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
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
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 VascularRESUMO
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.
RESUMO
This study examined the effect of chloroquine on vasodilation induced by levcromakalim in isolated endothelium-denuded rat aortas and clarified the underlying mechanisms. We examined the effects of chloroquine, hydroxychloroquine, lipid emulsion, reactive oxygen species (ROS) scavenger N-acetyl-Ê-cysteine (NAC), and KATP channel inhibitor glibenclamide on levcromakaliminduced vasodilation. The effects of chloroquine, hydroxychloroquine, NAC, and levcromakalim on membrane hyperpolarization and ROS production were examined in aortic vascular smooth muscle cells (VSMCs). Chloroquine inhibited levcromakalim-induced vasodilation more than hydroxychloroquine. NAC attenuated chloroquine-mediated inhibition of levcromakalim-induced vasodilation, while lipid emulsion had no effect. Glibenclamide eliminated levcromakalim-induced vasodilation in aortas pretreated with chloroquine. Chloroquine and hydroxychloroquine inhibited levcromakalim-induced membrane hyperpolarization in VSMCs. Chloroquine and hydroxychloroquine both produced ROS, but chloroquine produced more. NAC inhibited chloroquine-induced ROS production in VSMCs. Collectively, these results suggest that, partially through ROS production, chloroquine inhibits levcromakalim-induced vasodilation. In addition, chloroquine-induced KATP channel-induced vasodilation impairment was not restored by lipid emulsion.
Assuntos
Vasodilatação , Vasodilatadores , Ratos , Animais , Cromakalim/farmacologia , Vasodilatadores/farmacologia , Canais KATP , Glibureto/farmacologia , Espécies Reativas de Oxigênio , Hidroxicloroquina/farmacologia , Cloroquina/farmacologia , Emulsões/farmacologia , Canais de Potássio , Aorta , LipídeosRESUMO
This study aimed to examine the effect of lipid emulsion on the vasodilation induced by a toxic dose of amlodipine in isolated rat aorta and elucidate its mechanism, with a particular focus on nitric oxide. The effects of endothelial denudation, NW-nitro-L-arginvine methyl ester (L-NAME), methylene blue, lipid emulsion, and linolenic acid on the amlodipine-induced vasodilation and amlodipine-induced cyclic guanosine monophosphate (cGMP) production were examined. Furthermore, the effects of lipid emulsion, amlodipine, and PP2, either alone or combined, on endothelial nitric oxide synthase (eNOS), caveolin-1, and Src-kinase phosphorylation were examined. Amlodipine-induced vasodilation was higher in endothelium-intact aorta than in endothelium-denuded aorta. L-NAME, methylene blue, lipid emulsion, and linolenic acid inhibited amlodipine-induced vasodilation and amlodipine-induced cGMP production in the endothelium-intact aorta. Lipid emulsion reversed the increased stimulatory eNOS (Ser1177) phosphorylation and decreased inhibitory eNOS (Thr495) phosphorylation induced via amlodipine. PP2 inhibited stimulatory eNOS, caveolin-1, and Src-kinase phosphorylation induced via amlodipine. Lipid emulsion inhibited amlodipine-induced endothelial intracellular calcium increase. These results suggest that lipid emulsion attenuated the vasodilation induced via amlodipine through inhibiting nitric oxide release in isolated rat aorta, which seems to be mediated via reversal of stimulatory eNOS (Ser1177) phosphorylation and inhibitory eNOS (Thr495) dephosphorylation, which are also induced via amlodipine.
