Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 15.919
Filtrar
1.
Toxicol Lett ; 341: 23-32, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33476711

RESUMO

Mercury is an environmental pollutant and a threat to human health. Mercuric chloride (HgCl2)-induced acute renal failure has been described by several reports, but the mechanisms of renal dysfunction remain elusive. This study tested the hypothesis that HgCl2 directly impairs renal vascular reactivity. Additionally, due to the mercury toxicity on the proximal tubule, we investigated whether the HgCl2-induced natriuresis is accompanied by inhibition of Na+/H+ exchanger isoform-3 (NHE3). We found that 90-min HgCl2 infusion (6.5 µg/kg i.v.) remarkably increased urinary output, reduced GFR and renal blood flow, and increased vascular resistance in rats. "In vitro" experiments of HgCl2 infusion in isolated renal vascular bed demonstrated an elevation of perfusion pressure in a concentration- and time-dependent manner, associated with changes on the endothelium-dependent vasodilatation and the flow-pressure relationship. Moreover, by employing "in vivo" stationary microperfusion of the proximal tubule, we found that HgCl2 inhibits NHE3 activity and increases the phosphorylation of NHE3 at serine 552 in the renal cortex, in line with the HgCl2-induced diuresis. Changes in renal proximal tubular function induced by HgCl2 were parallel to increased urinary markers of proximal tubular injury. Besides, atomic spectrometry showed that mercury accumulated in the renal cortex. We conclude that acute HgCl2 exposure causes renal vasoconstriction that is associated with reduced endothelial vasodilator agonist- and flow-mediated responses and inhibition of NHE3-mediated sodium reabsorption. Thus, our data suggest that HgCl2-induced acute renal failure may be attributable at least in part by its direct effects on renal hemodynamics and NHE3 activity.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Rim/irrigação sanguínea , Cloreto de Mercúrio/toxicidade , Trocador 3 de Sódio-Hidrogênio/antagonistas & inibidores , Animais , Poluentes Ambientais/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Resistência Vascular/efeitos dos fármacos
2.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 184-191, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093782

RESUMO

Sarcoidosis-Associated Pulmonary Hypertension (SAPH) is a common finding in patients with chronic sarcoidosis and is associated with increased mortality. The optimal treatment for SAPH is not known; however, therapies approved for Group 1 pulmonary hypertension have improved hemodynamics and functional status. Prostanoids, including epoprostenol, have been therapeutic in short-term studies of SAPH, but long-term efficacy is unknown. In this study, we evaluated the long-term effect of epoprostenol therapy in 12 patients with SAPH. Hemodynamic assessment after an average of 4.1 years of epoprostenol therapy demonstrated significant improvement in mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output; furthermore, patients demonstrated improved NYHA functional class. To evaluate further the long-term effect of epoprostenol, we compared survival of SAPH patients to a cohort of hemodynamically matched patients from the same center treated with epoprostenol for Idiopathic Pulmonary Arterial Hypertension (IPAH). Interestingly, there was no difference in survival, despite the additional systemic disease burden of the SAPH subjects. Subgroup analysis by Scadding stage demonstrated that Scadding stages 1-3 had improved survival compared to Scadding stage 4. These observations suggest that epoprostenol is an effective long-term therapy for patients with SAPH; it improves hemodynamics, functional class, and provides survival similar to that seen in a hemodynamically-matched cohort of IPAH patients. Furthermore, we identify a subgroup of SAPH patients (nonfibrotic lung disease Scadding 1-3) who may derive significant benefit from prostanoid therapy. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 184-191).


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Epoprostenol/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Artéria Pulmonar/efeitos dos fármacos , Sarcoidose/complicações , Adulto , Anti-Hipertensivos/efeitos adversos , Débito Cardíaco/efeitos dos fármacos , Doença Crônica , Epoprostenol/efeitos adversos , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Sarcoidose/diagnóstico , Sarcoidose/tratamento farmacológico , Fatores de Tempo , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos
3.
PLoS One ; 15(8): e0232302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822373

RESUMO

Sepsis is a life-threatening condition due to a dysregulated immunological response to infection. Apart from source control and broad-spectrum antibiotics, management is based on fluid resuscitation and vasoactive drugs. Fluid resuscitation implicates the risk of volume overload, which in turn is associated with longer stay in intensive care, prolonged use of mechanical ventilation and increased mortality. Antisecretory factor (AF), an endogenous protein, is detectable in most tissues and in plasma. The biologically active site of the protein is located in an 8-peptide sequence, contained in a synthetic 16-peptide fragment, named AF-16. The protein as well as the peptide AF-16 has multiple modulatory effects on abnormal fluid transport and edema formation/resolution as well as in a variety of inflammatory conditions. Apart from its' anti-secretory and anti-inflammatory characteristics, AF is an inhibitor of capillary leakage in intestine. It is not known whether the protein AF or the peptide AF-16 can ameliorate symptoms in sepsis. We hypothesized that AF-16 decreases the degree of hemodynamic instability, the need of fluid resuscitation, vasopressor dose and tissue edema in fecal peritonitis. To test the hypothesis, we induced peritonitis and sepsis by injecting autologous fecal solution into abdominal cavity of anesthetized pigs, and randomized (in a blind manner) the animals to intervention (AF-16, n = 8) or control (saline, n = 8) group. After the onset of hemodynamic instability (defined as mean arterial pressure < 60 mmHg maintained for > 5 minutes), intervention with AF-16 (20 mg/kg (50 mg/ml) in 0.9% saline) intravenously (only the vehicle in the control group) and a protocolized resuscitation was started. We recorded respiratory and hemodynamic parameters hourly for twenty hours or until the animal died and collected post mortem tissue samples at the end of the experiment. No differences between the groups were observed regarding hemodynamics, overall fluid balance, lung mechanics, gas exchange or histology. However, liver wet-to-dry ratio remained lower in AF-16 treated animals as compared to controls, 3.1 ± 0.4, (2.7-3.5, 95% CI, n = 8) vs 4.0 ± 0.6 (3.4-4.5, 95% CI, n = 8), p = 0.006, respectively. Bearing in mind the limited sample size, this experimental pilot study suggests that AF-16 may inhibit sepsis induced liver edema in peritonitis-sepsis.


