Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.059
Filtrar
1.
Biochem Biophys Res Commun ; 628: 155-162, 2022 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-36099691

RESUMO

BACKGROUND AND AIMS: Increased endoplasmic reticulum (ER) stress is strongly associated with the phenotypic switching of vascular smooth muscle cells (VSMCs) in atherosclerosis. Depletion of the ER Ca2+ content is one of the leading causes of increased ER stress in VSMCs. The ryanodine receptor (RyR) is a major Ca2+ release channel in the sarcoplasmic reticulum membrane. Calmodulin (CaM), which binds to RyR (CaM-RyR), stabilizes the closed state of RyR in the resting state in normal cells. Defective CaM-RyR interactions can cause abnormal Ca2+ leakage through RyR, resulting in decreased Ca2+ content, indicating that defective CaM-RyR interactions may be a cause of increased ER stress. Herein, we used a mouse VSMCs to assess whether CaM-RyR plays a pivotal role in VSMCs phenotypic switching, which is caused by ER stress, and whether dantrolene, which enhances the binding affinity of CaM to RyR, affects VSMCs phenotypic switching. METHODS AND RESULTS: Tunicamycin was used to mimic ER stress in vitro. Tunicamycin-induced ER stress caused CaM to dissociate from the RyR and translocate to the nucleus, which stimulated phenotypic switching through the activation of MEF2 and KLF5. Dantrolene suppressed tunicamycin-induced apoptosis, ER stress (restoring ER Ca2+ content), and phenotypic switching of VSMCs. Suramin, which directly unbinds CaM from RyR, promoted nuclear CaM accumulation with parallel VSMCs phenotypic switching, and dantrolene prevented these effects. CONCLUSIONS: We observed that ER stress causes CaM translocation to the nucleus and drives the phenotypic switching of VSMCs. Thus, restoration of the binding affinity of CaM to RyR may be a therapeutic target for atherosclerosis.


Assuntos
Aterosclerose , Calmodulina , Animais , Aterosclerose/metabolismo , Calmodulina/metabolismo , Dantroleno , Estresse do Retículo Endoplasmático , Camundongos , Músculo Liso Vascular/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Suramina , Tunicamicina/farmacologia
2.
BMC Anesthesiol ; 22(1): 298, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123618

RESUMO

BACKGROUND: Intravenous dantrolene is often prescribed for hypermetabolic syndromes other than the approved indication of malignant hyperthermia (MH). To clarify the extent of and indications for dantrolene use in conditions other than MH, we sought to document current practices in the frequency, diagnoses, clinical characteristics and outcomes associated with dantrolene treatment in critical care settings. METHODS: Inpatients receiving intravenous dantrolene from October 1, 2004 to September 30, 2014 were identified retrospectively in the U.S. Veterans Health Administration national database. Extracted data included; diagnoses of hypermetabolic syndromes; triggering drugs; dantrolene dosages; demographics; vital signs; laboratory values; in-hospital mortality; complications; and lengths of stay. Frequency and mortality of patients who did not receive dantrolene were obtained in selected diagnoses for exploratory comparisons. RESULTS: Dantrolene was administered to 304 inpatients. The most frequent diagnoses associated with dantrolene treatment were neuroleptic malignant syndrome (NMS; N = 108, 35.53%) and sepsis (N = 47, 15.46%), with MH accounting for only 13 (4.28%) cases. Over half the patients had psychiatric comorbidities and received psychotropic drugs before dantrolene treatment. Common clinical findings in patients receiving dantrolene included elevated temperature (mean ± SD; 38.7 ± 1.3 °C), pulse (116.33 ± 22.80/bpm), respirations (27.75 ± 9.58/min), creatine kinase levels (2,859.37 ± 6,646.88 IU/L) and low pO2 (74.93 ± 40.16 mmHg). Respiratory, renal or cardiac failure were common complications. Mortality rates in-hospital were 24.01% overall, 7.69% in MH, 20.37% in NMS and 42.55% in sepsis, compared with mortality rates in larger and possibly less severe groups of unmatched patients with MH (5.26%), NMS (6.66%), or sepsis (41.91%) who did not receive dantrolene. CONCLUSIONS: In over 95% of cases, dantrolene administration was associated with diagnoses other than MH in critically-ill patients with hypermetabolic symptoms and medical and psychiatric comorbidities. Exploratory survey data suggested that the efficacy and safety of dantrolene in preventing mortality in hypermetabolic syndromes other than MH remain uncertain. However, randomized and controlled studies using standardized criteria between groups matched for severity are essential to guide practice in using dantrolene.