Assuntos
Anlodipino , Emulsões Gordurosas Intravenosas , Óxido Nítrico , Fosfolipídeos , Óleo de Soja , Vasodilatação , Vasodilatadores , Emulsões Gordurosas Intravenosas/farmacologia , Óxido Nítrico/metabolismo , Aorta , Feminino , Animais , Técnicas In Vitro , Anlodipino/toxicidade , Vasodilatadores/toxicidade , NG-Nitroarginina Metil Éster/farmacologia , Fosfolipídeos/farmacologia , Óleo de Soja/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismoRESUMO
In this study, we examined whether aortic contraction, induced by the alpha-2 adrenoceptor agonist dexmedetomidine, is involved in the transactivation of the epidermal growth factor receptor (EGFR) in isolated endothelium-denuded rat aortas. Additionally, we aimed to elucidate the associated underlying cellular mechanisms. The effects of the alpha-2 adrenoceptor inhibitor rauwolscine, EGFR tyrosine kinase inhibitor AG1478, Src kinase inhibitors PP1 and PP2, and matrix metalloproteinase inhibitor GM6001 on EGFR tyrosine phosphorylation and c-Jun NH2-terminal kinase (JNK) phosphorylation induced by dexmedetomidine in rat aortic smooth muscles were examined. In addition, the effects of these inhibitors on dexmedetomidine-induced contraction in isolated endothelium-denuded rat aorta were examined. Dexmedetomidine-induced contraction was inhibited by the alpha-1 adrenoceptor inhibitor prazosin, rauwolscine, AG1478, PP1, PP2, and GM6001 alone or by a combined treatment with prazosin and AG1478. AG1478 (3 × 10-6 M) inhibited dexmedetomidine-induced contraction in isolated endothelium-denuded rat aortas pretreated with rauwolscine. Dexmedetomidine-induced EGFR tyrosine and JNK phosphorylation were inhibited by rauwolscine, PP1, PP2, GM6001, and AG1478. Furthermore, dexmedetomidine-induced JNK phosphorylation reduced upon EGFR siRNA treatment. Therefore, these results suggested that the transactivation of EGFR associated with dexmedetomidine-induced contraction, mediated by the alpha-2 adrenoceptor, Src kinase, and matrix metalloproteinase, caused JNK phosphorylation and increased calcium levels.
Assuntos
Dexmedetomidina , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Aorta/metabolismo , Dexmedetomidina/farmacologia , Receptores ErbB/metabolismo , Músculo Liso Vascular/metabolismo , Fosforilação , Prazosina/farmacologia , Ratos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Ativação Transcricional , Tirosina/metabolismo , Ioimbina/farmacologia , Quinases da Família src/metabolismoRESUMO
A 46-year-old woman demonstrated refractory Kounis syndrome (KS) after induction of anesthesia. Despite conventional management of anaphylaxis and advanced cardiac life support, her cardiovascular function continued to deteriorate until she had a cardiac arrest, and after extracorporeal membrane oxygenation (ECMO) therapy, electrical cardiac activity reappeared. A large number of patients with KS-"allergic angina syndrome"-has been known to recover well with vasodilators; however, this patient showed antibiotics-induced refractory KS during general anesthesia. Severe bronchospasms with desaturation appeared as initial anaphylactic features; however, these did not respond to conventional treatment for anaphylaxis. Patient's hemodynamic signs eventually worsened, leading to cardiac arrest despite ephedrine administration and chest compressions. During cardiopulmonary cerebral resuscitation, the central line was secured, and epinephrine, atropine, as well as sodium bicarbonate were administered repeatedly; nevertheless, cardiac arrest was sustained. After initiation of veno-arterial ECMO, atrial fibrillation was observed, which was later converted to sinus tachycardia by electrical cardioversions and amiodarone. Coronary angiography was performed before the patient was admitted to the intensive care unit; there were no indications of an impending cardiac arrest. The patient was discharged uneventfully owing to early use of ECMO despite the emergence of KS symptoms that were initially masked by anesthesia but later worsened abruptly.
Assuntos
Anafilaxia , Oxigenação por Membrana Extracorpórea , Parada Cardíaca , Síndrome de Kounis , Anestesia Geral/efeitos adversos , Feminino , Parada Cardíaca/etiologia , Parada Cardíaca/terapia , Humanos , Síndrome de Kounis/etiologia , Síndrome de Kounis/terapia , Pessoa de Meia-IdadeRESUMO
We examined the effect of endothelium and lipid emulsion on vasodilation induced by minoxidil at a toxic dose and determined the underlying mechanism. The effects of endothelial denudation, NW-nitro-L-arginine methyl ester (L-NAME), methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), and glibenclamide, alone or in combination, on minoxidil-induced vasodilation in endothelium-intact rat aorta were examined. Additionally, the effects of lipid emulsion on minoxidil-induced membrane hyperpolarization and minoxidil concentration were examined. The vasodilatory effects of minoxidil at the toxic dose were higher in endothelium-intact aorta than in endothelium-denuded aorta. L-NAME, methylene blue, ODQ, and glibenclamide attenuated minoxidil-induced vasodilation of endothelium-intact rat aorta. Combined treatment with L-NAME and glibenclamide almost eliminated minoxidil-induced vasodilation. However, lipid emulsion pretreatment did not significantly alter minoxidil-induced vasodilation. Lipid emulsion did not significantly alter minoxidil-induced membrane hyperpolarization and minoxidil concentration. Overall, minoxidil-induced vasodilation is mediated by ATP-sensitive potassium channels and pathways involving nitric oxide and guanylate cyclase.