Assuntos
Edema/tratamento farmacológico , Peptídeos/farmacologia , Peritonite/complicações , Sepse/complicações , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Edema/complicações , Edema/patologia , Edema/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Hemoglobinas/metabolismo , Interleucina-6/sangue , Lactatos/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Peptídeos/uso terapêutico , Projetos Piloto , Troca Gasosa Pulmonar/efeitos dos fármacos , Suínos , Fator de Necrose Tumoral alfa/sangue , Resistência Vascular/efeitos dos fármacos
5.
Int Heart J ; 61(4): 799-805, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32728000

RESUMO

Therapeutic strategies for pulmonary arterial hypertension (PAH) have made remarkable progress over the last two decades. Currently, 3 types of drugs can be used to treat PAH; prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists (ERA). In Japan, the first generation ERA bosentan was reimbursed in 2005, following which the 2nd generation ERAs ambrisentan and macitentan were reimbursed in 2009 and 2015, respectively. The efficacy of each ERA on hemodynamics in PAH patients remains to be elucidated. The aims of this study were to evaluate the hemodynamic effects of ERAs and compare these effects among each generation of ERAs.We retrospectively examined the clinical parameters of 42 PAH patients who were prescribed an ERA (15 bosentan, 12 ambrisentan, and 15 macitentan) and who underwent a hemodynamic examination before and after ERA introduction at our institution from January 2007 to July 2019.In a total of 42 patients, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were significantly decreased and cardiac index was significantly increased after ERA introduction (P < 0.001) and the World Health Organization-Functional class (WHO-Fc) was significantly improved after ERA introduction (P = 0.005). Next, in a comparison between 1st and 2nd generation ERAs, 2nd generation ERAs were found to have brought about greater improvements in hemodynamic parameters (mPAP and PVR. P < 0.01), heart rate, brain natriuretic peptide, arterial oxygen saturation, and mixed venous oxygen saturation than the 1st generation ERA bosentan.We conclude that all ERAs could successfully improve the hemodynamics of PAH patients and that the newer generation ERAs, ambrisentan and macitentan, seemed to be preferable to bosentan.


Assuntos
Bosentana/uso terapêutico , Antagonistas dos Receptores de Endotelina/uso terapêutico , Fenilpropionatos/uso terapêutico , Hipertensão Arterial Pulmonar/tratamento farmacológico , Piridazinas/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Administração Oral , Adulto , Idoso , Bosentana/administração & dosagem , Estudos de Casos e Controles , Antagonistas dos Receptores de Endotelina/administração & dosagem , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenilpropionatos/administração & dosagem , Inibidores da Fosfodiesterase 5/uso terapêutico , Placebos/administração & dosagem , Prostaglandinas I/uso terapêutico , Hipertensão Arterial Pulmonar/fisiopatologia , Pressão Propulsora Pulmonar/efeitos dos fármacos , Piridazinas/administração & dosagem , Pirimidinas/administração & dosagem , Estudos Retrospectivos , Sulfonamidas/administração & dosagem , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos
6.
J Interv Cardiol ; 2020: 5036396, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32728350

RESUMO

Objectives: We aimed to identify mechanical and pharmacological revascularization strategies correlated with the index of microcirculatory resistance (IMR) in ST-elevation myocardial infarction (STEMI) patients. Background: Microvascular dysfunction (MVD) after STEMI is correlated with infarct size and poor long-term prognosis, and the IMR is a useful analytical method for the quantitative assessment of MVD. However, therapeutic strategies that can reliably reduce MVD remain uncertain. Methods: Patients with STEMI who underwent primary percutaneous coronary intervention (PCI) were enrolled. The IMR was measured with a pressure sensor/thermistor-tipped guidewire immediately after primary PCI. High IMR was defined as values ≥66th percentile of IMR in enrolled patients (IMR > 30.9 IU). Results: A total of 160 STEMI patients were analyzed (high IMR = 54 patients). Clinical factors for Killip class (P=0.006), delayed hospitalization from symptom onset (P=0.004), peak troponin-I level (P=0.042), and multivessel disease (P=0.003) were associated with high IMR. Achieving final thrombolysis in myocardial infarction myocardial perfusion grade 3 tended to be associated with low IMR (P=0.119), whereas the presence of distal embolization was significantly associated with high IMR (P=0.034). In terms of therapeutic strategies that involved adjusting clinical and angiographic factors associated with IMR, preloading of third-generation P2Y12 inhibitors correlated with reducing IMR value (ß = -10.30, P < 0.001). Mechanical therapeutic strategies including stent diameter/length, preballoon dilatation, direct stenting, and thrombectomy were not associated with low IMR value (all P > 0.05), and postballoon dilatation was associated with high IMR (ß = 8.30, P=0.020). Conclusions: In our study, mechanical strategies were suboptimal in achieving myocardial salvage. Preloading of third-generation P2Y12 inhibitors revealed decreased IMR value, indicative of MVD prevention.