Assuntos
Hipertermia Maligna , Sepse , Creatina Quinase/uso terapêutico , Dantroleno/uso terapêutico , Humanos , Hipertermia Maligna/diagnóstico , Hipertermia Maligna/tratamento farmacológico , Hipertermia Maligna/epidemiologia , Estudos Retrospectivos , Sepse/complicações , Saúde dos Veteranos
3.
Biochem Biophys Res Commun ; 624: 141-145, 2022 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-35940127

RESUMO

Dantrolene inhibits Ca2+ leakage from destabilized ryanodine receptors and therefore may serve as a therapeutic agent against endoplasmic reticulum stress-associated diseases. However, its effectiveness in treating autoimmune diseases remains unclear. Here, we investigated the effect of dantrolene on collagen-induced arthritis (CIA) in mice. Oral administration of dantrolene resulted in significantly lower arthritic scores in both male and female CIA mice than in the control mice. Micro-computed tomographic and histological analyses showed that dantrolene suppressed bone and chondral destruction. The serum levels of anti-type II collagen (CII) IgG were positively correlated with the arthritic scores (r = 0.704, p < 0.01). In addition, the serum levels of anti-CII IgG were significantly lower in the dantrolene group than in the control group (p < 0.05). These results demonstrate that oral administration of dantrolene to CIA mice inhibits the production of serum anti-CII IgG and consequently prevents arthritis. Therefore, dantrolene may be a potential anti-rheumatic drug.


Assuntos
Artrite Experimental , Animais , Artrite Experimental/patologia , Colágeno Tipo II , Dantroleno/farmacologia , Dantroleno/uso terapêutico , Feminino , Imunoglobulina G , Masculino , Camundongos , Camundongos Endogâmicos DBA , Canal de Liberação de Cálcio do Receptor de Rianodina
4.
J Exp Clin Cancer Res ; 41(1): 242, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953818

RESUMO

BACKGROUND: Uterine serous cancer (USC) is the most common non-endometrioid subtype of uterine cancer, and is also the most aggressive. Most patients will die of progressively chemotherapy-resistant disease, and the development of new therapies that can target USC remains a major unmet clinical need. This study sought to determine the molecular mechanism by which a novel unfavorable prognostic biomarker ryanodine receptor 1 (RYR1) identified in advanced USC confers their malignant phenotypes, and demonstrated the efficacy of targeting RYR1 by repositioned FDA-approved compounds in USC treatment. METHODS: TCGA USC dataset was analyzed to identify top genes that are associated with patient survival or disease stage, and can be targeted by FDA-approved compounds. The top gene RYR1 was selected and the functional role of RYR1 in USC progression was determined by silencing and over-expressing RYR1 in USC cells in vitro and in vivo. The molecular mechanism and signaling networks associated with the functional role of RYR1 in USC progression were determined by reverse phase protein arrays (RPPA), Western blot, and transcriptomic profiling analyses. The efficacy of the repositioned compound dantrolene on USC progression was determined using both in vitro and in vivo models. RESULTS: High expression level of RYR1 in the tumors is associated with advanced stage of the disease. Inhibition of RYR1 suppressed proliferation, migration and enhanced apoptosis through Ca2+-dependent activation of AKT/CREB/PGC-1α and AKT/HK1/2 signaling pathways, which modulate mitochondrial bioenergetics properties, including oxidative phosphorylation, ATP production, mitochondrial membrane potential, ROS production and TCA metabolites, and glycolytic activities in USC cells. Repositioned compound dantrolene suppressed USC progression and survival in mouse models. CONCLUSIONS: These findings provided insight into the mechanism by which RYR1 modulates the malignant phenotypes of USC and could aid in the development of dantrolene as a repurposed therapeutic agent for the treatment of USC to improve patient survival.


Assuntos
Cistadenocarcinoma Seroso , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Neoplasias Uterinas , Animais , Cistadenocarcinoma Seroso/patologia , Dantroleno/uso terapêutico , Feminino , Humanos , Camundongos , Fenótipo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo
5.
AANA J ; 90(4): 271-277, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35943752

RESUMO

Intravenous dantrolene is the first-line treatment of malignant hyperthermia (MH), however, it is not always accessible in lower-middle income countries (LMICs). Facilities in the United States are in a transition period where dantrolene is being replaced with Ryanodex, therefore, there is an opportunity for excess dantrolene to be utilized in LMICs where neither dantrolene nor Ryanodex exist. Thirty-six vials of recently expired, unused dantrolene were obtained for a hospital in a LMIC and an MH program was developed in conjunction with the Lao Friends Hospital for Children (LFHC) anesthesia providers, LFHC liaison, LFHC leadership team, and an expert in the field of MH. Components of the MH program included developing a facility-specific protocol, treatment guidelines, supply list, and educational tools. A designated MH drawer was also created in preparation for an MH event. By procuring dantrolene and implementing an MH program in a facility where no MH protocol, treatment guidelines, supply list, or educational tools existed, LFHC is better equipped to handle a potentially lethal scenario.


