RESUMO
BACKGROUND AND PURPOSE: Mutation of serine 1179 to aspartate on the endothelial NO synthase (eNOS) increases NO production in the absence of stimulation by agonists. The present study was designed to determine the effect of recombinant S1179DeNOS gene expression on the vasomotor function of human pial arteries. METHODS: Pial arteries were isolated from 28 patients undergoing temporal lobectomy for intractable seizures. Adenoviral vectors (10(10) pfu/mL) encoding beta-galactosidase (AdCMVLacZ) or S1179DeNOS (AdCMVS1179DeNOS) were used for ex vivo gene transfer, and vasomotor function was evaluated in control and transduced arteries. RESULTS: Contractions to cumulative additions of U46619 were not affected by expression of LacZ or S1179DeNOS. Endothelium-dependent relaxations to bradykinin or endothelium-independent relaxations to Diethylaminodiazen-1-ium-1,2-dioate were significantly reduced in arteries expressing S1179DeNOS. A superoxide dismutase mimetic, manganese (III) tetrakis (4-benzoic acid) porphyrin chloride, failed to improve the reduced relaxations to bradykinin. The levels of cGMP were significantly elevated in arteries expressing S1179DeNOS. CONCLUSIONS: Our results support the concept that high local production of NO in pial arterial wall causes adaptive reduction of vasodilator reactivity to NO.
Assuntos
Artérias Cerebrais/enzimologia , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Adulto , Ácido Aspártico/genética , Artérias Cerebrais/fisiopatologia , GMP Cíclico/biossíntese , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Epilepsia/enzimologia , Epilepsia/fisiopatologia , Feminino , Expressão Gênica , Humanos , Masculino , Óxido Nítrico Sintase Tipo III , Mutação Puntual , Proteínas Recombinantes/metabolismo , Serina/genética , VasodilataçãoRESUMO
STUDY OBJECTIVE: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of the neuromuscular junction that manifests with muscle weakness, autonomic and bulbar dysfunction, and increased sensitivity to neuromuscular blocking drugs. The objective of this study is to review perioperative outcomes on a series of patients with LEMS. DESIGN: The medical records of surgical patients with LEMS from January 1, 1990, to December 31, 2012, were retrospectively reviewed. SETTING: Major academic hospital. PATIENTS: Surgical patients with LEMS. MEASUREMENTS AND MAIN RESULTS: Thirty-seven patients underwent 60 surgeries, with most performed to diagnose or treat lung malignancy (n = 31; 51.7%). Equal number of patients had LEMS associated with small cell lung cancer (n = 16; 43.2%) or an autoimmune process (n = 16; 43.2%), with the remainder having various malignancies. Neuromuscular blocking drug medications were used in 23 (38.3%) of cases, including 8 patients who were not treated for LEMS symptoms. Four patients (11%) had respiratory complications. Interestingly, 3 patients were either undiagnosed or not treated for LEMS at the time of perioperative complication, and developed weakness after use of neuromuscular blocking drugs. CONCLUSION: Patients with LEMS have increased sensitivity to neuromuscular blocking drugs. The risk for the development of prolonged muscle weakness or postoperative respiratory failure after being exposed to neuromuscular blocking drugs is increased in patients with undiagnosed or untreated LEMS.
Assuntos
Anestesia/métodos , Síndrome Miastênica de Lambert-Eaton/fisiopatologia , Bloqueadores Neuromusculares/administração & dosagem , Junção Neuromuscular/patologia , Idoso , Feminino , Humanos , Síndrome Miastênica de Lambert-Eaton/complicações , Síndrome Miastênica de Lambert-Eaton/diagnóstico , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Bloqueadores Neuromusculares/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Insuficiência Respiratória/epidemiologia , Insuficiência Respiratória/etiologia , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/etiologia , Carcinoma de Pequenas Células do Pulmão/cirurgiaRESUMO
Oxidative stress has been implicated as an important mechanism of vascular endothelial dysfunction induced by aging. Previous studies suggested that tetrahydrobiopterin (BH4), an essential cofactor of endothelial NO synthase, could be a molecular target for oxidation. We tested the hypothesis that oxidative stress, in particular oxidation of BH4, may contribute to attenuation of endothelium-dependent relaxation in aged mice. Vasomotor function of isolated carotid arteries was studied using a video dimension analyzer. Vascular levels of BH4 and its oxidation products were measured via HPLC. In aged mice (age, 95 +/- 2 wk), endothelium-dependent relaxation to ACh (10(-5) to 10(-9) M) as well as endothelium-independent relaxation to the NO donor diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10(-5) to 10(-9) M) were significantly reduced compared with relaxation detected in young mice (age, 23 +/- 0.5 wk). Incubation of aged mouse carotid arteries with the cell-permeable SOD mimetic Mn(III)tetra(4-benzoic acid)porphyrin chloride normalized relaxation to ACh and DEA-NONOate. Furthermore, production of superoxide anion in aorta and serum levels of amyloid P component, which is the murine analog of C-reactive protein, was increased in old mice. In aorta, neither the concentration of BH4 nor the ratio of reduced BH4 to the oxidation products were different between young and aged mice. Our results demonstrate that in mice, aging impairs relaxation mediated by NO most likely by increased formation of superoxide anion. Oxidation of BH4 does not appear to be an important mechanism underlying vasomotor dysfunction in aged mouse arteries.