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1.
Crit Care Med ; 47(11): e911-e918, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31567350

RESUMO

OBJECTIVES: Mechanical ventilation can cause ventilator-induced brain injury via afferent vagal signaling and hippocampal neurotransmitter imbalances. The triggering mechanisms for vagal signaling during mechanical ventilation are unknown. The objective of this study was to assess whether pulmonary transient receptor potential vanilloid type-4 (TRPV4) mechanoreceptors and vagal afferent purinergic receptors (P2X) act as triggers of ventilator-induced brain injury. DESIGN: Controlled, human in vitro and ex vivo studies, as well as murine in vivo laboratory studies. SETTING: Research laboratory. SUBJECTS: Wild-type, TRPV4-deficient C57BL/6J mice, 8-10 weeks old. Human postmortem lung tissue and human lung epithelial cell line BEAS-2B. INTERVENTION: Mice subjected to mechanical ventilation were studied using functional MRI to assess hippocampal activity. The effects of lidocaine (a nonselective ion-channel inhibitor), P2X-purinoceptor antagonist (iso-PPADS), or genetic TRPV4 deficiency on hippocampal dopamine-dependent pro-apoptotic signaling were studied in mechanically ventilated mice. Human lung epithelial cells (BEAS-2B) were used to study the effects of mechanical stretch on TRPV4 and P2X expression and activation. TRPV4 levels were measured in postmortem lung tissue from ventilated and nonventilated patients. MEASUREMENTS AND MAIN RESULTS: Hippocampus functional MRI analysis revealed considerable changes in response to the increase in tidal volume during mechanical ventilation. Intratracheal lidocaine, iso-PPADS, and TRPV4 genetic deficiency protected mice against ventilationinduced hippocampal pro-apoptotic signaling. Mechanical stretch in both, BEAS-2B cells and ventilated wild-type mice, resulted in TRPV4 activation and reduced Trpv4 and P2x expression. Intratracheal replenishment of adenosine triphosphate in Trpv4 mice abrogated the protective effect of TRPV4 deficiency. Autopsy lung tissue from ventilated patients showed decreased lung TRPV4 levels compared with nonventilated CONCLUSIONS:: TRPV4 mechanosensors and purinergic receptors are involved in the mechanisms of ventilator-induced brain injury. Inhibition of this neural signaling, either using nonspecific or specific inhibitors targeting the TRPV4/adenosine triphosphate/P2X signaling axis, may represent a novel strategy to prevent or treat ventilator-induced brain injury.

3.
J Physiol ; 597(4): 1045-1058, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29660141

RESUMO

KEY POINTS: Carbonic anhydrase (CA) inhibitors such as acetazolamide inhibit hypoxic pulmonary vasoconstriction (HPV) in humans and other mammals, but the mechanism of this action remains unknown. It has been postulated that carbonic anhydrase may act as a nitrous anhydrase in vivo to generate nitric oxide (NO) from nitrite and that this formation is increased in the presence of acetazolamide. Acetazolamide reduces HPV in pigs without evidence of any NO generation, whereas nebulized sodium nitrite reduces HPV by NO formation; however; combined infusion of acetazolamide with sodium nitrite inhalation did not further increase exhaled NO concentration over inhaled nitrite alone in pigs exposed to alveolar hypoxia. We conclude that acetazolamide does not function as either a nitrous anhydrase or a nitrite reductase in the lungs of pigs, and probably other mammals, to explain its vasodilating actions in the pulmonary or systemic circulations. ABSTRACT: The carbonic anhydrase (CA) inhibitors acetazolamide and its structurally similar analogue methazolamide prevent or reduce hypoxic pulmonary vasoconstriction (HPV) in dogs and humans in vivo, by a mechanism unrelated to CA inhibition. In rodent blood and isolated blood vessels, it has been reported that inhibition of CA leads to increased generation of nitric oxide (NO) from nitrite and vascular relaxation in vitro. We tested the physiological relevance of augmented NO generation by CA from nitrite with acetazolamide in anaesthetized pigs during alveolar hypoxia in vivo. We found that acetazolamide prevents HPV in anaesthetized pigs, as in other mammalian species. A single nebulization of sodium nitrite reduces HPV, but this action wanes in the succeeding 3 h of hypoxia as nitrite is metabolized and excreted. Pulmonary artery pressure reduction and NO formation as measured by exhaled gas concentration from inhaled sodium nitrite were not increased by acetazolamide during alveolar hypoxia. Thus, our data argue against a physiological role of carbonic anhydrase as a nitrous anhydrase or nitrite reductase as a mechanism for its inhibition of HPV in the lung and blood in vivo.

