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1.
Cardiovasc Res ; 116(1): 183-192, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30715197

RESUMO

AIMS: Perinatal iron deficiency (ID) alters developmental trajectories of offspring, predisposing them to cardiovascular dysfunction in later life. The mechanisms underlying this long-term programming of renal function have not been defined. We hypothesized perinatal ID causes hypertension and alters kidney metabolic function and morphology in a sex-dependent manner in adult offspring. Furthermore, we hypothesized these effects are exacerbated by chronic consumption of a high salt diet. METHODS AND RESULTS: Pregnant Sprague Dawley rats were fed either an iron-restricted or replete diet prior to and throughout pregnancy. Adult offspring were fed normal or high salt diets for 6 weeks prior to experimentation at 6 months of age. Blood pressure (BP) was assessed via indwelling catheters in anaesthetized offspring; kidney mitochondrial function was assessed via high-resolution respirometry; reactive oxygen species and nitric oxide were quantified via fluorescence microscopy. Adult males, but not females, exhibited increased systolic BP due to ID (P = 0.01) and high salt intake (P = 0.02). In males, but not in females, medullary mitochondrial content was increased by high salt (P = 0.003), while succinate-dependent respiration was reduced by ID (P < 0.05). The combination of perinatal ID and high salt reduced complex IV activity in the cortex of males (P = 0.01). Perinatal ID increased cytosolic superoxide generation (P < 0.001) concomitant with reduced nitric oxide bioavailability (P < 0.001) in male offspring, while high salt increased mitochondrial superoxide in the medulla (P = 0.04) and cytosolic superoxide within the cortex (P = 0.01). Male offspring exhibited glomerular basement membrane thickening (P < 0.05), increased collagen deposition (P < 0.05), and glomerular hypertrophy (interaction, P = 0.02) due to both perinatal ID and high salt. Female offspring exhibited no alterations in mitochondrial function or morphology due to either high salt or ID. CONCLUSION: Perinatal ID causes long-term sex-dependent alterations in renal metabolic function and morphology, potentially contributing to hypertension and increased cardiovascular disease risk.


Assuntos
Ferro na Dieta , Ferro/deficiência , Nefropatias/etiologia , Rim/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo , Efeitos Tardios da Exposição Pré-Natal , Sódio na Dieta , Fatores Etários , Fenômenos Fisiológicos da Nutrição Animal , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Rim/patologia , Rim/fisiopatologia , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/fisiopatologia , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Mitocôndrias/patologia , Óxido Nítrico/metabolismo , Estado Nutricional , Gravidez , Ratos Sprague-Dawley , Fatores Sexuais , Superóxidos/metabolismo , Fatores de Tempo
2.
J Physiol ; 597(18): 4715-4728, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31368136

RESUMO

KEY POINTS: Perinatal iron deficiency causes changes in offspring mesenteric artery function in adulthood, particularly in males, which can be exacerbated by chronic intake of a high salt diet. Perinatal iron deficient male offspring exhibit enhanced conversion of big endothelin-1 to active endothelin-1, coinciding with decreased nitric oxide levels. Perinatal iron deficient male offspring have reduced nitric oxide-mediated endothelial-dependent vasodilatation coincident with increased vascular superoxide levels following consumption of a high salt diet. Perinatal iron deficiency has no apparent effects on vascular function in female offspring, even when fed a high salt diet. These results help us better understand underlying vascular mechanisms contributing to increased cardiovascular risk from perinatal stressors such as iron deficiency. ABSTRACT: Pre- and immediate postnatal stressors, such as iron deficiency, can alter developmental trajectories and predispose offspring to long-term cardiovascular dysfunction. Here, we investigated the impact of perinatal iron deficiency on vascular function in the adult offspring, and whether these long-term effects were exacerbated by prolonged consumption of a high salt diet in adulthood. Female Sprague Dawley rats were fed either an iron-restricted or -replete diet prior to and throughout pregnancy. Six weeks prior to experimentation at 6 months of age, adult offspring were fed either a normal or high salt diet. Mesenteric artery responses to vasodilators and vasoconstrictors were assessed ex vivo by wire myography. Male perinatal iron deficient offspring exhibited decreased reliance on nitric oxide with methacholine-induced vasodilatation (interaction P = 0.03), coincident with increased superoxide levels when fed the high salt diet (P = 0.01). Male perinatal iron deficient offspring exhibit enhanced big endothelin-1 conversion to active endothelin-1 (P = 0.02) concomitant with decreased nitric oxide levels (P = 0.005). Female offspring vascular function was unaffected by perinatal iron deficiency, albeit the high salt diet was associated with impaired vasodilation and decreased nitric oxide production (P = 0.02), particularly in the perinatal iron deficient offspring. These findings implicate vascular dysfunction in the sex-specific programming of cardiovascular dysfunction in the offspring by perinatal iron deficiency.