Assuntos
Anestesia , Hipertermia Maligna , Criança , Dantroleno/uso terapêutico , Humanos , Hipertermia Maligna/tratamento farmacológico , Estados Unidos
6.
Biochem Biophys Res Commun ; 623: 51-58, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35872542

RESUMO

Dantrolene is a ryanodine receptor blocker that is used clinically for treatment of malignant hyperthermia. This study was conducted using murine aortic vascular smooth muscle cells (MOVAS) and a mouse arterial injury model to investigate the inhibitory effect of dantrolene on smooth muscle cell proliferation and migration. We investigated whether dantrolene suppressed platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell proliferation and migration in vitro. The effect of dantrolene on smooth muscle phenotype was evaluated using immunostaining. In addition, smooth muscle cell proliferation and phenotype switching were tested by applying dantrolene around blood vessels using a mouse arterial injury model. Dantrolene inhibited PDGF-induced cell proliferation and migration of MOVAS. Dantrolene also inhibited the switch from contractile to synthetic phenotype both in vitro and in vivo. Dantrolene is effective at inhibiting vascular smooth muscle cell proliferation, migration, and neointimal formation following arterial injury in mice.


Assuntos
Músculo Liso Vascular , Lesões do Sistema Vascular , Animais , Movimento Celular , Proliferação de Células , Células Cultivadas , Dantroleno/farmacologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/patologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Crescimento Derivado de Plaquetas/farmacologia , Lesões do Sistema Vascular/tratamento farmacológico , Lesões do Sistema Vascular/patologia
7.
Anaesth Intensive Care ; 50(4): 312-319, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35549722

RESUMO

Dantrolene is currently the only drug known to specifically treat malignant hyperthermia (MH) crises. Although dantrolene attenuates Ca2+ disorders by acting mainly on the ryanodine receptor type 1 (RYR1), some patients who manifest MH without RYR1 variants have also been successfully treated with dantrolene. Thus, dantrolene appears to have an inhibitory effect on patients with and without RYR1 variants. This study aimed to investigate whether the effects of dantrolene differed depending on the presence or absence of RYR1 variants using muscle cells from MH-predisposed individuals. The study participants were individuals diagnosed with MH predisposition by the Ca2+-induced Ca2+ release rate test. They were genetically tested and divided into two groups: with and without RYR1 variants. We investigated whether these two groups showed differences in the changes in the half-maximal effective concentration (EC50) for caffeine and the resting intracellular Ca2+ concentration ([Ca2+]i) before and after dantrolene administration. Dantrolene administration significantly increased the EC50 (P < 0.0001) and decreased the resting [Ca2+]i (P < 0.0001). The inhibitory effects of dantrolene and the presence of RYR1 variants showed no statistically significant interactions related to the EC50 (P = 0.59) and resting [Ca2+]i (P = 0.21). In conclusion, the presence or absence of RYR1 variants does not appear to influence the effect of dantrolene.


Assuntos
Hipertermia Maligna , Cafeína/farmacologia , Cálcio/metabolismo , Dantroleno/farmacologia , Humanos , Hipertermia Maligna/tratamento farmacológico , Hipertermia Maligna/genética , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética
8.
Air Med J ; 41(3): 320-322, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35595342

RESUMO

Malignant hyperthermia (MH) is a rare disorder that leads to a hypermetabolic response; if unrecognized, it can quickly lead to serious morbidity and mortality. It is imperative that critical care transport providers are able to recognize and initiate treatment for MH. A 33-year-old man presented to the emergency department with seizures and altered mental status after ingesting methamphetamine. The patient was intubated in the emergency department with succinylcholine and propofol. After intubation, the patient became tetanic, hyperthermic, and hypercarbic. Given the concern for MH, the patient was treated with dantrolene and transported by helicopter air ambulance to the affiliated quaternary care center where he progressed to multiorgan failure and died. MH is a genetic disorder that manifests after exposure to certain stimuli, most notably inhaled anesthetics and succinylcholine. The hypermetabolic response is triggered by unregulated release of intracellular calcium secondary to a dysfunctional calcium channel. MH is often diagnosed clinically. Early clinical manifestations of MH include an increase in end-tidal carbon dioxide, tachycardia, muscle rigidity, and hyperthermia. For prehospital clinicians, the most likely offending agent is succinylcholine. The pharmacologic treatment of MH is dantrolene. Prompt recognition and treatment of MH can decrease morbidity and mortality.