4.
J Clin Monit Comput ; 32(3): 493-502, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28653135

RESUMO

Adherence to low tidal volume (VT) ventilation and selected positive end-expiratory pressures are low during mechanical ventilation for treatment of the acute respiratory distress syndrome. Using a pig model of severe lung injury, we tested the feasibility and physiological responses to a novel fully closed-loop mechanical ventilation algorithm based on the "open lung" concept. Lung injury was induced by surfactant washout in pigs (n = 8). Animals were ventilated following the principles of the "open lung approach" (OLA) using a fully closed-loop physiological feedback algorithm for mechanical ventilation. Standard gas exchange, respiratory- and hemodynamic parameters were measured. Electrical impedance tomography was used to quantify regional ventilation distribution during mechanical ventilation. Automatized mechanical ventilation provided strict adherence to low VT-ventilation for 6 h in severely lung injured pigs. Using the "open lung" approach, tidal volume delivery required low lung distending pressures, increased recruitment and ventilation of dorsal lung regions and improved arterial blood oxygenation. Physiological feedback closed-loop mechanical ventilation according to the principles of the open lung concept is feasible and provides low tidal volume ventilation without human intervention. Of importance, the "open lung approach"-ventilation improved gas exchange and reduced lung driving pressures by opening atelectasis and shifting of ventilation to dorsal lung regions.


Assuntos
Lesão Pulmonar/terapia , Respiração com Pressão Positiva/métodos , Respiração Artificial/métodos , Animais , Sistemas de Computação , Impedância Elétrica , Pulmão , Monitorização Fisiológica/métodos , Troca Gasosa Pulmonar , Respiração , Tensoativos , Suínos , Volume de Ventilação Pulmonar , Tomografia/métodos
6.
J Vis Exp ; (115)2016 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-27684585

RESUMO

Various animal models of lung injury exist to study the complex pathomechanisms of human acute respiratory distress syndrome (ARDS) and evaluate future therapies. Severe lung injury with a reproducible deterioration of pulmonary gas exchange and hemodynamics can be induced in anesthetized pigs using repeated lung lavages with warmed 0.9% saline (50 ml/kg body weight). Including standard respiratory and hemodynamic monitoring with clinically applied devices in this model allows the evaluation of novel therapeutic strategies (drugs, modern ventilators, extracorporeal membrane oxygenators, ECMO), and bridges the gap between bench and bedside. Furthermore, induction of lung injury with lung lavages does not require the injection of pathogens/endotoxins that impact on measurements of pro- and anti-inflammatory cytokines. A disadvantage of the model is the high recruitability of atelectatic lung tissue. Standardization of the model helps to avoid pitfalls, to ensure comparability between experiments, and to reduce the number of animals needed.


Assuntos
Modelos Animais de Doenças , Síndrome do Desconforto Respiratório do Adulto/terapia , Animais , Lavagem Broncoalveolar , Humanos , Pulmão , Tensoativos , Suínos , Irrigação Terapêutica
7.
Tissue Eng Part C Methods ; 21(3): 303-13, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25164028