Assuntos
Microcirculação/efeitos dos fármacos , Intervenção Coronária Percutânea , Complicações Pós-Operatórias , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Infarto do Miocárdio com Supradesnível do Segmento ST , Stents/classificação , Angiografia Coronária/métodos , Circulação Coronária/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/instrumentação , Intervenção Coronária Percutânea/métodos , Inibidores da Agregação de Plaquetas/administração & dosagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Prevenção Secundária/métodos , Trombectomia/métodos , Resistência Vascular/efeitos dos fármacos
7.
Am J Respir Cell Mol Biol ; 63(4): 510-518, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32609558

RESUMO

Optimal oxygen saturation as measured by pulse oximetry (SpO2) in neonatal lung injury, such as meconium aspiration syndrome (MAS) and persistent pulmonary hypertension of newborn (PPHN), is not known. Our goal was to determine the SpO2 range in lambs with MAS and PPHN that results in the highest brain oxygen delivery (bDO2) and pulmonary blood flow (Qp) and the lowest pulmonary vascular resistance and oxidative stress. Meconium was instilled into endotracheal tubes in 25 near-term gestation lambs, and the umbilical cord was occluded to induce asphyxia and gasping, causing MAS and PPHN. Lambs were randomized into four groups and ventilated for 6 hours with fixed fraction of inspired oxygen (FiO2) = 1.0 irrespective of SpO2, and three groups had FiO2 titrated to keep preductal SpO2 between 85% and 89%, 90% and 94%, and 95% and 99%, respectively. Tissues were collected to measure nitric oxide synthase activity, 3-nitrotyrosine, and 8-isoprostanes. Throughout the 6-hour exposure period, lambs in the 95-99% SpO2 target group had the highest Qp, lowest pulmonary vascular resistance, and highest bDO2 but were exposed to higher FiO2 (0.5 ± 0.21 vs. 0.29 ± 0.17) with higher lung 3-nitrotyrosine (0.67 [interquartile range (IQR), 0.43-0.73] ng/mcg protein vs. 0.1 [IQR, 0.09-0.2] ng/mcg protein) and lower lung nitric oxide synthase activity (196 [IQR, 192-201] mMol nitrite/mg protein vs. 270 [IQR, 227-280] mMol nitrite/mg protein) compared with the 90-94% target group. Brain 3-nitrotyrosine was lower in the 85-89% target group, and brain/lung 8-isoprostane levels were not significantly different. In term lambs with MAS and PPHN, Qp and bDO2 through the first 6 hours are higher with target SpO2 in the 95-99% range. However, the 90-94% target range is associated with significantly lower FiO2 and lung oxidative stress. Clinical trials comparing the 90-94% versus the 95-99% SpO2 target range in term infants with PPHN are warranted.


Assuntos
Hipertensão Pulmonar/metabolismo , Pulmão/metabolismo , Síndrome de Aspiração de Mecônio/metabolismo , Oxigênio/metabolismo , Animais , Animais Recém-Nascidos , Dinoprosta/análogos & derivados , Dinoprosta/farmacologia , Feminino , Hipertensão Pulmonar/tratamento farmacológico , Pulmão/efeitos dos fármacos , Masculino , Síndrome de Aspiração de Mecônio/tratamento farmacológico , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oximetria/métodos , Síndrome da Persistência do Padrão de Circulação Fetal/tratamento farmacológico , Síndrome da Persistência do Padrão de Circulação Fetal/metabolismo , Gravidez , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Ovinos/metabolismo , Tirosina/análogos & derivados , Tirosina/farmacologia , Resistência Vascular/efeitos dos fármacos
8.
J Cardiovasc Magn Reson ; 22(1): 50, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32698897

