RESUMO
Lipid emulsions are used as adjuvant drugs to alleviate intractable cardiovascular collapse induced by drug toxicity. We aimed to examine the effect of lipid emulsions on labetalol-induced vasodilation and the underlying mechanism in the isolated rat aorta. We studied the effects of endothelial denudation, NW-nitro-l-arginine methyl ester (l-NAME), calmidazolium, methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), and lipid emulsions on labetalol-induced vasodilation. We also evaluated the effects of lipid emulsions on cyclic guanosine monophosphate (cGMP) formation, endothelial nitric oxide synthase (eNOS) phosphorylation, and endothelial calcium levels induced by labetalol. Labetalol-induced vasodilation was higher in endothelium-intact aortas than that in endothelium-denuded aortas. l-NAME, calmidazolium, methylene blue, and ODQ inhibited labetalol-induced vasodilation in endothelium-intact aortas. Lipid emulsions inhibited labetalol-induced vasodilation in endothelium-intact and endothelium-denuded aortas. l-NAME, ODQ, and lipid emulsions inhibited labetalol-induced cGMP formation in endothelium-intact aortas. Lipid emulsions reversed the stimulatory and inhibitory eNOS (Ser1177 and Thr495) phosphorylation induced by labetalol in human umbilical vein endothelial cells and inhibited the labetalol-induced endothelial calcium increase. Moreover, it decreased labetalol concentration. These results suggest that lipid emulsions inhibit vasodilation induced by toxic doses of labetalol, which is mediated by the inhibition of endothelial nitric oxide release and reduction of labetalol concentration.
Assuntos
Aorta , GMP Cíclico , Emulsões , Labetalol , Óxido Nítrico Sintase Tipo III , Vasodilatação , Animais , Vasodilatação/efeitos dos fármacos , Ratos , Aorta/efeitos dos fármacos , Aorta/metabolismo , Labetalol/farmacologia , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , GMP Cíclico/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Ratos Sprague-Dawley , Humanos , Lipídeos , Fosforilação/efeitos dos fármacos , Cálcio/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismoRESUMO
Background: Epinephrine (EPI) or norepinephrine (NOR) is widely used to treat cardiovascular collapse during lipid emulsion (LE) resuscitation for drug toxicity. However, the effect of LE on the vasoconstriction caused by EPI or NOR remains unknown. The purpose of this study was to examine the effect of an LE (Intralipid) on the vasoconstriction caused by EPI and NOR in isolated rat aorta. Methods: The effect of LE on the vasoconstriction caused by EPI or NOR in isolated rat aorta was examined. Additionally, the effect of LE on the calcium increase caused by EPI or NOR was investigated. The distribution constant (KD: lipid to aqueous phase) of EPI or NOR between a LE (1%) and an aqueous phase was determined. Results: LE (1 and 2%) did not significantly alter vasoconstriction caused by EPI or NOR in isolated endothelium-intact aorta. Moreover, the LE did not significantly alter the increased calcium level caused by EPI or NOR. The log KD of EPI in the LE (1%) was -0.71, -0.99, and -1.00 at 20, 50, and 100 mM ionic strength, respectively. The log KD of NOR in the LE (1%) was -1.22, -1.25, and -0.96 at 20, 50, and 100 mM ionic strength, respectively. Conclusions: Taken together, the Intralipid emulsion did not alter vasoconstriction induced by EPI or NOR that seems to be due to the hydrophilicity of EPI or NOR, leading to sustained hemodynamic support produced by EPI or NOR used during LE resuscitation.
RESUMO
Dexmedetomidine is widely used to induce sedation in the perioperative period. This study examined the effect of hypothermia (33 and 25 °C) on dexmedetomidine-induced contraction in an endothelium-intact aorta with or without the nitric oxide synthase inhibitor NW-nitro-L-arginine methyl ester (L-NAME). In addition, the effect of hypothermia on the contraction induced by dexmedetomidine in an endothelium-denuded aorta with or without a calcium-free Krebs solution was examined. The effects of hypothermia on the protein kinase C (PKC), myosin light chain (MLC20) phosphorylation, and Rho-kinase membrane translocation induced by dexmedetomidine were examined. Hypothermia inhibited dexmedetomidine-induced contraction in the endothelium-intact aorta with L-NAME or endothelium-denuded aorta. Hypothermia had almost no effect on the dexmedetomidine-induced contraction in the endothelium-denuded aorta with the calcium-free Krebs solution; however, the subsequent contraction induced by the addition of calcium was inhibited by hypothermia. Conversely, the transition from profound hypothermia back to normothermia reversed the hypothermia-induced inhibition of subsequent calcium-induced contractions. Hypothermia inhibited any contraction induced by KCl, PDBu, and NaF, as well as PKC and MLC20 phosphorylation and Rho-kinase membrane translocation induced by dexmedetomidine. These results suggest that hypothermia inhibits dexmedetomidine-induced contraction, which is mediated mainly by the impediment of calcium influx and partially by the attenuation of pathways involving PKC and Rho-kinase activation.