RESUMO

Decellularization and recellularization of parenchymal organs may facilitate the generation of autologous functional liver organoids by repopulation of decellularized porcine liver matrices with induced liver cells. We present an accelerated (7 h overall perfusion time) and effective protocol for human-scale liver decellularization by pressure-controlled perfusion with 1% Triton X-100 and 1% sodium dodecyl sulfate via the hepatic artery (120 mmHg) and portal vein (60 mmHg). In addition, we analyzed the effect of oscillating pressure conditions on pig liver decellularization (n=19). The proprietary perfusion device used to generate these pressure conditions mimics intra-abdominal conditions during respiration to optimize microperfusion within livers and thus optimize the homogeneity of the decellularization process. The efficiency of perfusion decellularization was analyzed by macroscopic observation, histological staining (hematoxylin and eosin [H&E], Sirius red, and alcian blue), immunohistochemical staining (collagen IV, laminin, and fibronectin), and biochemical assessment (DNA, collagen, and glycosaminoglycans) of decellularized liver matrices. The integrity of the extracellular matrix (ECM) postdecellularization was visualized by corrosion casting and three-dimensional computed tomography scanning. We found that livers perfused under oscillating pressure conditions (P(+)) showed a more homogenous course of decellularization and contained less DNA compared with livers perfused without oscillating pressure conditions (P(-)). Microscopically, livers from the (P(-)) group showed remnant cell clusters, while no cells were found in livers from the (P(+)) group. The grade of disruption of the ECM was higher in livers from the (P(-)) group, although the perfusion rates and pressure did not significantly differ. Immunohistochemical staining revealed that important matrix components were still present after decellularization. Corrosion casting showed an intact vascular (portal vein and hepatic artery) and biliary framework. In summary, the presented protocol for pig liver decellularization is quick (7 h) and effective. The application of oscillating pressure conditions improves the homogeneity of perfusion and thus the outcome of the decellularization process.


Assuntos
Fígado/citologia , Pressão , Engenharia Tecidual/métodos , Animais , Cateteres , Colágeno Tipo IV/metabolismo , Corrosão , DNA/metabolismo , Matriz Extracelular/metabolismo , Feminino , Fibronectinas/metabolismo , Glicosaminoglicanos/metabolismo , Humanos , Imagem Tridimensional , Imuno-Histoquímica , Laminina/metabolismo , Fígado/diagnóstico por imagem , Masculino , Tamanho do Órgão , Perfusão , Coloração e Rotulagem , Sus scrofa , Tomografia Computadorizada por Raios X
8.
J Appl Physiol (1985) ; 116(7): 715-23, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24481964

RESUMO

Acetazolamide (ACZ) prevents hypoxic pulmonary vasoconstriction (HPV) in isolated lungs, animals, and humans, but not by carbonic anhydrase (CA) inhibition. We studied administration routes in, and certain structural aspects of, ACZ critical to HPV inhibition. Analogs of ACZ during acute hypoxia were tested in unanesthetized dogs. Dogs breathed normoxic gas for 1 h (inspired O2 fraction = 0.21), followed by 10% O2 for 2 h (hypoxia) in these protocols: 1) controls; 2) ACZ intravenously (2 mg · kg(-1) · h(-1)); 3) ACZ orally (5 mg/kg, 12 and 1 h before the experiment); 4) inhaled ACZ (750 mg); 5) methazolamide (MTZ) intravenously (3 mg · kg(-1) · h(-1)); and 6) N-methyl-acetazolamide (NMA) intravenously (10 mg · kg(-1) · h(-1)). In controls, mean pulmonary arterial pressure (MPAP) increased 7 mmHg, and pulmonary vascular resistance (PVR) 224 dyn · s · cm(-5) with hypoxia (P < 0.05). With intravenous and inhaled ACZ, MPAP and PVR did not change during hypoxia. With oral ACZ, HPV was only slightly suppressed; MPAP increased 5 mmHg and PVR by 178 dyn · s · cm(-5) during hypoxia. With MTZ and NMA, the MPAP rise (4 ± 2 mmHg) was reduced, and PVR did not increase during hypoxia compared with normoxia (MTZ intravenous: 81 ± 77 and 68 ± 82 dyn · s · cm(-5) with NMA intravenous). Inhaled ACZ prevents HPV, but not without causing systemic CA inhibition. NMA, a compound lacking CA inhibiting effects by methylation at the sulfonamide moiety, and MTZ, a CA-inhibiting analog methylated at the thiadiazole ring, are only slightly less effective than ACZ in reducing HPV.