RESUMO

BACKGROUND: Bronchopulmonary dysplasia (BPD) associated with pulmonary hypertension (PH) is a significant source of morbidity and mortality in premature infants. Recent advances have allowed the use of cardiovascular magnetic resonance (CMR) in the assessment of respiratory and cardiac disease in infants with BPD. In adults and older pediatric patients, decreased CMR interventricular septal curvature correlates with increased mean pulmonary artery pressure and pulmonary vascular resistance. The current study sought to determine the relationship of CMR derived septal curvature in neonates with BPD and BPD-PH with a need for PH therapy. METHODS: Forty moderate or severe BPD and 12 mild BPD or control infants were imaged without contrast between 38 and 47 weeks post-menstrual age on a neonatal-sized, neonatal intensive care unit-sited 1.5 T CMR scanner. CMR indices including eccentricity index (CMR-EI) and septal curvature were measured and compared to BPD severity and clinical outcomes including hospital length of stay (LOS), duration of respiratory support, respiratory support level at discharge and PH therapy. RESULTS: CMR-EI was directly associated and septal curvature was inversely associated with BPD severity. In a univariate analysis, CMR-EI and septal curvature were associated with increased hospital LOS, duration of respiratory support, respiratory support at hospital discharge, and need for PH therapy. In multivariable analysis CMR-EI was associated with hospital LOS and duration of respiratory support and septal curvature was associated with respiratory support at hospital discharge. Septal curvature was the only clinical or CMR variable associated with need for PH therapy (R2 = 0.66, p = 0.0014) in multivariable analysis demonstrating improved discrimination beyond CMR-EI. CONCLUSIONS: CMR derived septal curvature correlates significantly with clinical outcomes including hospital LOS, duration of respiratory support, respiratory support level at hospital discharge, and PH therapy in neonates with BPD and BPD-PH. Further, CMR derived septal curvature demonstrated improved discrimination of need for PH therapy and respiratory support at discharge compared to clinical variables and other CMR indices, supporting septal curvature as a non-invasive marker of PH in this population with potential to guide management strategies.


Assuntos
Pressão Arterial , Displasia Broncopulmonar/diagnóstico por imagem , Hipertensão Pulmonar/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Artéria Pulmonar/fisiopatologia , Resistência Vascular , Septo Interventricular/diagnóstico por imagem , Anti-Hipertensivos/uso terapêutico , Pressão Arterial/efeitos dos fármacos , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/fisiopatologia , Displasia Broncopulmonar/terapia , Feminino , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Recém-Nascido , Tempo de Internação , Masculino , Valor Preditivo dos Testes , Artéria Pulmonar/efeitos dos fármacos , Terapia Respiratória , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos , Septo Interventricular/efeitos dos fármacos , Septo Interventricular/fisiopatologia
9.
Diab Vasc Dis Res ; 17(5): 1479164120930589, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32589047

RESUMO

BACKGROUND: In many cases, Ilomedin® infusions are applied as part of a perioperative measure in patients with peripheral arterial occlusive disease because it makes a relevant vasodilatatory effect in patients with type 2 diabetes mellitus and with/without peripheral neuropathy. AIMS: A prospective case-control study was performed to investigate the effect of prostanoids on peripheral resistance in patients with type 2 diabetes mellitus and patients without type 2 diabetes mellitus, as well as the role of peripheral neuropathy in patients undergoing arterial reconstruction. METHODS: Sixty patients undergoing arterial reconstruction were enrolled. Sufficient data were collected on 38 patients. Prior to surgery, peripheral nerve conduction velocity was measured. Blood flow volume at the common femoral artery was assessed intraoperatively using a Doppler flowmeter at four time points: at baseline before arterial reconstruction (T0), after reconstruction (T1), after 5 (T2) and 10 min (T3) after intra-arterial application of 3000 ng of Ilomedin. Peripheral resistance units were calculated as a function of mean arterial pressure and flow volume using the following formula: peripheral resistance unit = mean arterial pressure (mm Hg) / flow volume (mL/min). RESULTS: Ilomedin produced an immediate and significant drop of peripheral resistance in patients without type 2 diabetes mellitus as well as in patients with type 2 diabetes mellitus. Patients with peripheral neuropathy showed a less pronounced effect to Ilomedin compared to individuals with normal nerve conduction velocity.


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Iloprosta/administração & dosagem , Doença Arterial Periférica/tratamento farmacológico , Doença Arterial Periférica/cirurgia , Resistência Vascular/efeitos dos fármacos , Procedimentos Cirúrgicos Vasculares , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Humanos , Iloprosta/efeitos adversos , Infusões Intra-Arteriais , Cuidados Intraoperatórios , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Estudos Prospectivos , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Vasodilatadores/efeitos adversos , Adulto Jovem
10.
J Surg Res ; 253: 127-138, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32353638