Assuntos
Anemia Ferropriva/fisiopatologia , Dieta/efeitos adversos , Endotélio Vascular/efeitos dos fármacos , Parto/efeitos dos fármacos , Cloreto de Sódio na Dieta/farmacologia , Doenças Vasculares/induzido quimicamente , Animais , Endotélio Vascular/metabolismo , Feminino , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Óxido Nítrico/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Doenças Vasculares/metabolismo , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
3.
PLoS One ; 14(5): e0215221, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120888

RESUMO

Poor reporting quality may contribute to irreproducibility of results and failed 'bench-to-bedside' translation. Consequently, guidelines have been developed to improve the complete and transparent reporting of in vivo preclinical studies. To examine the impact of such guidelines on core methodological and analytical reporting items in the preclinical anesthesiology literature, we sampled a cohort of studies. Preclinical in vivo studies published in Anesthesiology, Anesthesia & Analgesia, Anaesthesia, and the British Journal of Anaesthesia (2008-2009, 2014-2016) were identified. Data was extracted independently and in duplicate. Reporting completeness was assessed using the National Institutes of Health Principles and Guidelines for Reporting Preclinical Research. Risk ratios were used for comparative analyses. Of 7615 screened articles, 604 met our inclusion criteria and included experiments reporting on 52 490 animals. The most common topic of investigation was pain and analgesia (30%), rodents were most frequently used (77%), and studies were most commonly conducted in the United States (36%). Use of preclinical reporting guidelines was listed in 10% of applicable articles. A minority of studies fully reported on replicates (0.3%), randomization (10%), blinding (12%), sample-size estimation (3%), and inclusion/exclusion criteria (5%). Statistics were well reported (81%). Comparative analysis demonstrated few differences in reporting rigor between journals, including those that endorsed reporting guidelines. Principal items of study design were infrequently reported, with few differences between journals. Methods to improve implementation and adherence to community-based reporting guidelines may be necessary to increase transparent and consistent reporting in the preclinical anesthesiology literature.


Assuntos
Avaliação Pré-Clínica de Medicamentos/normas , Relatório de Pesquisa/normas , Analgésicos/uso terapêutico , Animais , Bases de Dados Factuais , Guias como Assunto , Dor/tratamento farmacológico
4.
J Neural Eng ; 16(3): 036003, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30790787

RESUMO

OBJECTIVE: The overall goal of this study was to investigate the effects of various anesthetic protocols on the intraoperative responses to intraspinal microstimulation (ISMS). ISMS is a neuroprosthetic approach that targets the motor networks in the ventral horns of the spinal cord to restore function after spinal cord injury. In preclinical studies, ISMS in the lumbosacral enlargement produced standing and walking by activating networks controlling the hindlimb muscles. ISMS implants are placed surgically under anesthesia, and refinements in placement are made based on the evoked responses. Anesthesia can have a significant effect on the responses evoked by spinal neuroprostheses; therefore, in preparation for clinical testing of ISMS, we compared the evoked responses under a common clinical neurosurgical anesthetic protocol with those evoked under protocols commonly used in preclinical studies. APPROACH: Experiments were conducted in seven pigs. An ISMS microelectrode array was implanted in the lumbar enlargement and responses to ISMS were measured under three anesthetic protocols: (1) isoflurane, an agent used pre-clinically and clinically, (2) total intravenous anesthesia (TIVA) with propofol as the main agent commonly used in clinical neurosurgical procedures, (3) TIVA with sodium pentobarbital, an anesthetic agent used mostly preclinically. Responses to ISMS were evaluated based on stimulation thresholds, movement kinematics, and joint torques. Motor evoked potentials (MEP) and plasma concentrations of propofol were also measured. MAIN RESULTS: ISMS under propofol anesthesia produced large and functional responses that were not statistically different from those produced under pentobarbital anesthesia. Isoflurane, however, significantly suppressed the ISMS-evoked responses. SIGNIFICANCE: This study demonstrated that the choice of anesthesia is critical for intraoperative assessments of motor responses evoked by spinal neuroprostheses. Propofol and pentobarbital anesthesia did not overly suppress the effects of ISMS; therefore, propofol is expected to be a suitable anesthetic agent for clinical intraoperative testing of an intraspinal neuroprosthetic system.