Assuntos
Óxido Nítrico , Vasodilatação , Animais , Aorta , Endotélio Vascular , Minoxidil , NG-Nitroarginina Metil Éster , Óxido Nítrico Sintase Tipo III , RatosRESUMO
This study aimed to examine the effect of lipid emulsion (LE) on the vasoconstriction induced by dexmedetomidine (DMT) in the isolated rat aorta and elucidate the associated cellular mechanism. The effect of LE, NW-nitro-L-arginine methyl ester (L-NAME), and methyl-ß-cyclodextrin (MßCD) on the DMT-induced contraction was examined. We investigated the effect of LE on the DMT-induced cyclic guanosine monophosphate (cGMP) formation and DMT concentration. The effect of DMT, LE, 4-Amino-3-(4-chlorophenyl)-1-(t-butyl)-1H-pyrazolo[3,4-d]pyrimidine,4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), and rauwolscine on the phosphorylation of endothelial nitric oxide synthase (eNOS), caveolin-1, and Src kinase was examined in the human umbilical vein endothelial cells. L-NAME, MßCD, and LE (1%, standardized mean difference (SMD): 2.517) increased the DMT-induced contraction in the endothelium-intact rat aorta. LE (1%) decreased the DMT (10-6 M) concentration (SMD: -6.795) and DMT-induced cGMP formation (SMD: -2.132). LE (1%) reversed the DMT-induced eNOS (Ser1177 and Thr496) phosphorylation. PP2 inhibited caveolin-1 and eNOS phosphorylation induced by DMT. DMT increased the Src kinase phosphorylation. Thus, LE (1%) enhanced the DMT-induced contraction by inhibition of NO synthesis, which may be caused by the decreased DMT concentration. DMT-induced NO synthesis may be caused by the increased eNOS (Ser1177) phosphorylation and decreased eNOS (Thr495) phosphorylation potentially mediated by Src kinase-induced caveolin-1 phosphorylation.
Assuntos
Aorta/efeitos dos fármacos , Dexmedetomidina/farmacologia , Emulsões , Endotélio/efeitos dos fármacos , Lipídeos/química , Vasoconstrição/efeitos dos fármacos , Animais , GMP Cíclico/metabolismo , Endotélio Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ioimbina/farmacologia , beta-Ciclodextrinas/químicaRESUMO
This study examined the possible upstream cellular signaling pathway associated with nitric oxide (NO)-mediated inhibition of phenylephrine-induced contraction in isolated rat aortae in response to mild hypothermia, with a particular focus on endothelial Rho-kinase. We examined the effects of mild hypothermia (33°C), wortmannin, Nω-nitro-L-arginine methyl ester (L-NAME), Y-27632, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and methylene blue, alone and combined, on phenylephrine-induced contraction in isolated rat aortae. Finally, we examined the effects of mild hypothermia, wortmannin, Y-27632 and L-NAME, alone and combined, on endothelial nitric oxide synthase (eNOS) and endothelial Rho-kinase membrane translocation induced by phenylephrine. Mild hypothermia attenuated phenylephrine-induced contraction only in endothelium-intact aortae. L-NAME, wortmannin, ODQ and methylene blue increased phenylephrine-induced contraction of endothelium-intact aortae pretreated at 33°C. Wortmannin did not significantly alter the L-NAME-induced enhancement of phenylephrine-induced maximal contraction of endothelium-intact aortae pretreated at 33°C. Wortmannin abolished the ability of Y-27632 to magnify the hypothermic inhibition of maximal phenylephrine-induced contraction. Wortmannin and L-NAME inhibited the enhancing effect of mild hypothermia on phenylephrine-induced eNOS phosphorylation. Y-27632 and L-NAME attenuated the enhancing effect of hypothermia on phenylephrine-induced endothelial Rho-kinase membrane translocation. The results suggest that hypothermia-induced, NO-dependent inhibition of phenylephrine-induced contraction is mediated by phosphoinositide 3-kinase and inhibited by endothelial Rho-kinase activation.