Assuntos
Hipertermia Maligna , Metanfetamina , Adulto , Cálcio/uso terapêutico , Dantroleno/uso terapêutico , Humanos , Masculino , Hipertermia Maligna/tratamento farmacológico , Hipertermia Maligna/etiologia , Metanfetamina/uso terapêutico , Succinilcolina
9.
Am J Case Rep ; 23: e936217, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35514081

RESUMO

BACKGROUND Considering the ongoing coronavirus disease 2019 (COVID-19) pandemic, sufficient information about common and serious adverse events is needed to rapidly distribute COVID-19 vaccines worldwide. We report a case of neuroleptic malignant syndrome (NMS) with adrenal insufficiency after initial vaccination with Pfizer/BioNTech BNT162b2. CASE REPORT A 48-year-old man presented to the Emergency Department with fever and an altered mental status 7 days after receiving the first dose of the BNT162b2 COVID-19 vaccine. The patient had a history of end-stage renal disease and epilepsy treated with valproate. He was diagnosed with NMS based on the clinical findings of hyperthermia, muscular rigidity, and an elevated creatine kinase level. Additionally, a reduction in the response of cortisol to adrenocorticotropic hormone (ACTH) stimulation was observed in the rapid ACTH stimulation test. The patient was treated with dantrolene, bromocriptine, and hydrocortisone, and he responded well to treatment. Dantrolene and bromocriptine were tapered off over 4 weeks. Hydrocortisone was also tapered, and the patient was discharged on oral hydrocortisone (30 mg). CONCLUSIONS The present case suggests a possible link between the BNT162b2 COVID-19 vaccine and NMS with adrenal insufficiency based on the temporal relationship between vaccine administration and disease onset, although the patient was taking valproate, a potential cause of NMS. Having a high level of suspicion is important because the diagnosis of NMS with adrenal insufficiency is often challenging due to non-specific clinical manifestations. However, this case does not negate the utility of vaccination because these complications are extremely rare and can be treated with early diagnosis and proper management.


Assuntos
Insuficiência Adrenal , Vacina BNT162 , COVID-19 , Síndrome Maligna Neuroléptica , Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/complicações , Hormônio Adrenocorticotrópico , Vacina BNT162/efeitos adversos , Bromocriptina/uso terapêutico , COVID-19/prevenção & controle , Dantroleno/uso terapêutico , Humanos , Hidrocortisona/uso terapêutico , Masculino , Pessoa de Meia-Idade , Síndrome Maligna Neuroléptica/diagnóstico , Síndrome Maligna Neuroléptica/etiologia , Síndrome Maligna Neuroléptica/terapia , Vacinação/efeitos adversos , Ácido Valproico/efeitos adversos
10.
Anaesthesiol Intensive Ther ; 54(2): 99-102, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35579281

RESUMO

INTRODUCTION: Malignant hyperthermia (MH) is a life-threatening syndrome caused by sudden skeletal muscle hypermetabolism in response to inhalation anaesthetics and depolarising relaxants. The estimated incidence of MH is between 1 : 10,000 and 1 : 250,000 anaesthetic procedures. In Poland the incidence of MH is unknown. Dantrolene is imported as a life-saving drug and temporally authorised for sale. The aim of the study is to assess the incidence of MH and access to dantrolene in the Mazovia Province. METHODS: Anonymous questionnaires were sent to anaesthesia departments in the Mazovia Province after prior contact by phone and e-mail. The survey was approved by the local ethical review board. RESULTS: Completed surveys were received from 60 respondents which represents 72% of anaesthesiology departments in Mazovia. In the last 5 years there have been 4 episodes of MH in the Mazovia Province. Three patients survived the MH crisis. In a centre that did not have access to dantrolene, the patient died. Dantrolene is found only in 11 (18.3%) anaesthesiology departments in Mazovia. Only 6 (10%) hospitals are able to administer dantrolene within 5 minutes of suspecting MH crisis, while 5 centres may receive it after a few days. Only 38% of units have an algorithm for dealing with MH crisis in the operating theatres. CONCLUSIONS: MH is rare, but if untreated, it can be fatal. Therefore prompt diagnosis and treatment are crucial to avoid fatal outcome. Every centre using inhalational anaesthetics and/or succinylcholine should have dantrolene. To ensure the safety of our patients, we must be better prepared.