Assuntos
Anestésicos Inalatórios/administração & dosagem , Anestésicos Intravenosos/administração & dosagem , Potencial Evocado Motor/fisiologia , Monitorização Neurofisiológica Intraoperatória/métodos , Próteses Neurais , Medula Espinal/fisiologia , Animais , Eletromiografia/métodos , Potencial Evocado Motor/efeitos dos fármacos , Isoflurano/administração & dosagem , Vértebras Lombares/fisiologia , Vértebras Lombares/cirurgia , Masculino , Propofol/administração & dosagem , Medula Espinal/efeitos dos fármacos , Medula Espinal/cirurgia , Suínos
5.
Anesth Analg ; 129(1): e20-e22, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-29200074

RESUMO

We tested whether propofol or Intralipid inoculated with Staphylococcus epidermidis would promote bacterial growth within an intravenous (IV) injection hub, a site prone to bacterial contamination. In tubes incubated under optimal conditions, S epidermidis exhibited growth in Intralipid, but not in propofol. In contrast, within the IV hub incubated with either propofol or intralipid at room temperature, S epidermidis bacterial numbers declined with time, and virtually no contamination remained after 12 hours. These data suggest that certain IV lines are inhospitable for S epidermidis.


Assuntos
Contaminação de Medicamentos , Contaminação de Equipamentos , Fosfolipídeos/análise , Propofol/análise , Óleo de Soja/análise , Staphylococcus epidermidis/crescimento & desenvolvimento , Dispositivos de Acesso Vascular/microbiologia , Emulsões/administração & dosagem , Emulsões/análise , Injeções Intravenosas , Viabilidade Microbiana , Fosfolipídeos/administração & dosagem , Propofol/administração & dosagem , Óleo de Soja/administração & dosagem , Fatores de Tempo
6.
PLoS One ; 13(8): e0202871, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30161186

RESUMO

BACKGROUND: Medication overdose is a prevalent issue and despite mixed reports of efficacy, the use of intravenous lipid emulsions, notably Intralipid®, for the management of toxicity from lipid-soluble drugs is becoming increasingly prevalent. Whether alternative lipid emulsion formulations have similar efficacy for resuscitation compared to Intralipid is not known. Here, we compared the efficacy of Intralipid and ClinOleic® for resuscitation following overdose with the lipid-soluble beta-adrenergic antagonist propranolol. METHODS: Male Sprague-Dawley rats (age 3-4 months) were anesthetized with isoflurane and instrumented for direct hemodynamic assessments. In Study One, rats (n = 22) were pre-treated with Intralipid 20% (n = 12) or ClinOleic 20% (n = 10) to determine whether the hemodynamic effects of propranolol could be prevented. In Study Two, rats were randomly assigned to Intralipid 20% (1, 2, or 3 mL/kg IV, n = 21) or ClinOleic 20% (1, 2, or 3 mL/kg IV, n = 20) resuscitation groups following propranolol overdose (15 mg/kg IV). In Study Three the effect of Intralipid 20% (1 mL/kg IV, n = 3) and ClinOleic 20% (1 mL/kg IV, n = 3) in the absence of propranolol was investigated. The primary endpoint in all studies was survival time (up to a maximum of 120 minutes), and secondary endpoints were time to achieve 50%, 75%, and 90% of baseline hemodynamic parameters. RESULTS: In Study One, pre-treatment with Intralipid prior to propranolol administration resulted in prolonged survival compared to pre-treatment with ClinOleic at low doses (1 mL/kg; P = 0.002), but provided no benefit at higher doses (3 mL/kg; P = 0.95). In Study Two, Intralipid conferred a survival advantage over ClinOleic, with 18/21 rats surviving 120 minutes in the Intralipid group and only 4/20 survivors in the ClinOleic group (P<0.0001). Median survival times (with interquartile ranges) for rats treated with Intralipid, and ClinOleic, and saline were 120 (80.5-120) min, 21.5 (3.25-74.5) min, and 1 (0.25-2.5) min respectively (P<0.001). Only 3/21 rats in the Intralipid group survived less than 30 minutes, whereas 12/20 ClinOleic treated rats had survival times of less than 30 minutes. The number of rats achieving 75%, and 90% of baseline mean arterial pressure was also greater in the Intralipid group (P<0.05 for both values). Treatment in Study Three did not alter survival times. CONCLUSIONS: Low-dose Intralipid (1, 2, or 3 mL/kg IV) confers a survival advantage up to 120 minutes post-propranolol overdose (the end-point of the experiment) and better hemodynamic recovery compared to ClinOleic (1, 2, or 3 mL/kg IV) in rats with propranolol overdose. As health care centres choose alternate intravenous lipid emulsions, limited availability of Intralipid could impact efficacy and success of overdose treatment for lipid-soluble drugs.