Assuntos
Acetazolamida/administração & dosagem , Hipóxia/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Respiração , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Acetazolamida/química , Administração por Inalação , Administração Oral , Animais , Pressão Arterial/efeitos dos fármacos , Inibidores da Anidrase Carbônica/administração & dosagem , Inibidores da Anidrase Carbônica/química , Modelos Animais de Doenças , Cães , Feminino , Hipóxia/enzimologia , Infusões Intravenosas , Metilação , Artéria Pulmonar/fisiopatologia , Relação Estrutura-Atividade , Fatores de Tempo , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/química
9.
Artigo em Alemão | MEDLINE | ID: mdl-24193690

RESUMO

Early weaning and discontinuation of mechanical ventilation can help prevent respiratory muscle dysfunction in critically ill patients. Prolonged mechanical ventilation and failure to use adequate strategies to discontinue mechanical ventilation can even enhance and perpetuate respiratory muscle dysfunction. On the other hand, premature attempts to extubate may result in re-intubation due to respiratory failure and are associated with poor outcomes and high mortality rates of up to 30-50%. Therefore, accurate monitoring of the respiratory muscle function is a valuable tool for the clinician at the bedside to assess to optimal weaning strategy and, ideally, would predict either weaning failure or success. In this review, we briefly summarize the available techniques, measurements and equipment required for the monitoring of respiratory muscle function in the intensive care unit.


Assuntos
Eletromiografia/métodos , Monitorização Fisiológica/métodos , Testes de Função Respiratória/métodos , Paralisia Respiratória/etiologia , Paralisia Respiratória/prevenção & controle , Desmame do Respirador/efeitos adversos , Desmame do Respirador/métodos , Cuidados Críticos/métodos , Humanos , Medição de Risco
10.
Anesthesiology ; 117(3): 592-601, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22820847

RESUMO

BACKGROUND: Nitrite (NO2) is a physiologic source of nitric oxide and protects against ischemia-reperfusion injuries. We hypothesized that nitrite would be protective in a rat model of ventilator-induced lung injury and sought to determine if nitrite protection is mediated by enzymic catalytic reduction to nitric oxide. METHODS: Rats were anesthetized and mechanically ventilated. Group 1 had low tidal volume ventilation (LVT) (6 ml/kg and 2 cm H2O positive end-expiratory pressure; n=10); group 2 had high tidal volume ventilation (HVT) (2 h of 35 cm H2O inspiratory peak pressure and 0 cm H2O positive end-expiratory pressure; n=14); groups 3-5: HVT with sodium nitrite (NaNO2) pretreatment (0.25, 2.5, 25 µmol/kg IV; n=6-8); group 6: HVT+NaNO2+nitric oxide scavenger 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide(n=6); group 7: HVT+NaNO2+nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (n=7); and group 8: HVT+NaNO2+xanthine oxidoreductase inhibitor allopurinol (n=6). Injury assessment included physiologic measurements (gas exchange, lung compliance, lung edema formation, vascular perfusion pressures) with histologic and biochemical correlates of lung injury and protection. RESULTS: Injurious ventilation caused statistically significant injury in untreated animals. NaNO2 pretreatment mitigated the gas exchange deterioration, lung edema formation, and histologic injury with maximal protection at 2.5 µmol/kg. Decreasing nitric oxide bioavailability by nitric oxide scavenging, nitric oxide synthase inhibition, or xanthine oxidoreductase inhibition abolished the protection by NaNO2. CONCLUSIONS: Nitrite confers protection against ventilator-induced lung injury in rats. Catalytic reduction to nitric oxide and mitigation of ventilator-induced lung injury is dependent on both xanthine oxidoreductase and nitric oxide synthases.