Assuntos
Anestésicos Inalatórios , Hipertermia Maligna , Anestésicos Inalatórios/efeitos adversos , Dantroleno/uso terapêutico , Humanos , Hipertermia Maligna/epidemiologia , Hipertermia Maligna/terapia , Salas Cirúrgicas , Succinilcolina/uso terapêutico
11.
PLoS One ; 17(2): e0263395, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35104283

RESUMO

Many anesthetics, including Propofol, have been reported to induce elevation of intracellular calcium, and we were interested to investigate the possible contribution of calcium elevation to the mechanism of the newly approved remimazolam actions. Remimazolam is an intravenous anesthetic first approved in Japan in July 2020, and is thought to exert its anesthetic actions via γ-aminobutyric acid A (GABAA) receptors; however, the precise mechanisms of how remimazolam elevates intracellular calcium levels remains unclear. We examined the remimazolam-induced elevation of intracellular calcium using SHSY-5Y neuroblastoma cells, COS-7 cells, HEK293 cells, HeLa cells, and human umbilical vein endothelial cells (HUVECs) loaded with fluorescent dyes for live imaging. We confirmed that high concentrations of remimazolam (greater than 300 µM) elevated intracellular calcium in a dose-dependent manner in these cells tested. This phenomenon was not influenced by elimination of extracellular calcium. The calcium elevation was abolished when intracellular or intraendoplasmic reticulum (ER) calcium was depleted by BAPTA-AM or thapsigargin, respectively, suggesting that calcium was mobilized from the ER. Inhibitors of G-protein coupled receptors (GPCRs)-mediated signals, including U-73122, a phospholipase C (PLC) inhibitor and xestospongin C, an inositol 1,4,5-triphosphate receptors (IP3R) antagonist, significantly suppressed remimazolam-induced calcium elevation, whereas dantrolene, a ryanodine receptor antagonist, did not influence remimazolam-induced calcium elevation. Meanwhile, live imaging of ER during remimazolam stimulation using ER-tracker showed no morphological changes. These results suggest that high doses of remimazolam increased intracellular calcium concentration in a dose-dependent manner in each cell tested, which was predicted to be caused by calcium mobilization from the ER. In addition, our studies using various inhibitors revealed that this calcium elevation might be mediated by the GPCRs-IP3 pathway. However, further studies are required to identify which type of GPCRs is involved.


Assuntos
Benzodiazepinas/farmacologia , Cálcio/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Cafeína/farmacologia , Linhagem Celular , Dantroleno/farmacologia , Retículo Endoplasmático/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/química , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tapsigargina/farmacologia
12.
World Neurosurg ; 161: e602-e607, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35189422

RESUMO

OBJECTIVE: Cerebral vasospasm remains a significant source of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage. Dantrolene has shown promise in several animal studies in the treatment of cerebral vasospasm. The present study seeks to critically review the evidence of its use in human subjects, aiming to 1) describe the forms and dosages used, 2) describe its safety profile, and 3) describe its effectiveness in treating cerebral vasospasm. METHODS: A systematic review of intra-arterial dantrolene use in cerebral vasospasm was performed. A total of 86 articles were identified across all databases, 6 of which were ultimately included in the present study. Primary outcomes included a description of the form and dosage of dantrolene prescribed, the incidence of adverse effects after dantrolene use, and its efficacy for the treatment of cerebral vasospasm. RESULTS: Study designs included 2 randomized controlled trials (33.3%), 2 case series (33.3%), and 2 case reports (33.3%). Both the intra-arterial and intravenous administration of dantrolene has been performed with varying dose regimens. Although there exists limited clinical information regarding side effects, a case of liver toxicity was reported. All existing studies reported benefit in vasospasm measured either by transcranial Doppler or digital subtraction angiography. The level of evidence was low, consisting largely of retrospective studies that had a high likelihood of bias. CONCLUSIONS: Dantrolene is a promising new therapeutic agent in the treatment of cerebral vasospasm. Although existing reports of its use are encouraging, high-quality prospective randomized trials are necessary for recommendations pertaining to dose, route, indications, and efficacy.


Assuntos
Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Animais , Dantroleno/uso terapêutico , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/etiologia
13.
Heart Rhythm ; 19(6): 986-997, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35134547

RESUMO

BACKGROUND: Right ventricular (RV) dysfunction and its associated arrhythmias are recognized as important determinants of the prognosis of pulmonary arterial hypertension (PAH). OBJECTIVE: Here, we aimed to investigate whether direct pharmacological intervention in the RV muscle with dantrolene (DAN), a stabilizer of the cardiac ryanodine receptor (RyR2), has a protective effect against RV dysfunction and arrhythmia in a monocrotaline (MCT)-induced PAH rat model. METHODS: Male 8-week-old Sprague-Dawley rats were injected with MCT for the induction of PAH. Induction of ventricular tachycardia (VT) by catecholamines was also evaluated in association with RyR2-mediated Ca2+ release properties in isolated cardiomyocytes. A pulmonary artery-banding model has also been established to assess the independent effects of chronic pressure overload on RV morphology and function. RESULTS: In the MCT-induced PAH rat model, RV hypertrophy, dilation, and functional decline were observed, with a survival rate of 0% 2 months after MCT induction. In contrast, chronic DAN treatment improved all these RV parameters and increased survival by 80%. Chronic DAN treatment also prevented the dissociation of calmodulin from RyR2, thereby inhibiting Ca2+ sparks and spontaneous Ca2+ transients in MCT-induced hypertrophied RV cardiomyocytes. Epinephrine induced VT in more than 50% of rats with MCT-induced PAH, but complete suppression of VT was achieved by chronic DAN treatment. CONCLUSION: Stabilization of RyR2 by DAN has potential as a new therapeutic agent against the development of RV dysfunction and fatal arrhythmia associated with PAH.