Assuntos
Aorta/metabolismo , Hipotermia Induzida/efeitos adversos , Óxido Nítrico/genética , Quinases Associadas a rho/genética , Amidas/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/crescimento & desenvolvimento , Aorta/patologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Humanos , Contração Muscular/efeitos dos fármacos , Contração Muscular/genética , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Fenilefrina/farmacologia , Fosfatidilinositol 3-Quinases/genética , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Vasoconstrição/genéticaRESUMO
The goal of this study was to examine the effect of lipid emulsion on the vasodilation induced by ATP-sensitive potassium (KATP) channels in isolated rat aortae and the underlying mechanism. The effects of Intralipid, containing 100% long-chain fatty acids, and Lipofundin MCT/LCT, containing 50% long-chain fatty acids plus 50% medium-chain fatty acids, on the vasodilation induced by levcromakalim in endothelium-intact aorta with or without NW-nitro-L-arginine methyl ester (L-NAME) and in endothelium-denuded aorta were examined. The effects of L-arginine, L-NAME, glibenclamide, and Lipofundin MCT/LCT, alone or combined, on the levcromakalim-induced vasodilation were examined. Lipofundin MCT/LCT inhibited the levcromakalim-induced vasodilation of isolated endothelium-intact aortae, whereas Intralipid did not. In addition, Lipofundin MCT/LCT had no effect on the levcromakalim-induced vasodilation of endothelium-denuded rat aortae and endothelium-intact aortae with L-NAME. L-arginine and Lipofundin MCT/LCT produced more levcromakalim-induced vasodilation than Lipofundin MCT/LCT alone. Glibenclamide inhibited levcromakalim-induced vasodilation. Levcromakalim did not significantly alter endothelial nitric oxide synthase phosphorylation, whereas Lipofundin MCT/LCT decreased cyclic guanosine monophosphate. Lipofundin MCT/LCT did not significantly alter levcromakalim-induced membrane hyperpolarization. Taken together, these results suggest that Lipofundin MCT/LCT inhibits the vasodilation induced by levcromakalim by inhibiting basally released endothelial nitric oxide, which seems to occur through medium-chain fatty acids.
Assuntos
Ácidos Graxos/química , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfolipídeos/farmacologia , Sorbitol/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Aorta/metabolismo , Cromakalim , GMP Cíclico/metabolismo , Combinação de Medicamentos , Emulsões , Células Endoteliais/metabolismo , Masculino , Potenciais da Membrana , Fosforilação , Canais de Potássio/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
The goal of this study was to examine the effect of lipid emulsion on the vasodilation induced in isolated endothelium-denuded rat aortae by a toxic dose of amlodipine. We examined the effects of lipid emulsion and verapamil on amlodipine-induced vasodilation. We also examined the effects of a mixture of lipid emulsion and amlodipine, as well as the centrifuged aqueous extract (CAE) obtained by ultracentrifuging such a mixture and then removing the upper lipid layer, on amlodipine-induced vasodilation. The effect of lipid emulsion on the amlodipine concentration was examined. Lipid emulsion attenuated amlodipine-induced vasodilation in isolated aortae. Both CAE and lipid emulsion containing amlodipine inhibited amlodipine-induced vasodilation. However, there was no significant difference in amlodipine-induced vasodilation between aortae treated with CAE and those treated with lipid emulsion containing amlodipine. Verapamil inhibited amlodipine-induced vasodilation. Lipid emulsion decreased the concentration of amlodipine. Lipid emulsion attenuated the vasodilation induced by a toxic amlodipine dose in NaF-precontracted aortae. The data show that lipid emulsion inhibited the vasodilation induced by a toxic amlodipine dose in isolated rat aortae by reducing the concentration of amlodipine. Amlodipine-induced vasodilation seems to be mediated mainly by blockade of L-type calcium channels and partially by inhibition of the Rho-kinase pathway.