Assuntos
Overdose de Drogas/terapia , Emulsões Gordurosas Intravenosas/farmacologia , Fosfolipídeos/farmacologia , Óleos Vegetais/farmacologia , Propranolol/efeitos adversos , Óleo de Soja/farmacologia , Animais , Overdose de Drogas/fisiopatologia , Emulsões/farmacologia , Hemodinâmica , Estimativa de Kaplan-Meier , Masculino , Distribuição Aleatória , Ratos Sprague-Dawley
7.
FASEB J ; 32(6): 3254-3263, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29401611

RESUMO

Prenatal iron deficiency alters fetal developmental trajectories, which results in persistent changes in organ function. Here, we studied the effects of prenatal iron deficiency on fetal kidney and liver mitochondrial function. Pregnant Sprague-Dawley rats were fed partially or fully iron-restricted diets to induce a state of moderate or severe iron deficiency alongside iron-replete control rats. We assessed mitochondrial function via high-resolution respirometry and reactive oxygen species generation via fluorescence microscopy on gestational d 21. Hemoglobin levels were reduced in dams in the moderate (-31%) and severe groups (-54%) compared with controls, which was accompanied by 55% reductions in fetal hemoglobin levels in both moderate and severe groups versus controls. Male iron-deficient kidneys exhibited globally reduced mitochondrial content and respiration, as well as increased cytosolic superoxide and decreased NO. Female iron-deficient kidneys exhibited complex II down-regulation and increased mitochondrial oxidative stress. Male iron-deficient livers exhibited reduced complex IV respiration and increased cytosolic superoxide, whereas female liver tissues exhibited no alteration in oxidant levels or mitochondrial function. These findings indicate that prenatal iron deficiency causes changes in mitochondrial content and function as well as oxidant status in a sex- and organ-dependent manner, which may be an important mechanism that underlies the programming of cardiovascular disease.-Woodman, A. G., Mah, R., Keddie, D., Noble, R. M. N., Panahi, S., Gragasin, F. S., Lemieux, H., Bourque, S. L. Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.


Assuntos
Feto/metabolismo , Ferro/deficiência , Rim/embriologia , Fígado/embriologia , Mitocôndrias Hepáticas/metabolismo , Estresse Oxidativo , Complicações na Gravidez/metabolismo , Caracteres Sexuais , Animais , Feminino , Feto/patologia , Rim/patologia , Fígado/patologia , Masculino , Mitocôndrias Hepáticas/patologia , Gravidez , Complicações na Gravidez/patologia , Ratos , Ratos Sprague-Dawley
8.
Sci Rep ; 7: 46573, 2017 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-28440316