Assuntos
Hipertensão Pulmonar , Disfunção Ventricular Direita , Animais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/prevenção & controle , Dantroleno/farmacologia , Modelos Animais de Doenças , Hipertensão Pulmonar/tratamento farmacológico , Masculino , Monocrotalina , Prognóstico , Ratos , Ratos Sprague-Dawley , Canal de Liberação de Cálcio do Receptor de Rianodina , Função Ventricular Direita
14.
Eur Rev Med Pharmacol Sci ; 26(1): 198-203, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35048995

RESUMO

OBJECTIVE: We have previously shown that the intranasal administration of dantrolene ameliorated cognitive dysfunction in the 5XFAD mouse model of Alzheimer's disease. This study examines the morphology of the nasal mucosa after 10 months of intranasal dantrolene in 5XFAD mice. MATERIALS AND METHODS: 5XFAD mice were either treated with intranasal dantrolene (5 mg/kg, 3 times/wk) from 2 months to 12 months of age or given no treatment at all. The mice were euthanatized at 12 months of age and the snouts were processed for histological examination. The morphology of the nasal mucosa was assessed and compared between the two groups. RESULTS: There were no significant differences in the thickness of the olfactory epithelium or the proportion of the thickness of the glandular layer to the wall of mucosa and submucosa in the nasal passages. CONCLUSIONS: Long-term intranasal administration of dantrolene did not significantly change the nasal mucosa morphology in 5XFAD mice.


Assuntos
Doença de Alzheimer , Dantroleno , Administração Intranasal , Doença de Alzheimer/patologia , Animais , Dantroleno/farmacologia , Dantroleno/uso terapêutico , Camundongos , Mucosa Nasal/patologia , Mucosa Olfatória/patologia
15.
Exp Neurol ; 351: 113985, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35063438

RESUMO

Ryanodine receptors (RyR) located on the membrane of the endoplasmic reticulum (ER), are a potent regulator of intracellular calcium levels upon activation. Dysregulated Ca2+ homeostasis is characteristic of hypoxic-ischemic (HI) brain injury and ultimately leads to neurodegeneration. RyRs have thereby been implicated in the Ca2+ imbalance that occurs during and after HI. In this study, we investigated the effects of RyR antagonist, dantrolene, on HI brain injury in neonatal mice. We found that administration of dantrolene (i.p.) on postnatal day 7 mice reduced the infarction volume and morphological damage induced by HI, and improved functional recovery as assessed by neurobehavioral testing. The neuroprotective effect of dantrolene was further demonstrated in neuronal cell culture in vitro, where dantrolene significantly reduced oxygen-glucose deprivation (OGD)-induced cell death. Fura-2 calcium imaging confirmed that dantrolene reduced the intracellular calcium level in cultured cortical neurons in vitro. Finally, Western blot analysis showed that dantrolene treatment reduced cleaved caspase-3 and -9 apoptotic proteins, and elevated pro-survival protein kinase C (PKC) protein levels. Taken together, our results demonstrate that dantrolene exerts neuroprotective effects against neonatal HI brain injury. This suggests that RyRs play a role in mediating the ionic imbalance induced by HI and therefore represent a potential target for drug development.


Assuntos
Lesões Encefálicas , Bloqueadores dos Canais de Cálcio , Dantroleno , Hipóxia-Isquemia Encefálica , Fármacos Neuroprotetores , Animais , Animais Recém-Nascidos , Lesões Encefálicas/tratamento farmacológico , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/uso terapêutico , Dantroleno/uso terapêutico , Homeostase , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Hipóxia-Isquemia Encefálica/metabolismo , Camundongos , Fármacos Neuroprotetores/uso terapêutico , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
16.
Br J Pharmacol ; 179(11): 2713-2732, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34877651