Assuntos
Anlodipino/farmacologia , Aorta/efeitos dos fármacos , Lipídeos/farmacologia , Vasodilatação/efeitos dos fármacos , Anlodipino/toxicidade , Animais , Aorta/fisiopatologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/genética , Emulsões/farmacologia , Humanos , Lipídeos/antagonistas & inibidores , Lipídeos/química , Masculino , Técnicas de Cultura de Órgãos , Ratos , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/genética , Vasodilatação/fisiologia , Verapamil/farmacologia , Quinases Associadas a rho/genéticaRESUMO
The present in vitro study examined whether lipid emulsion attenuates the vasodilation evoked by toxic doses of calcium channel blockers (bepridil, verapamil, nifedipine and diltiazem) via their partitioning into the lipid phase. The effects of the calcium channel blockers alone, the lipid emulsion and calcium channel blocker mixture, and the centrifuged aqueous extract (CAE) obtained from ultracentrifugation of the lipid emulsion and calcium channel blocker mixture on isolated endothelium-denuded rat aortas precontracted with phenylephrine were observed. The effects of lipid emulsion on calcium channel blocker concentration in the Krebs solution were examined using ultraperformance liquid chromatography. A mixture of lipid emulsion with either bepridil or verapamil and the corresponding CAE more effectively attenuated vasodilation than either bepridil or verapamil alone, whereas the vasodilation induced by the mixture of lipid emulsion and either bepridil or verapamil was not significantly different from that induced by the corresponding CAE. The magnitude of the lipid emulsion-mediated reduction in vasodilation and calcium channel blocker concentration was as follows: bepridil > verapamil > nifedipine or diltiazem. These results suggest that lipid emulsion attenuates vasodilation induced by a toxic dose of bepridil and verapamil, seemingly through partitioning of the calcium channel blocker into the lipid phase.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/toxicidade , Lipídeos/química , Vasodilatação/efeitos dos fármacos , Animais , Bloqueadores dos Canais de Cálcio/administração & dosagem , Emulsões , RatosRESUMO
Lipid emulsion has been shown to be an effective treatment for systemic toxicity induced by local anesthetics, which is reflected in case reports. A systemic review and meta-analysis confirm the efficacy of this treatment. Investigators have suggested mechanisms associated with the lipid emulsion-mediated recovery of cardiovascular collapse caused by local anesthetic systemic toxicity; these mechanisms include lipid sink, a widely accepted theory in which highly soluble local anesthetics (particularly bupivacaine) are absorbed into the lipid phase of plasma from tissues (e.g., the heart) affected by local-anesthetic-induced toxicity; enhanced redistribution (lipid shuttle); fatty acid supply; reversal of mitochondrial dysfunction; inotropic effects; glycogen synthase kinase-3ß phosphorylation associated with inhibition of the mitochondrial permeability transition pore opening; inhibition of nitric oxide release; and reversal of cardiac sodium channel blockade. The current review includes the following: 1) an introduction, 2) a list of the proposed mechanisms, 3) a discussion of the best lipid emulsion treatment for reversal of local anesthetic toxicity, 4) a description of the effect of epinephrine on lipid emulsion-mediated resuscitation, 5) a description of the recommended lipid emulsion treatment, and 6) a conclusion.
Assuntos
Anestésicos Locais/efeitos adversos , Emulsões Gordurosas Intravenosas/uso terapêutico , Animais , Bupivacaína/efeitos adversos , Lipídeos , RessuscitaçãoRESUMO
The goal of this study was to investigate the effect of lipid emulsion on a toxic dose of local anesthetic-mediated reduction of vasodilation evoked by the ATP-sensitive potassium (KATP) channel agonist levcromakalim. The effect of lipid emulsion (LE) and linoleic acid on the local anesthetic-mediated reduction of vasodilation and membrane hyperpolarization evoked by levcromakalim was assessed in isolated endothelium-denuded vessels (rat aorta and mesenteric artery) and aortic vascular smooth muscle cells. The effect of LE and linoleic acid on KATP channel activity in transfected HEK-293 cells was investigated, as was the effect of LE on bupivacaine concentration. The efficacy of LE in attenuating the local anesthetic-mediated reduction of vasodilation evoked by levcromakalim was correlated with the lipid solubility of the local anesthetic. Linoleic acid attenuated the bupivacaine-mediated reduction of vasodilation evoked by levcromakalim. LE decreased the bupivacaine-mediated reduction of membrane hyperpolarization evoked by levcromakalim but did not significantly alter the mepivacaine-mediated reduction. LE and linoleic acid both reversed the bupivacaine-mediated decrease of KATP activity and enhanced KATP activity. LE decreased the bupivacaine concentration. Linoleic acid may be the major contributor to LE-induced attenuation of bupivacaine-mediated reduction of vasodilation evoked by levcromakalim via the direct activation of KATP channels and indirect effects.