RESUMO

Prenatal iron-deficiency (ID) is known to alter fetal developmental trajectories, which predisposes the offspring to chronic disease in later life, although the underlying mechanisms remain unclear. Here, we sought to determine whether varying degrees of maternal anaemia could induce organ-specific patterns of hypoxia in the fetuses. Pregnant female Sprague Dawley rats were fed iron-restricted or iron-replete diets to induce a state of moderate (M-ID) or severe ID (S-ID) alongside respective controls. Ultrasound biomicroscopy was performed on gestational day (GD)20 to assess uterine and umbilical artery blood flow patterns. On GD21, tissues were collected and assessed for hypoxia using pimonidazole staining. Compared to controls, maternal haemoglobin (Hb) in M- and S-ID were reduced 17% (P < 0.01) and 48% (P < 0.001), corresponding to 39% (P < 0.001) and 65% (P < 0.001) decreases in fetal Hb. Prenatal ID caused asymmetric fetal growth restriction, which was most pronounced in S-ID. In both severities of ID, umbilical artery resistive index was increased (P < 0.01), while pulsatility index only increased in S-ID (P < 0.05). In both M-and S-ID, fetal kidneys and livers showed evidence of hypoxia (P < 0.01 vs. controls), whereas fetal brains and placentae remained normoxic. These findings indicate prenatal ID causes organ-specific fetal hypoxia, even in the absence of severe maternal anaemia.


Assuntos
Anemia Ferropriva , Encéfalo , Doenças Fetais/sangue , Ferro/deficiência , Placenta , Anemia Ferropriva/sangue , Anemia Ferropriva/embriologia , Anemia Ferropriva/patologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/embriologia , Encéfalo/patologia , Feminino , Placenta/irrigação sanguínea , Placenta/embriologia , Placenta/patologia , Gravidez , Ratos , Ratos Sprague-Dawley
9.
Can J Anaesth ; 64(4): 361-369, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28070833

RESUMO

PURPOSE: To determine if a non-exercise algorithm-derived assessment of cardiorespiratory fitness (CRFA) accurately predicted estimated values obtained using a six-minute walk test (CRF6MWD) and the Duke Activity Status Index (CRFDASI). METHODS: Following research ethics board approval, an observational cohort study was conducted in selected, consenting patients undergoing elective surgery. Participants completed questionnaires assessing their self-reported exercise capacity. Their height, weight, waist circumference, and vital signs were measured. A six-minute walk test was performed twice with a 45-min rest interval between tests. The correlation between CRFA and both CRF6MWD and CRFDASI was determined. RESULTS: Two hundred forty-two participants were included. Mean age was 62 (range 45-88 yr); 150 (62%) were male, 87 (36%) self-reported walking or jogging > 16 km per week, and 49 (20%) were current smokers. The CRFA and CRF6MWD were highly correlated (Pearson r = 0.878; P < 0.001). CRFA and CRFDASI were less strongly correlated (Pearson r = 0.252; P < 0.001). Among patients capable of walking > 427 m in the six-minute walk test, CRFA, CRF6MWD, and CRFDASI were equivalent. CONCLUSION: A non-exercise algorithm can estimate cardiorespiratory fitness in patients presenting for elective surgery. The variables required to compute CRFA can be obtained in a clinic setting without the need to engage in formal exercise testing. Further evaluation of CRFA as a predictor of long-term outcome in patients is warranted.


Assuntos
Aptidão Cardiorrespiratória/fisiologia , Teste de Esforço/métodos , Cuidados Pré-Operatórios/métodos , Inquéritos e Questionários , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Procedimentos Cirúrgicos Operatórios
10.
Hypertension ; 67(5): 1038-44, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26928803