RESUMO

BACKGROUND AND PURPOSE: QT prolongation and intracellular Ca2+ loading with diastolic Ca2+ release via ryanodine receptors (RyR2) are the predominant mechanisms underlying hypokalaemia-induced ventricular arrhythmia. We investigated the antiarrhythmic actions of two RyR2 inhibitors: dantrolene and VK-II-86, a carvedilol analogue lacking antagonist activity at ß-adrenoceptors, in hypokalaemia. EXPERIMENTAL APPROACH: Surface ECG and ventricular action potentials (APs) were recorded from whole-heart murine Langendorff preparations. Ventricular arrhythmia incidence was compared in hearts perfused with low [K+ ], and those pretreated with dantrolene or VK-II-86. Whole-cell patch clamping was used in murine and canine ventricular cardiomyocytes to study effects of dantrolene and VK-II-86 on AP parameters in low [K+ ] and effects of VK-II-86 on the inward rectifier current (IK1 ), late sodium current (INa_L ) and the L-type Ca2+ current (ICa ). Effects of VK-II-86 on IKr were investigated in transfected HEK-293 cells. A fluorogenic probe quantified the effects of VK-II-86 on oxidative stress in hypokalaemia. KEY RESULTS: Dantrolene reduced the incidence of ventricular arrhythmias induced by low [K+ ] in explanted murine hearts by 94%, whereas VK-II-86 prevented all arrhythmias. VK-II-86 prevented hypokalaemia-induced AP prolongation and depolarization but did not alter AP parameters in normokalaemia. Hypokalaemia was associated with decreased IK1 and IKr , and increased INa-L , and ICa . VK-II-86 prevented all hypokalaemia-induced changes in ion channel activity and oxidative stress. CONCLUSIONS AND IMPLICATIONS: VK-II-86 prevents hypokalaemia-induced arrhythmogenesis by normalizing calcium homeostasis and repolarization reserve. VK-II-86 may provide an effective treatment in hypokalaemia and other arrhythmias caused by delayed repolarization or Ca2+ overload.


Assuntos
Hipopotassemia , Canal de Liberação de Cálcio do Receptor de Rianodina , Potenciais de Ação , Animais , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/prevenção & controle , Cálcio/metabolismo , Carvedilol/farmacologia , Dantroleno/efeitos adversos , Cães , Células HEK293 , Humanos , Hipopotassemia/complicações , Hipopotassemia/tratamento farmacológico , Camundongos , Miócitos Cardíacos , Sódio/metabolismo
17.
Am J Physiol Regul Integr Comp Physiol ; 322(1): R14-R27, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34755549

RESUMO

Eccentric contractions (ECC) facilitate cytosolic calcium ion (Ca2+) release from the sarcoplasmic reticulum (SR) and Ca2+ influx from the extracellular space. Ca2+ is a vital signaling messenger that regulates multiple cellular processes via its spatial and temporal concentration ([Ca2+]i) dynamics. We hypothesized that 1) a specific pattern of spatial/temporal intramyocyte Ca2+ dynamics portends muscle damage following ECC and 2) these dynamics would be regulated by the ryanodine receptor (RyR). [Ca2+]i in the tibialis anterior muscles of anesthetized adult Wistar rats was measured by ratiometric (i.e., ratio, R, 340/380 nm excitation) in vivo bioimaging with Fura-2 pre-ECC and at 5 and 24 h post-ECC (5 × 40 contractions). Separate groups of rats received RyR inhibitor dantrolene (DAN; 10 mg/kg ip) immediately post-ECC (+DAN). Muscle damage was evaluated by histological analysis on hematoxylin-eosin stained muscle sections. Compared with control (CONT, no ECC), [Ca2+]i distribution was heterogeneous with increased percent total area of high [Ca2+]i sites (operationally defined as R ≥ 1.39, i.e., ≥1 SD of mean control) 5 h post-ECC (CONT, 14.0 ± 8.0; ECC5h: 52.0 ± 7.4%, P < 0.01). DAN substantially reduced the high [Ca2+]i area 5 h post-ECC (ECC5h + DAN: 6.4 ± 3.1%, P < 0.01) and myocyte damage (ECC24h, 63.2 ± 1.0%; ECC24h + DAN: 29.1 ± 2.2%, P < 0.01). Temporal and spatially amplified [Ca2+]i fluctuations occurred regardless of DAN (ECC vs. ECC + DAN, P > 0.05). These results suggest that the RyR-mediated local high [Ca2+]i itself is related to the magnitude of muscle damage, whereas the [Ca2+]i fluctuation is an RyR-independent phenomenon.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Contração Muscular , Fibras Musculares de Contração Rápida/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Animais , Autólise , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Calpaína/metabolismo , Dantroleno/farmacologia , Desmina/metabolismo , Cinética , Masculino , Fibras Musculares de Contração Rápida/efeitos dos fármacos , Fibras Musculares de Contração Rápida/patologia , Ratos Wistar
18.
Semin Thorac Cardiovasc Surg ; 34(1): 123-132, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33460764