Assuntos
Bupivacaína/efeitos adversos , Ativação do Canal Iônico/efeitos dos fármacos , Canais KATP/metabolismo , Ácido Linoleico/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Cromakalim/farmacologia , Emulsões/química , Genisteína/farmacologia , Células HEK293 , Humanos , Indóis/farmacologia , Lipídeos/química , Masculino , Maleimidas/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteína Quinase C/metabolismo , Ratos Sprague-DawleyRESUMO
INTRODUCTION: The etiology of calf pain varies widely; therefore, it is difficult to diagnose and requires careful history taking and physical examination by primary care unit physicians. Because ultrasonography is easy to perform, cheap, and readily available to physicians during a routine consultation, it is the first choice of modality for the evaluation of calf pain. However, simple inflammation around the nerve should also be considered as a possible etiology. Here we describe a 35-year-old man with chronic pain in the right calf that was actually caused by fibroma-induced chronic inflammation around the tibial and peroneal nerves but misdiagnosed as centralized neuropathic pain. CASE REPORT: The patient presented with chronic pain and a tingling sensation in the right calf. He had a slowly growing tibial nerve neurilemmoma that was excised at 28 years of age; however, the pain and tingling sensation persisted. He visited several hospitals for 7 years and was misdiagnosed with peripheral nerve injury-induced neuropathic pain. At 35 years of age, he visited our hospital for further evaluation. Ultrasonography revealed a mass in the popliteal region, which was excised and confirmed to be a fibroma via histopathological analysis. Severe inflammation was observed in the operative field. His symptoms finally ameliorated after this surgery. CONCLUSION: The findings from this case suggest that ultrasonography should be used as the primary modality for the evaluation of calf pain. Although the features of unresolved calf pain are similar to those of neuropathic pain, more curable etiologies should be considered.
Assuntos
Fibroma/complicações , Inflamação/etiologia , Nervo Fibular , Nervo Tibial , Adulto , Dor Crônica/etiologia , Erros de Diagnóstico , Humanos , Perna (Membro) , Masculino , Neuralgia/diagnóstico , Neuralgia/etiologia , Traumatismos dos Nervos Periféricos/diagnóstico , UltrassonografiaRESUMO
The goal of this in vitro study was to examine the effect of the alpha-2 adrenoceptor agonist dexmedetomidine on phenylephrine (alpha-1 adrenoceptor agonist)-induced contraction in isolated rat aortae and to elucidate the associated cellular mechanisms, with a particular focus on alpha-1 adrenoceptor antagonism. Dexmedetomidine dose-response curves were generated in isolated endothelium-intact and endothelium-denuded rat aortae precontracted with phenylephrine or 5-hydroxytryptamine. Endothelium-denuded aortic rings were pretreated with either dexmedetomidine or the reversible alpha-1 adrenoceptor antagonist phentolamine, followed by post-treatment with the irreversible alpha-1 adrenoceptor blocker phenoxybenzamine. Control rings were treated with phenoxybenzamine alone. All rings were repeatedly washed with Krebs solution to remove all pretreatment drugs, including phenoxybenzamine, phentolamine and dexmedetomidine. Phenylephrine dose-response curves were then generated. The effect of rauwolscine on the dexmedetomidine-mediated change in phenylephrine-induced endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein endothelial cells was examined using western blotting. The magnitude of the dexmedetomidine-mediated inhibition of phenylephrine-induced contraction was higher in endothelium-intact aortae than in endothelium-denuded aortae or endothelium-intact aortae treated with Nω-nitro-L-arginine methyl ester. However, dexmedetomidine did not significantly alter 5-hydroxytryptamine-induced contraction. In further experiments, prazosin attenuated dexmedetomidine-induced contraction. Additionally, pretreatment with either dexmedetomidine plus phenoxybenzamine or phentolamine plus phenoxybenzamine produced greater phenylephrine-induced contraction than phenoxybenzamine alone, suggesting that dexmedetomidine protects aortae from the alpha-1 adrenoceptor blockade induced by phenoxybenzamine. Rauwolscine attenuated the dexmedetomidine-mediated enhancement of phenylephrine-induced eNOS phosphorylation. Taken together, these results suggest that dexmedetomidine attenuates phenylephrine-induced contractions via alpha-1 adrenoceptor blockade and endothelial nitric oxide release in the isolated rat aorta.