RESUMO

BACKGROUND: Noncompressible hemorrhage is the leading cause of preventable death in military and civilian trauma. Our aim was to examine the effect of adenosine, lidocaine, and magnesium (Mg2+; ALM) on cardiovascular and cerebral function in a porcine hepatic hemorrhage model. MATERIALS AND METHODS: Pigs (59.1 ± 0.34 kg) were anesthetized, instrumented, and randomly assigned into sham (n = 6), saline controls (n = 10) or ALM (n = 10) groups before laparoscopic liver resection. After 30 min, groups received 4 mL/kg 3% NaCl ± ALM bolus (Phase 1) followed 60 min later with 3 mL/kg/h 0.9% NaCl ± ALM drip (4 h; Phase 2), then transfusion. Hemodynamics, carotid artery flow, and intracranial pressure were measured continuously. Microdialysis samples were analyzed for metabolites. RESULTS: Saline controls had 20% mortality (mean survival time: 307 ± 38 min) with no ALM deaths over 6 h. Bolus administration increased mean arterial pressure (MAP) in both groups, and drip led to further increases to 62 ± 10 mmHg in controls compared with a steady fall to 47 ± 8 mmHg in ALM group at 240 min. The lower MAP was associated with a dramatic fall in systemic vascular resistance and improved oxygen delivery. ALM drip significantly increased cardiac output and stroke volume with lower dP/dtMin, indicating a less stiff heart. ALM drip also significantly decreased cerebral perfusion pressure, reduced cerebral oxygen consumption (28%), and reduced brain glycerol (60%), lactate (47%), and relative expression of hypoxia-inducible factor (38%) compared with saline controls. CONCLUSIONS: ALM therapy improved cardiac function and oxygen delivery by lowering systemic vascular resistance after noncompressible hemorrhage. ALM also appeared to protect the brain at hypotensive MAPs with significantly lower cerebral perfusion pressure, lower O2 consumption, and significantly lower cortical lactate and glycerol levels compared to saline controls.


Assuntos
Hidratação/métodos , Hipotensão/terapia , Hipóxia Encefálica/prevenção & controle , Ressuscitação/métodos , Choque Hemorrágico/terapia , Adenosina/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Modelos Animais de Doenças , Esquema de Medicação , Quimioterapia Combinada/métodos , Feminino , Glicerol/análise , Humanos , Hipotensão/etiologia , Hipóxia Encefálica/etiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Infusões Intravenosas/métodos , Injeções Intravenosas/métodos , Ácido Láctico/análise , Lidocaína/administração & dosagem , Fígado/irrigação sanguínea , Fígado/lesões , Magnésio/administração & dosagem , Oxigênio/metabolismo , Choque Hemorrágico/etiologia , Volume Sistólico/efeitos dos fármacos , Sus scrofa , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
11.
PLoS One ; 15(5): e0233176, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421724

RESUMO

INTRODUCTION: Levosimendan is approved for acute heart failure. Within this context, pulmonary hypertension represents a frequent co-morbidity. Hence, the effects of levosimendan on segmental pulmonary vascular resistance (PVR) are relevant. So far, this issue has been not studied. Beyond that the relaxant effects of levosimendan in human pulmonary vessel are unknown. We addressed these topics in rats' isolated perfused lungs (IPL) and human precision-cut lung slices (PCLS). MATERIAL AND METHODS: In IPL, levosimendan (10 µM) was perfused in untreated and endothelin-1 pre-contracted lungs. The pulmonary arterial pressure (PPA) was continuously recorded and the capillary pressure (Pcap) was determined by the double-occlusion method. Thereafter, segmental PVR, expressed as precapillary (Rpre) and postcapillary resistance (Rpost) and PVR were calculated. Human PCLS were prepared from patients undergoing lobectomy. Levosimendan-induced relaxation was studied in naïve and endothelin-1 pre-contracted PAs and PVs. In endothelin-1 pre-contracted PAs, the role of K+-channels was studied by inhibition of KATP-channels (glibenclamide), BKCa2+-channels (iberiotoxin) and Kv-channels (4-aminopyridine). All changes of the vascular tone were measured by videomicroscopy. In addition, the increase of cAMP/GMP due to levosimendan was measured by ELISA. RESULTS: Levosimendan did not relax untreated lungs or naïve PAs and PVs. In IPL, levosimendan attenuated the endothelin-1 induced increase of PPA, PVR, Rpre and Rpost. In human PCLS, levosimendan relaxed pre-contracted PAs or PVs to 137% or 127%, respectively. In pre-contracted PAs, the relaxant effect of levosimendan was reduced, if KATP- and Kv-channels were inhibited. Further, levosimendan increased cGMP in PAs/PVs, but cAMP only in PVs. DISCUSSION: Levosimendan reduces rats' segmental PVR and relaxes human PAs or PVs, if the pulmonary vascular tone is enhanced by endothelin-1. Regarding levosimendan-induced relaxation, the activation of KATP- and Kv-channels is of impact, as well as the formation of cAMP and cGMP. In conclusion, our results suggest that levosimendan improves pulmonary haemodynamics, if PVR is increased as it is the case in pulmonary hypertension.


Assuntos
Hipertensão Pulmonar , Pulmão , Artéria Pulmonar , Veias Pulmonares , Simendana/farmacologia , Resistência Vascular/efeitos dos fármacos , Animais , Feminino , Humanos , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Perfusão , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Veias Pulmonares/metabolismo , Veias Pulmonares/fisiopatologia , Ratos , Ratos Wistar
13.
Am J Physiol Regul Integr Comp Physiol ; 318(4): R822-R827, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32130026