Assuntos
Dexmedetomidina , Hipotermia , Ratos , Animais , Dexmedetomidina/farmacologia , Quinases Associadas a rho/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Cálcio/metabolismo , Hipotermia/metabolismo , Proteína Quinase C/metabolismo , Endotélio Vascular/metabolismo , Contração MuscularRESUMO
Lipid emulsion has been shown to effectively relieve refractory cardiovascular collapse resulting from toxic levels of nonlocal anesthetics. The goal of this study was to examine the effect of lipid emulsions on neuropsychiatric drug-induced toxicity using relevant case reports of human patients, with a particular focus on the Glasgow Coma Scale (GCS) score and corrected QT interval, to analyze drugs that frequently require lipid emulsion treatment. The following keywords were used to retrieve relevant case reports from PubMed: "antidepressant or antipsychotic drug or amitriptyline or bupropion or citalopram or desipramine or dosulepin or dothiepin or doxepin or escitalopram or fluoxetine or haloperidol or olanzapine or phenothiazine or quetiapine or risperidone or trazodone" and "lipid emulsion or Intralipid." Lipid emulsion treatment reversed the corrected QT interval prolongation and decreases in Glasgow Coma Scale scores caused by toxic doses of neuropsychiatric drugs, especially lipid-soluble drugs such as amitriptyline, trazodone, quetiapine, lamotrigine, and citalopram. The log P (octanol/water partition coefficient) of the group which required more than 3 lipid emulsion treatments was higher than that that of the group which required less than 3 lipid emulsion treatments. The main rationale to administer lipid emulsion as an adjuvant was as follows: hemodynamic depression intractable to supportive treatment (88.3%)â >â lipophilic drugs (8.3%)â >â suspected overdose or no spontaneous breathing (1.6%). Adjuvant lipid emulsion treatment contributed to the recovery of 98.30% of patients with neuropsychiatric drug-induced toxicity. However, further analyses using many case reports are needed to clarify the effects of lipid emulsion resuscitation.
Assuntos
Dotiepina , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Trazodona , Humanos , Fumarato de Quetiapina , Amitriptilina , Citalopram , Emulsões Gordurosas Intravenosas/uso terapêuticoRESUMO
BACKGROUND: Local anesthetic systemic toxicity (LAST) is rare, but fatal; the current widely used treatment is lipid emulsion (LE). The goal of this study was to analyze and review case reports on LE treatment for LAST in pediatric patients. METHODS: We performed a systematic review using case reports on LE treatment for LAST in pediatric patients, searching PubMed and Scopus databases to March 2023 using the following keywords: ("local anesthetic toxicity" OR "local anesthetic systemic toxicity" OR LAST") AND ("newborn" OR "infant" OR "child" OR "children" OR "adolescent" OR "pediatric") AND ("lipid emulsion" OR "Intralipid"). RESULTS: Our search yielded 21 cases, revealing that nearly 43% patients with LAST were less than 1 year old, and most cases were caused by bupivacaine (approximately 67% cases). "Inadvertent intravascular injection" by anesthesiologists and "overdose of local anesthetics" mainly by surgeons were responsible for 52% and 24% cases of LAST, respectively. LAST occurred in the awake state (52%) and under general anesthesia (48%), mainly causing seizures and arrhythmia, respectively. Approximately 55% of patients received LE treatment inâ <10 minutes after LAST, mainly improving cardiovascular symptoms. A 20% LE (1.5 mL/kg) dose followed by 0.25 mL/kg/minutes dose was frequently used. LE and anticonvulsants were mainly used in the awake state, whereas LE with or without vasopressors was mainly used under general anesthesia. LE treatment led to full recovery from LAST in 20 cases; however, 1 patient died due to underlying disease. CONCLUSION: Consequently, our findings reveal that LE is effective in treating pediatric LAST.