Assuntos
Aorta/efeitos dos fármacos , Aorta/metabolismo , Dexmedetomidina/farmacologia , Óxido Nítrico/metabolismo , Fenilefrina/farmacologia , Receptores Adrenérgicos/metabolismo , Agonistas Adrenérgicos/farmacologia , Animais , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Fenoxibenzamina/farmacologia , Ratos , Serotonina/farmacologiaRESUMO
The goal of this in vitro study was to examine the effect of a lipid emulsion on toxic-dose bupivacaine-induced vasodilation in a model of tyrosine phosphatase inhibitor sodium orthovanadate-induced contraction in endothelium-denuded rat aortae and to elucidate the associated cellular mechanism. The effect of a lipid emulsion on vasodilation induced by a toxic dose of a local anesthetic during sodium orthovanadate-induced contraction was examined. In addition, the effects of various inhibitors, either bupivacaine alone or a lipid emulsion plus bupivacaine, on protein kinase phosphorylation induced by sodium orthovanadate in rat aortic vascular smooth muscle cells was examined. A lipid emulsion reversed the vasodilation induced by bupivacaine during sodium orthovanadate-induced contraction. The lipid emulsion attenuated the bupivacaine-mediated inhibition of the sodium orthovanadate-induced phosphorylation of protein tyrosine, c-Jun NH2-terminal kinase (JNK), myosin phosphatase target subunit 1 (MYPT1), phospholipase C (PLC) γ-1 and extracellular signal-regulated kinase (ERK). These results suggest that a lipid emulsion reverses toxic-dose bupivacaine-induced vasodilation during sodium orthovanadate-induced contraction via the activation of a pathway involving either tyrosine kinase, JNK, Rho-kinase and MYPT1 or tyrosine kinase, PLC γ-1 and ERK, and this reversal is associated with the lipid solubility of the local anesthetic and the induction of calcium sensitization.
Assuntos
Aorta/efeitos dos fármacos , Aorta/fisiologia , Bupivacaína/farmacologia , Emulsões , Lipídeos/química , Tirosina/metabolismo , Vasodilatação/efeitos dos fármacos , Anestésicos Locais/química , Anestésicos Locais/farmacologia , Anestésicos Locais/toxicidade , Animais , Bupivacaína/química , Bupivacaína/toxicidade , Cálcio/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Masculino , Fosforilação , Proteínas Tirosina Quinases/metabolismo , RatosRESUMO
The goal of this in vitro study was to examine the effects of pre-acidification and pre-akalinization on the lipid emulsion-mediated reversal of toxic dose levobupivacaine-induced vasodilation in isolated rat aorta. Isolated aortic rings with and without the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) were exposed to four types of Krebs solution (pH 7.0, 7.2, 7.4, and 7.6), followed by the addition of 60 mM potassium chloride. When the toxic dose of levobupivacaine (3 × 10(-4) M) produced a stable and sustained vasodilation in the isolated aortic rings that were precontracted with 60 mM potassium chloride, increasing lipid emulsion concentrations (SMOFlipid(®): 0.24, 0.48, 0.95 and 1.39%) were added to generate concentration-response curves. The effects of mild pre-acidification alone and mild pre-acidification in combination with a lipid emulsion on endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein endothelial cells were investigated by Western blotting. Mild pre-acidification caused by the pH 7.2 Krebs solution enhanced the lipid emulsion-mediated reversal of levobupivacaine-induced vasodilation in isolated endothelium-intact aortic rings, whereas mild pre-acidification caused by the pH 7.2 Krebs solution did not significantly alter the lipid emulsion-mediated reversal of the levobupivacaine-induced vasodilation in isolated endothelium-denuded aortic rings or endothelium-intact aortic rings with L-NAME. A lipid emulsion attenuated the increased eNOS phosphorylation induced by the pH 7.2 Krebs solution. Taken together, these results suggest that mild pre-acidification enhances the lipid emulsion-mediated reversal of toxic dose levobupivacaine-induced vasodilation in the endothelium-intact aorta via the inhibition of nitric oxide.