RESUMO

The impairment of intracellular calcium homeostasis plays an essential role during ischemia-reperfusion injury. Calcium release from sarcoplasmic reticulum which is triggered by myocardial ischemia is mainly mediated by ryanodine receptors. Dantrolene sodium is a ryanodine receptor antagonist. The objective of the present study was to evaluate the in-vivo impact of dantrolene sodium on myocardial ischemia-reperfusion injury in swine models. An in vivo, experimental trial comparing 10 experimental animals which received dantrolene sodium with 9 control swine models was conducted. Their left anterior descending coronary artery was temporarily occluded for 75 minutes via a vessel tourniquet, which was then released. Myocardial reperfusion was allowed for 24 hours. Dantrolene was administered at the onset of the reperfusion period and levels of troponin, creatine phosphokinase and creatine kinase myocardial band between the two groups were compared. Additionally, various other hemodynamic parameters and left ventricular morphology and function were examined. There were significantly lower values of troponin, creatine phosphokinase and creatine kinase myocardial band in the dantrolene group indicating less ischemia-reperfusion injury. Moreover, the postischemic cardiac index was also greater in the dantrolene group, whereas viable myocardium was also better preserved. In conclusion, the in vivo cardioprotective role of dantrolene sodium against ischemia-reperfusion injury in swine models was indicated in this study. Therefore, dantrolene sodium administration could be a promising treatment against ischemia-reperfusion injury in humans. However, large randomized clinical studies should be firstly carried out to prove this hypothesis.


Assuntos
Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Animais , Cálcio/metabolismo , Creatina Quinase/metabolismo , Dantroleno/farmacologia , Dantroleno/uso terapêutico , Homeostase , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Rianodina , Canal de Liberação de Cálcio do Receptor de Rianodina , Suínos , Resultado do Tratamento , Troponina
19.
Rev. colomb. anestesiol ; 49(4): e600, Oct.-Dec. 2021.
Artigo em Inglês | LILACS, COLNAL | ID: biblio-1341248

RESUMO

Malignant hyperthermia (MH) is often neglected in anesthesia because of its rare incidence (around 1:100,000 general anesthetics). However, when it occurs, it becomes the anesthesiologist's nightmare. In the United States, Canada, and in most European countries, it is mandatory to store dantrolene wherever halogenated agents and/or succinylcholine are used by anesthesia providers (including sites that use only succinylcholine and no volatiles for electroconvulsive therapies). Unfortunately, its availability in Colombia is not mandatory or universal


La hipertermia maligna (HM) es algo a menudo se descuida durante el acto anestésico debido a su muy baja incidencia (aproximadamente 1:100.000 anestesias generales). Sin embargo, cuando se presenta, se convierte en una pesadilla para el anestesiólogo. En los Estados Unidos, Canadá y la mayoría de los países de Europa es obligatorio contar con dantroleno siempre que los anestesiólogos administran agentes halogenados y/o succinilcolina (incluidos los centros que utilizan succinilcolina sola sin agentes volátiles para terapias electroconvulsivas). En Colombia, infortunadamente, su disponibilidad no es obligatoria ni universal


Assuntos
Humanos , Hipertermia Maligna , Bicarbonato de Sódio , Dantroleno , Anestesiologia
20.
J Int Med Res ; 49(9): 3000605211044201, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34586942

RESUMO

Malignant hyperthermia (MH) is a potentially fatal hypermetabolic syndrome that occurs when susceptible individuals are exposed to triggering agents. Variability in the order and time of occurrence of symptoms often makes clinical diagnosis difficult. A late diagnosis or misdiagnosis of delayed-onset MH may lead to fatal complications. We herein report a case of delayed-onset MH in the postoperative recovery room. A 77-year-old man awoke from anesthesia and was transferred to the recovery room. Ten minutes after his arrival, his mental status became stuporous and he developed masseter muscle rigidity, hyperventilation, and a body temperature of 39.8°C. The patient was suspected to have MH, and 60 mg of dantrolene sodium (1 mg/kg) was administered via intravenous drip with symptomatic treatment. Within 10 minutes of dantrolene administration, the patient's clinical signs subsided. This case report demonstrates that rapid diagnosis and treatment are crucial to ensure a good prognosis for patients with MH. A high level of suspicion based on clinical symptoms and early administration of therapeutic drugs such as dantrolene will also improve the clinical course. Therefore, suspicion and prompt diagnosis are absolutely essential. This case report emphasizes the importance of continuous education in the diagnosis and treatment of MH.


Assuntos
Anestesia , Hipertermia Maligna , Idoso , Temperatura Corporal , Dantroleno/uso terapêutico , Humanos , Hipertermia , Masculino , Hipertermia Maligna/diagnóstico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...