Assuntos
Anestésicos Locais , Emulsões Gordurosas Intravenosas , Humanos , Anestésicos Locais/efeitos adversos , Anestésicos Locais/administração & dosagem , Emulsões Gordurosas Intravenosas/uso terapêutico , Emulsões Gordurosas Intravenosas/administração & dosagem , Criança , Lactente , Pré-Escolar , Adolescente , Bupivacaína/efeitos adversos , Bupivacaína/administração & dosagem , Recém-Nascido , Feminino , MasculinoRESUMO
Vasoconstriction induced by levobupivacaine, a local anesthetic, is mediated by increased levels of calcium, tyrosine kinase, c-Jun NH2-terminal kinase (JNK), and phospholipase D, which are associated with prolonged local anesthesia. Epidermal growth factor receptor (EGFR) phosphorylation is associated with vasoconstriction. However, its role in levobupivacaine-induced contractions remains unknown. We determined whether EGFR phosphorylation is associated with levobupivacaine-induced contractions in isolated rat thoracic aortas and identified the underlying cellular signaling pathways. The effects of various inhibitors and a calcium-free solution alone or in combination on levobupivacaine-induced contractions were then assessed. Furthermore, we examined the effects of various inhibitors on levobupivacaine-induced EGFR and JNK phosphorylation and calcium levels in vascular smooth muscle cells (VSMCs) of rat aortas. The EGFR tyrosine kinase inhibitor AG1478, matrix metalloproteinase (MMP) inhibitor GM6001, Src kinase inhibitors PP1 and PP2, and JNK inhibitor SP600125 attenuated levobupivacaine-induced contractions. Moreover, although the calcium-free solution abolished levobupivacaine-induced contractions, calcium reversed this inhibitory effect. The magnitude of the calcium-mediated reversal of abolished levobupivacaine-induced contractions was lower in the combination treatment with calcium-free solution and AG1478 than in the treatment with calcium-free solution alone. Levobupivacaine induced EGFR and JNK phosphorylation. However, AG1478, GM6001, and PP2 attenuated levobupivacaine-induced EGFR and JNK phosphorylation. Moreover, although levobupivacaine induced JNK phosphorylation in control siRNA-transfected VSMCs, EGFR siRNA inhibited levobupivacaine-induced JNK phosphorylation. Furthermore, AG1478 inhibited levobupivacaine-induced calcium increases in VSMCs. Collectively, these findings suggest that levobupivacaine-induced EGFR phosphorylation, which may occur via the Src kinase-MMP pathway, contributes to vasoconstriction via JNK phosphorylation and increased calcium levels.
Assuntos
Cálcio , Receptores ErbB , Quinazolinas , Tirfostinas , Animais , Ratos , Aorta Torácica , Cálcio/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Levobupivacaína/farmacologia , Fosforilação , RNA Interferente Pequeno/metabolismo , Quinases da Família src/metabolismoAssuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Emulsões Gordurosas Intravenosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Emulsões Gordurosas Intravenosas/administração & dosagem , Emulsões Gordurosas Intravenosas/uso terapêutico , Recidiva , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapiaRESUMO
This study aimed to examine the endothelial dependence of vasodilation induced by the phosphodiesterase inhibitor theophylline in isolated rat thoracic aortas and elucidate the underlying mechanism, with emphasis on endothelial nitric oxide (NO). The effects of various inhibitors and endothelial denudation on theophylline-induced vasodilation, and the effect of theophylline on vasodilation induced by NO donor sodium nitroprusside, cyclic guanosine monophosphate (cGMP) analog bromo-cGMP, and ß-agonist isoproterenol in endothelium-denuded aorta were examined. The effects of theophylline and sodium nitroprusside on cGMP formation were also examined. We examined the effect of theophylline on endothelial nitric oxide synthase (eNOS) phosphorylation and intracellular calcium levels. Theophylline-induced vasodilation was greater in endothelium-intact aortas than that in endothelium-denuded aortas. The NOS inhibitor, NW-nitro-L-arginine methyl ester; non-specific guanylate cyclase (GC) inhibitor, methylene blue; and NO-sensitive GC inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one inhibited theophylline-induced vasodilation in endothelium-intact aortas. Theophylline increased the vasodilation induced by sodium nitroprusside, bromo-cGMP, and isoproterenol. Theophylline increased cGMP formation in endothelium-intact aortas, and sodium nitroprusside-induced cGMP formation in endothelium-denuded aortas. Moreover, theophylline increased stimulatory eNOS (Ser1177) phosphorylation and endothelial calcium levels, but decreased the phosphorylation of inhibitory eNOS (Thr495). These results suggested that theophylline-induced endothelium-dependent vasodilation was mediated by increased endothelial NO release and phosphodiesterase inhibition.
Assuntos
Óxido Nítrico , Vasodilatação , Ratos , Animais , Teofilina/farmacologia , Isoproterenol/farmacologia , Nitroprussiato/farmacologia , Diester Fosfórico Hidrolases/farmacologia , Cálcio , Aorta Torácica , Aorta , Óxido Nítrico Sintase Tipo III , GMP Cíclico/farmacologia , GMP Cíclico/fisiologia , Endotélio VascularAssuntos
Disfunção Erétil , Inibidores de Hidroximetilglutaril-CoA Redutases , Masculino , Humanos , Citrato de Sildenafila/efeitos adversos , Ereção Peniana , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Piperazinas/efeitos adversos , Interações Medicamentosas , Disfunção Erétil/tratamento farmacológicoRESUMO
Another affiliation: 2 Department of Anesthesiology and Pain Medicine, Gyeongsang National University College of Medicine, Jinju-si, Gyeongsangnam-do, Republic of Korea was added for the author Kyeong-Eon Park at his own request.