RESUMO

This study was undertaken to determine whether perinatal maternal resveratrol (Resv)--a phytoalexin known to confer cardiovascular protection--could prevent the development of hypertension and improve vascular function in adult spontaneously hypertensive rat offspring. Dams were fed either a control or Resv-supplemented diet (4 g/kg diet) from gestational day 0.5 until postnatal day 21. Indwelling catheters were used to assess blood pressure and vascular function in vivo; wire myography was used to assess vascular reactivity ex vivo. Perinatal Resv supplementation in dams had no effect on fetal body weights, albeit continued maternal treatment postnatally resulted in growth restriction in offspring by postnatal day 21; growth restriction was no longer evident after 5 weeks of age. Maternal perinatal Resv supplementation prevented the onset of hypertension in adult offspring (-18 mm Hg; P=0.007), and nitric oxide synthase inhibition (with L-NG-nitroarginine methyl ester) normalized these blood pressure differences, suggesting improved nitric oxide bioavailability underlies the hemodynamic alterations in the Resv-treated offspring. In vivo and ex vivo, vascular responses to methylcholine were not different between treatment groups, but prior treatment with L-NG-nitroarginine methyl ester attenuated the vasodilation in untreated, but not Resv-treated adult offspring, suggesting a shift toward nitric oxide-independent vascular control mechanisms in the treated group. Finally, bioconversion of the inactive precursor big endothelin-1 to active endothelin-1 in isolated mesenteric arteries was reduced in Resv-treated offspring (-28%; P<0.05), and this difference could be normalized by L-NG-nitroarginine methyl ester treatment. In conclusion, perinatal maternal Resv supplementation mitigated the development of hypertension and causes persistent alterations in vascular responsiveness in spontaneously hypertensive rats.


Assuntos
Suplementos Nutricionais , Hipertensão/prevenção & controle , Prenhez , Estilbenos/farmacologia , Adulto , Crianças Adultas , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Assistência Perinatal/métodos , Gravidez , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Valores de Referência , Resveratrol
11.
A A Case Rep ; 6(6): 160-2, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26825990

RESUMO

Pseudotumor cerebri syndrome (PTCS) is a rare disorder chiefly observed in obese women of childbearing age. We describe a case of a parturient with PTCS managed successfully with an intrathecal catheter, after inadvertent dural puncture, for labor analgesia, surgical anesthesia, and treatment of headache because of intracranial hypertension during the peripartum period. Prolonged placement of the intrathecal catheter (i.e., >24 hours) may have contributed to the absence of postdural puncture headache symptoms and an uneventful postpartum period. Intrathecal catheter placement may therefore be a viable option in patients with PTCS should inadvertent dural puncture occur.


Assuntos
Analgesia Obstétrica/métodos , Cateterismo/instrumentação , Pseudotumor Cerebral/tratamento farmacológico , Adulto , Parto Obstétrico , Feminino , Humanos , Injeções Espinhais , Cefaleia Pós-Punção Dural/prevenção & controle , Gravidez
14.
Hypertension ; 62(4): 753-8, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23940196

RESUMO

Prenatal hypoxia can alter the growth trajectory of the fetus and cause lasting health complications including vascular dysfunction. We hypothesized that offspring that were intrauterine growth restricted (IUGR) because of prenatal hypoxia would exhibit altered vascular endothelin-1 (ET-1) signaling in later life. Isolated mesenteric artery responses to big ET-1 (bET-1) and ET-1 were assessed by using wire myography. Male IUGR offspring had 3-fold greater bET-1-induced vasoconstriction compared with controls (n=7 per group; P<0.001); NO synthase inhibition with L-N(G)-nitro-arginine-methyl ester potentiated bET-1-induced vasoconstriction, albeit this effect was 2-fold greater (P<0.05) in male control compared with IUGR offspring. Vascular responses to bET-1 were similar between female IUGR and control offspring (n=9-11 per group). In the presence of L-N(G)-nitro-arginine-methyl ester, pretreatment with the chymase inhibitor chymostatin, the gelatinase inhibitor GM6001, or the neutral endopeptidase inhibitor thiorphan did not alter responses to bET-1; however, the ET-converting enzyme inhibitor CGS35066 almost completely abolished vascular responses to bET-1 in control and IUGR groups. Systolic blood pressure in IUGR male offspring was more responsive to ET-1 antagonism in vivo compared with controls (-9 versus -4 mm Hg; n=5 per group; P=0.02); no such differences were observed in female offspring (n=5-6 per group). These results demonstrate that vascular ET-1 function is programmed by prenatal hypoxia and provide further insights into the sex differences in the long-term vascular effects of developmental stressors.


