impair the function of cerebellar cortical neuronal circuitry by inhibition of the climbing fiber - Purkinje cells synaptic transmission through activation of CB1 receptors in vivo in mice.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"469-477"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10041899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Canagliflozin Ameliorates Ventricular Remodeling through Apelin/Angiotensin-Converting Enzyme 2 Signaling in Heart Failure with Preserved Ejection Fraction Rats.","authors":"Tingting Zhang,&nbsp;Xinyu Wang,&nbsp;Zhongli Wang,&nbsp;Jianlong Zhai,&nbsp;Lili He,&nbsp;Yan Wang,&nbsp;Qingjuan Zuo,&nbsp;Sai Ma,&nbsp;Guorui Zhang,&nbsp;Yifang Guo","doi":"10.1159/000533277","DOIUrl":"10.1159/000533277","url":null,"abstract":"<p><strong>Introduction: </strong>The aim of this study was to investigate the effect of canagliflozin (CANA) on ventricular remodeling in patients with preserved ejection fraction (HFpEF) heart failure and to further investigate its possible molecular mechanisms.</p><p><strong>Methods: </strong>A high-salt diet was used to induce the formation of HFpEF model in salt-sensitive rats. The rats were fed with CANA and irbesartan, respectively. The mice were divided into control group, model group, CANA group, irbesartan group, and combined drug group. After 12 weeks of feeding, the rats were evaluated by measuring the relevant indexes and echocardiography for cardiac function. Histological analysis was performed using Masson trichrome staining and immunohistochemical staining. RT-qPCR and Western blot were used to quantify the relevant genes and proteins.</p><p><strong>Results: </strong>In this study, CANA exhibited diuresis, decreased blood pressure, weight loss, and increased food and water intake. Following a high-salt diet, Dahl salt-sensitive rats developed hypertension followed by left ventricular diastolic dysfunction, myocardial fibrosis, and left ventricular remodeling. Myocardial hypertrophy and fibrosis were reduced, and left ventricular diastolic function and ventricular remodeling improved after CANA treatment. The combination of CANA and irbesartan was superior to monotherapy in reducing blood pressure and improving cardiac insufficiency and left ventricular diastolic dysfunction in rats. CANA improves myocardial fibrosis, left ventricular diastolic dysfunction, and ventricular remodeling by upregulating apelin, activating angiotensin-converting enzyme 2 (ACE2), and increasing ACE2/Ang (1-7)/MASR axis levels.</p><p><strong>Conclusion: </strong>CANA improves myocardial fibrosis, left ventricular diastolic dysfunction, and ventricular remodeling in HFpEF rats through upregulation of apelin/ACE2 signaling.</p>","PeriodicalId":20209,"journal":{"name":"Pharmacology","volume":" ","pages":"478-491"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10433964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}