RESUMO

Profound increases (>15 mmHg) in arterial carbon dioxide (i.e., hypercapnia) reduce renal blood flow. However, a relatively brief and mild hypercapnia can occur in patients with sleep apnea or in those receiving supplemental oxygen therapy during an acute exacerbation of chronic obstructive pulmonary disease. We tested the hypothesis that a brief, mild hypercapnic exposure increases vascular resistance in the renal and segmental arteries. Blood velocity in 14 healthy adults (26 ± 4 yr; 7 women, 7 men) was measured in the renal and segmental arteries with Doppler ultrasound while subjects breathed room air (Air) and while they breathed a 3% CO2, 21% O2, 76% N2 gas mixture for 5 min (CO2). The end-tidal partial pressure of CO2 ([Formula: see text]) was measured via capnography. Mean arterial pressure (MAP) was measured beat to beat via the Penaz method. Vascular resistance in the renal and segmental arteries was calculated as MAP divided by blood velocity. [Formula: see text] increased with CO2 (Air: 45 ± 3, CO2: 48 ± 3 mmHg, P < 0.01), but there were no changes in MAP (P = 0.77). CO2 decreased blood velocity in the renal (Air: 35.2 ± 8.1, CO2: 32.2 ± 7.3 cm/s, P < 0.01) and segmental (Air: 24.2 ± 5.1, CO2: 21.8 ± 4.2 cm/s, P < 0.01) arteries and increased vascular resistance in the renal (Air: 2.7 ± 0.9, CO2: 3.0 ± 0.9 mmHg·cm-1·s, P < 0.01) and segmental (Air: 3.9 ± 1.0, CO2: 4.4 ± 1.0 mmHg·cm-1·s, P < 0.01) arteries. These data provide evidence that the kidneys are hemodynamically responsive to a mild and acute hypercapnic stimulus in healthy humans.


Assuntos
Dióxido de Carbono/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipercapnia/fisiopatologia , Rim/irrigação sanguínea , Resistência Vascular/efeitos dos fármacos , Adulto , Artérias/efeitos dos fármacos , Feminino , Humanos , Masculino , Adulto Jovem
14.
BJOG ; 127(8): 1018-1025, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32133780

RESUMO

OBJECTIVE: To compare maternal haemodynamics in women at low and high risk for preterm pre-eclampsia (PE), and between those at high risk who are randomised to aspirin or placebo. DESIGN: Prospective, longitudinal observational study. SETTING: Maternity units in six UK hospitals. POPULATION: Women participating in the Aspirin for Prevention of Preterm Pre-eclampsia (ASPRE) trial. The population comprised three groups of women: low risk for preterm PE (n = 1362), high risk for preterm PE treated with aspirin (n = 208) and high risk for preterm PE on placebo (n = 220). METHODS: Women had four visits during pregnancy: 11-14, 19-24, 30-34, and 35-37 weeks' gestation. Blood pressure was measured with a device validated for pregnancy, and PE and maternal haemodynamics were assessed with a bioreactance monitor at each visit. A multilevel linear mixed-effects analysis was performed to examine longitudinal changes of maternal haemodynamic variables, controlling for demographic characteristics, past medical history and medication use. MAIN OUTCOME MEASURES: Longitudinal changes of cardiac output (CO), mean arterial pressure (MAP), and peripheral vascular resistance (PVR). RESULTS: The low-risk group demonstrated the expected changes with an increase in CO and reduction in MAP and PVR, with a quadratic change across gestation. In contrast, the high-risk groups had a declining CO, and higher MAP and PVR during pregnancy. The administration of aspirin did not appear to affect maternal haemodynamics. CONCLUSIONS: Women screened as high risk for preterm PE have a pathological cardiac adaptation to pregnancy and the prophylactic use of aspirin (150 mg oral daily from the first trimester) in this group may not alter this haemodynamic profile. TWEETABLE ABSTRACT: In women at high risk of pre-eclampsia, prophylactic use of aspirin may not alter the impaired maternal cardiac adaptation.


Assuntos
Aspirina/uso terapêutico , Débito Cardíaco/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/uso terapêutico , Pré-Eclâmpsia/prevenção & controle , Gravidez de Alto Risco/efeitos dos fármacos , Adulto , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Débito Cardíaco/fisiologia , Feminino , Idade Gestacional , Humanos , Estudos Longitudinais , Pré-Eclâmpsia/tratamento farmacológico , Gravidez , Gravidez de Alto Risco/fisiologia , Estudos Prospectivos , Fatores de Risco , Resultado do Tratamento , Resistência Vascular/efeitos dos fármacos , Resistência Vascular/fisiologia
15.
Am J Physiol Renal Physiol ; 318(4): F1053-F1065, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32174139