Assuntos
Endotelina-1/farmacologia , Retardo do Crescimento Fetal/fisiopatologia , Hipóxia/fisiopatologia , Artérias Mesentéricas/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Retardo do Crescimento Fetal/etiologia , Hipóxia/complicações , Masculino , Artérias Mesentéricas/fisiopatologia , Óxido Nítrico/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia
15.
Anesth Analg ; 116(4): 775-83, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23429803

RESUMO

BACKGROUND: Both propofol use and advanced age are predictors of intraoperative hypotension. We previously demonstrated that propofol enhances vasodilation in mesenteric arteries from aged rats, partly due to increased nitric oxide (NO) bioavailability. Patients chronically treated with angiotensin-converting enzyme (ACE) inhibitors may exhibit refractory hypotension under general anesthesia. We hypothesized that propofol enhances NO-mediated vasodilation in arteries from aged rats chronically treated with ACE inhibitors. METHODS: Sprague-Dawley rats aged 12 to 13 months were treated with or without captopril for 7 to 8 weeks, yielding a final age of 14 to 15 months at the time of experimentation. Before euthanasia, arterial blood pressures were obtained through carotid artery cannulation. Concentration-response curves to propofol (0.1-100 µM) or methacholine (MCh) (0.01-3 µM) were then assessed on isolated resistance mesenteric arteries (100-200 µm diameter) from both treatment (captopril) and control rats. MCh relaxation was also assessed after propofol pretreatment (1 and 10 µM). N(G)-nitro-l-arginine methyl ester (l-NAME) (100 µM) and meclofenamate (10 µM) were used to inhibit NO and prostaglandin synthesis, respectively. Concentration-response data were summarized as 50% of the maximum relaxation response or area under the curve. RESULTS: Mean arterial blood pressure in the captopril-treated rats was lower than in untreated rats (P = 0.049). When comparing relaxation in arteries from captopril-treated versus untreated rats, concentration-response curves revealed that captopril-treated rats display greater direct propofol relaxation (P = 0.018). MCh relaxation in the absence of propofol, however, was not different between captopril-treated and untreated rats (P = 0.80). Propofol pretreatment increased MCh relaxation in arteries from captopril-treated compared with untreated rats (P = 0.029 for 1 µM and P = 0.020 for 10 µM). Meclofenamate did not have an effect in this response (P = 0.22). l-NAME-dependent inhibition of MCh relaxation, however, was greater in arteries from control compared with captopril-treated rats (P = 0.0077). However, propofol increased the proportion of NO-dependent vasodilation to MCh similarly in both groups. This suggests that other vasodilatory pathways are involved in the differential response to MCh in the presence of propofol in captopril-treated rats. CONCLUSIONS: Our results show that mesenteric arterial relaxation in response to propofol, both by direct stimulation and through modulation of endothelium-dependent mechanisms, is, in part, NO-dependent. In captopril-treated rats, propofol further increased arterial relaxation through a non-NO-dependent vasodilating pathway (e.g., endothelium-derived hyperpolarizing factor), which may account for enhanced vasodilation during propofol exposure in patients treated with ACE inhibitors.


Assuntos
Envelhecimento/fisiologia , Anestésicos Intravenosos/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Propofol/farmacologia , Animais , Área Sob a Curva , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/fisiologia , Inibidores Enzimáticos/farmacologia , Cloreto de Metacolina/farmacologia , Agonistas Muscarínicos/farmacologia , Relaxamento Muscular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Vasoconstritores/farmacologia
16.
Front Physiol ; 3: 74, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22485091

RESUMO

The proportion of elderly people in the population is steadily increasing, and the inevitable consequence is that this subpopulation is more frequently represented in common medical procedures and surgeries. Understanding the circulatory changes that accompany the aging process is therefore becoming increasingly timely and relevant. In this short review, we discuss aspects of vascular control in aging that are particularly relevant in the maintenance of intraoperative hemodynamic stability. We subsequently review the effects of certain notable anesthetic agents with respect to the aging vasculature.

18.
Am J Physiol Heart Circ Physiol ; 297(1): H466-74, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19465540

RESUMO

Hypotension following administration of propofol, an anesthetic agent, is strongly predicted by advanced age and is partly due to direct vasodilation. We hypothesized that propofol increases nitric oxide (NO)-mediated vasodilation by enhancing its bioavailability in the aged adult vasculature, leading to greater vasodilation than in the young adult. Small mesenteric arteries from rats aged 13-15 versus 3 to 4 mo were compared in this study. Reactivity to propofol (1-100 microM) alone and with the addition of acetylcholine (ACh; 0.1-10 microM) in endothelial-intact and dunuded arteries following phenylephrine constriction was assessed using myography. N(G)-nitro-L-arginine methyl ester (L-NAME) and meclofenamate (Meclo) were used to inhibit NO and prostaglandin synthesis, respectively. Superoxide dismutase (SOD) and catalase were used as antioxidants during ACh relaxation and were compared with propofol in aging arteries. Propofol alone induced greater relaxation in 1) endothelial-intact compared with denuded arteries and 2) aged compared with young arteries, which were inhibited by L-NAME. ACh-induced relaxation was greater in young compared with aged control arteries; however, propofol pretreatment increased this relaxation in aged but not in young arteries. Additionally, propofol inhibited ACh-induced relaxation in arteries treated with L-NAME + Meclo [relaxation attributed to endothelium-derived hyperpolarizing factor (EDHF)]. Pretreatment with SOD and catalase increased relaxation to ACh in aged arteries similar to propofol. In conclusion, propofol causes relaxation in small mesenteric arteries in an endothelial-dependent and independent manner and increases ACh-induced relaxation in aged arteries. Interestingly, propofol inhibits EDHF-mediated relaxation but increases availability of NO, which leads to overall vascular relaxation.


Assuntos
Envelhecimento/fisiologia , Hipnóticos e Sedativos/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Propofol/farmacologia , Acetilcolina/farmacologia , Animais , Antioxidantes/farmacologia , Fatores Biológicos/fisiologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Depuradores de Radicais Livres/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Fenilefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Circulação Esplâncnica/efeitos dos fármacos , Circulação Esplâncnica/fisiologia , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
20.
Drugs Aging ; 22(10): 823-44, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16245957

RESUMO

The historical basis for understanding erectile function as a neurovascular phenomenon and the advance from fanciful to effective treatment of erectile dysfunction (ED) are reviewed, with emphasis on patients with cardiovascular disease (CVD). ED occurs in 60% of CVD patients by 40 years of age. Male ED and female sexual dysfunction (FSD) diminish quality of life and often warn of occult CVD. ED is often unrecognised but is readily diagnosed during a 5-minute interview using a truncated International Index of Erectile Function questionnaire. Erection of the penis and clitoral engorgement result from local, arousal-induced release of neuronal and endothelial-derived nitric oxide (NO). Arterial vasodilatation and relaxation of cavernosal smooth muscle cells cause arterial blood to flood trabecular spaces, compressing venous drainage, resulting in tumescence. Cyclic guanosine monophosphate (cGMP)-induced activation of protein kinase G mediates the effects of NO by enhancing calcium sequestration and activating large-conductance, calcium-sensitive K+ channels. Future treatment strategies will likely enhance these pathways. Phosphodiesterase-5 inhibitors (sildenafil, tadalafil and vardenafil) increase cGMP levels in erectile tissue. These agents are effective in 80% of CVD patients with ED and can be used safely, even in the presence of stable coronary disease or congestive heart failure, provided nitrates are avoided and patients do not have hypotension, severe aortic stenosis or evocable myocardial ischaemia. Second-line therapies (vacuum constrictor device and transurethral or intracavernosal prostaglandin E1) can also be used in CVD patients. Treatment of FSD and its relationship to CVD are less well established, but similarities to ED exist. ED can be prevented by reduction of CVD risk factors, exercise, weight loss and abstinence from smoking.


Assuntos
Doenças Cardiovasculares/complicações , Inibidores de Fosfodiesterase , Diester Fosfórico Hidrolases/metabolismo , Disfunções Sexuais Psicogênicas , 3',5'-GMP Cíclico Fosfodiesterases , Doenças Cardiovasculares/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Disfunção Erétil/enzimologia , Disfunção Erétil/etiologia , Disfunção Erétil/terapia , Feminino , Humanos , Masculino , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/efeitos adversos , Inibidores de Fosfodiesterase/uso terapêutico , Fatores de Risco , Disfunções Sexuais Psicogênicas/enzimologia , Disfunções Sexuais Psicogênicas/etiologia , Disfunções Sexuais Psicogênicas/terapia
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