RESUMO

We first tested the hypothesis that consuming a high-fructose corn syrup (HFCS)-sweetened soft drink augments kidney vasoconstriction to sympathetic stimulation compared with water (study 1). In a second study, we examined the mechanisms underlying these observations (study 2). In study 1, 13 healthy adults completed a cold pressor test, a sympathoexcitatory maneuver, before (preconsumption) and 30 min after drinking 500 mL of decarbonated HFCS-sweetened soft drink or water (postconsumption). In study 2, venous blood samples were obtained in 12 healthy adults before and 30 min after consumption of 500 mL water or soft drinks matched for caffeine content and taste, which were either artificially sweetened (Diet trial), sucrose-sweetened (Sucrose trial), or sweetened with HFCS (HFCS trial). In both study 1 and study 2, vascular resistance was calculated as mean arterial pressure divided by blood velocity, which was measured via Doppler ultrasound in renal and segmental arteries. In study 1, HFCS consumption increased vascular resistance in the segmental artery at rest (by 0.5 ± 0.6 mmHg·cm-1·s-1, P = 0.01) and during the cold pressor test (average change: 0.5 ± 1.0 mmHg·cm-1·s-1, main effect: P = 0.05). In study 2, segmental artery vascular resistance increased in the HFCS trial (by 0.8 ± 0.7 mmHg·cm-1·s-1, P = 0.02) but not in the other trials. Increases in serum uric acid were greater in the HFCS trial (0.3 ± 0.4 mg/dL, P ≤ 0.04) compared with the Water and Diet trials, and serum copeptin increased in the HFCS trial (by 0.8 ± 1.0 pmol/L, P = 0.06). These findings indicate that HFCS acutely increases vascular resistance in the kidneys, independent of caffeine content and beverage osmolality, which likely occurs via simultaneous elevations in circulating uric acid and vasopressin.


Assuntos
Bebidas Adoçadas Artificialmente/efeitos adversos , Xarope de Milho Rico em Frutose/efeitos adversos , Rim/irrigação sanguínea , Artéria Renal/inervação , Circulação Renal/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Velocidade do Fluxo Sanguíneo , Cafeína/administração & dosagem , Feminino , Voluntários Saudáveis , Xarope de Milho Rico em Frutose/administração & dosagem , Humanos , Masculino , Distribuição Aleatória , Artéria Renal/diagnóstico por imagem , Sistema Nervoso Simpático/fisiopatologia , Fatores de Tempo , Regulação para Cima , Ácido Úrico/sangue , Vasopressinas/sangue , Adulto Jovem
16.
Am J Physiol Lung Cell Mol Physiol ; 318(4): L762-L772, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32073878

RESUMO

Newborn pigs with chronic hypoxia-induced pulmonary hypertension (PH) have evidence of endothelial nitric oxide synthase (eNOS) uncoupling. In this model, we showed that therapies that promote eNOS coupling, either tetrahydrobiopterin (BH4), a NOS cofactor, or l-citrulline, a NO-l-arginine precursor, inhibit PH. We wanted to determine whether cotreatment with l-citrulline and a BH4 compound, sapropterin dihydrochloride, improves NO signaling and chronic hypoxia-induced PH more markedly than either alone. Normoxic (control) and hypoxic piglets were studied. Some hypoxic piglets received sole treatment with l-citrulline or BH4, or were cotreated with l-citrulline and BH4, from day 3 through day 10 of hypoxia. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess eNOS dimer-to-monomer ratios and NO production. In untreated hypoxic piglets, pulmonary vascular resistance (PVR) was higher and NO production and eNOS dimer-to-monomer ratios were lower than in normoxic piglets. Compared with the untreated hypoxic group, PVR was lower in hypoxic piglets cotreated with l-citrulline and BH4 and in those treated with l-citrulline alone but not for those treated solely with BH4. NO production and eNOS dimer-to-monomer ratios were greater for all three treated hypoxic groups compared with the untreated group. Notably, greater improvements in PVR, eNOS dimer-to-monomer ratios, and NO production were found in hypoxic piglets cotreated with l-citrulline and BH4 than in piglets treated with either alone. Cotreatment with l-citrulline and BH4 more effectively improves NO signaling and inhibits chronic hypoxia-induced PH than either treatment alone. Combination therapies may offer enhanced therapeutic capacity for challenging clinical conditions, such as chronic neonatal PH.


Assuntos
Biopterina/análogos & derivados , Citrulina/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/metabolismo , Óxido Nítrico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Arginina/metabolismo , Biopterina/farmacologia , Hipertensão Pulmonar/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Suínos , Resistência Vascular/efeitos dos fármacos
17.
Crit Care ; 24(1): 36, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019600

RESUMO

Vasoplegic syndrome is a common occurrence following cardiothoracic surgery and is characterized as a high-output shock state with poor systemic vascular resistance. The pathophysiology is complex and includes dysregulation of vasodilatory and vasoconstrictive properties of smooth vascular muscle cells. Specific bypass machine and patient factors play key roles in occurrence. Research into treatment of this syndrome is limited and extrapolated primarily from that pertaining to septic shock, but is evolving with the expanded use of catecholamine-sparing agents. Recent reports demonstrate potential benefit in novel treatment options, but large clinical trials are needed to confirm.


Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Vasoplegia/tratamento farmacológico , Vasoplegia/fisiopatologia , Corticosteroides/uso terapêutico , Angiotensina II/uso terapêutico , Ácido Ascórbico/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/métodos , Dopamina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Epinefrina/uso terapêutico , Humanos , Azul de Metileno/uso terapêutico , Norepinefrina/uso terapêutico , Fenilefrina/uso terapêutico , Simpatomiméticos/uso terapêutico , Resistência Vascular/efeitos dos fármacos , Resistência Vascular/fisiologia , Vasoconstritores/uso terapêutico , Vasoplegia/etiologia , Vasopressinas/uso terapêutico
18.
PLoS One ; 15(2): e0229015, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084180

RESUMO

Understanding (patho)physiological phenomena and mechanisms of failure in patients with Fontan circulation-a surgically established circulation for patients born with a functionally single ventricle-remains challenging due to the complex hemodynamics and high inter-patient variations in anatomy and function. In this work, we present a biomechanical model of the heart and circulation to augment the diagnostic evaluation of Fontan patients with early-stage heart failure. The proposed framework employs a reduced-order model of heart coupled with a simplified circulation including venous return, creating a closed-loop system. We deploy this framework to augment the information from data obtained during combined cardiac catheterization and magnetic resonance exams (XMR), performed at rest and during dobutamine stress in 9 children with Fontan circulation and 2 biventricular controls. We demonstrate that our modeling framework enables patient-specific investigation of myocardial stiffness, contractility at rest, contractile reserve during stress and changes in vascular resistance. Hereby, the model allows to identify key factors underlying the pathophysiological response to stress in these patients. In addition, the rapid personalization of the model to patient data and fast simulation of cardiac cycles make our framework directly applicable in a clinical workflow. We conclude that the proposed modeling framework is a valuable addition to the current clinical diagnostic XMR exam that helps to explain patient-specific stress hemodynamics and can identify potential mechanisms of failure in patients with Fontan circulation.


Assuntos
Dobutamina/farmacologia , Técnica de Fontan/métodos , Fenômenos Biomecânicos , Coração , Hemodinâmica/efeitos dos fármacos , Humanos , Modelos Cardiovasculares , Resistência Vascular/efeitos dos fármacos
19.
Am J Physiol Cell Physiol ; 318(3): C627-C639, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31891519

RESUMO

A Western-style diet (WD; high in fat and carbohydrates) increases vascular oxidative stress. We hypothesized that vascular cells adapt to a WD by developing resilience to oxidative stress. Male and female C57BL/6J mice (4 wk of age) were fed a control diet (CD) or a WD for 16-20 wk. Superior epigastric arteries (SEAs; diameter, ~125 µm) were isolated and pressurized for study. Basal reactive oxygen species production was greatest in SEAs from males fed the WD. During exposure to H2O2 (200 µM, 50 min), propidium iodide staining identified nuclei of disrupted endothelial cells (ECs) and smooth muscle cells (SMCs). For mice fed the CD, death of SMCs (21%) and ECs (6%) was greater (P < 0.05) in SEAs from males than females (9% and 2%, respectively). WD consumption attenuated cell death most effectively in SEAs from males. With no difference at rest, H2O2 increased intracellular Ca2+ concentration ([Ca2+]i) to the greatest extent in SEAs from males, as shown by fura 2 fluorescence. Selective disruption of the endothelium (luminal air bubble) increased [Ca2+]i and SMC death during H2O2 exposure irrespective of sex; the WD reduced both responses most effectively in males. Nonselective transient receptor potential (TRP) channel inhibition (ruthenium red, 5 µM) attenuated the rise of [Ca2+]i, as did selective inhibition of TRP vanilloid type 4 (TRPV4) channels (HC-067047, 1 µM), which also attenuated cell death. In contrast, inhibition of voltage-gated Ca2+ channels (diltiazem, 50 µM) was without effect. Thus, for resistance arteries during acute oxidative stress: 1) ECs are more resilient than (and can protect) SMCs, 2) vessels from females are inherently more resilient than those from males, and 3) a WD increases vascular resilience by diminishing TRPV4 channel-dependent Ca2+ entry.


Assuntos
Dieta Ocidental , Artérias Epigástricas/metabolismo , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo/fisiologia , Caracteres Sexuais , Resistência Vascular/fisiologia , Animais , Artérias Epigástricas/efeitos dos fármacos , Feminino , Peróxido de Hidrogênio/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
20.
Am J Physiol Heart Circ Physiol ; 318(2): H301-H325, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31886718

RESUMO

The introduction of duplex Doppler ultrasound almost half a century ago signified a revolutionary advance in the ability to assess limb blood flow in humans. It is now widely used to assess blood flow under a variety of experimental conditions to study skeletal muscle resistance vessel function. Despite its pervasive adoption, there is substantial variability between studies in relation to experimental protocols, procedures for data analysis, and interpretation of findings. This guideline results from a collegial discussion among physiologists and pharmacologists, with the goal of providing general as well as specific recommendations regarding the conduct of human studies involving Doppler ultrasound-based measures of resistance vessel function in skeletal muscle. Indeed, the focus is on methods used to assess resistance vessel function and not upstream conduit artery function (i.e., macrovasculature), which has been expertly reviewed elsewhere. In particular, we address topics related to experimental design, data collection, and signal processing as well as review common procedures used to assess resistance vessel function, including postocclusive reactive hyperemia, passive limb movement, acute single limb exercise, and pharmacological interventions.


Assuntos
Fármacos Cardiovasculares/farmacologia , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/diagnóstico por imagem , Ultrassonografia Doppler/normas , Resistência Vascular/fisiologia , Humanos , Músculo Esquelético/efeitos dos fármacos , Projetos de Pesquisa , Resistência Vascular/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...