Assuntos
Nitrito de Sódio/uso terapêutico , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Animais , Citocinas/fisiologia , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/fisiologia , Oxigênio/sangue , Respiração com Pressão Positiva , Ratos , Ratos Sprague-Dawley , Xantina Desidrogenase/fisiologia
12.
Shock ; 34(6): 628-35, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20458269

RESUMO

The authors aimed to test the hypothesis that xenon anesthesia limits adverse hypotensive effects of losartan during acute hemorrhage. In six conscious unsedated Beagle dogs, the systemic and pulmonary circulation were monitored invasively, and two subsequent 60-min hypotensive challenges were performed by (a) induction (propofol) and maintenance of anesthesia with isoflurane/remifentanil or xenon/remifentanil and by (b) subsequent hemorrhage (20 mL kg⁻¹ within 5 min) from a central vein. The same amount of blood was retransfused 1 h after hemorrhage. Experiments were performed with or without acute angiotensin II receptor subtype 1 blockade by i.v. losartan (100 µg·kg⁻¹·min⁻¹) starting 45 min before induction of anesthesia. Four experiments were performed in each individual dog. Xenon/remifentanil anesthesia provided higher baseline mean arterial blood pressure (85 ± 6 mmHg) than isoflurane/remifentanil anesthesia (67 ± 3 mmHg). In losartan-treated animals, isoflurane/remifentanil caused significant hypotension (42 ± 4 mmHg for isoflurane/remifentanil vs. 71 ± 6 mmHg for xenon/remifentanil). Independent of losartan, hemorrhage did not induce any further reduction of mean arterial blood pressure or cardiac output in either group. Spontaneous hemodynamic recovery was observed in all groups before retransfusion was started. Losartan did not alter the adrenaline, noradrenaline, and vasopressin response to acute hemorrhage. Losartan potentiates hypotension induced by isoflurane/remifentanil anesthesia but does not affect the hemodynamic stability during xenon/remifentanil anesthesia. Losartan does not deteriorate the hemodynamic adaptation to hemorrhage of 20 mL kg⁻¹ during xenon/remifentanil and isoflurane/remifentanil anesthesia. Therefore, xenon/remifentanil anesthesia protects against circulatory side effects of losartan pretreatment and thus may afford safer therapeutic use of losartan during acute hemorrhage.


Assuntos
Anestesia/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Hemorragia/fisiopatologia , Losartan/efeitos adversos , Piperidinas/uso terapêutico , Xenônio/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Cães , Feminino , Hemodinâmica/efeitos dos fármacos , Hipotensão/tratamento farmacológico , Remifentanil
13.
Vet Anaesth Analg ; 37(3): 258-68, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20230551

RESUMO

OBJECTIVE: To test the compensatory role of endothelin-1 when acute blood loss is superimposed on anaesthesia, by characterizing the effect of systemic endothelin receptor subtype A (ET(A)) blockade on the haemodynamic and hormonal responses to haemorrhage in dogs anaesthetized with xenon/remifentanil (X/R) or isoflurane/remifentanil (I/R). STUDY DESIGN: Prospective experimental randomized controlled study. ANIMALS: Six female Beagle dogs, 13.4 +/- 1.3 kg. METHODS: Animals were anaesthetized with remifentanil 0.5 microg kg(-1) minute(-1) plus either 0.8% isoflurane (I/R) or 63% xenon (X/R), with and without (Control) the systemic intravenous endothelin receptor subtype A antagonist atrasentan (four groups, n = 6 each). After 60 minutes of baseline anaesthesia, the dogs were bled (20 mL kg(-1)) over 5 minutes and hypovolemia was maintained for 1 hour. Continuous haemodynamic monitoring was performed via femoral and pulmonary artery catheters; vasoactive hormones were measured before and after haemorrhage. RESULTS: In Controls, systemic vascular resistance (SVR), vasopressin and catecholamine plasma concentrations were higher with X/R than with I/R anaesthesia at pre-haemorrhage baseline. The peak increase after haemorrhage was higher during X/R than during I/R anaesthesia (SVR 7420 +/- 867 versus 5423 +/- 547 dyne seconds cm(-5); vasopressin 104 +/- 23 versus 44 +/- 6 pg mL(-1); epinephrine 2956 +/- 310 versus 177 +/- 99 pg mL(-1); norepinephrine 862 +/- 117 versus 195 +/- 33 pg mL(-1), p < 0.05). Haemorrhage reduced central venous pressure from 3 +/- 1 to 1 +/- 1 cm H(2)O (I/R, ns) and from 8 +/- 1 to 5 +/- 1 cm H(2)O (X/R, p < 0.05), but did not reduce mean arterial pressure, nor cardiac output. Atrasentan did not alter the haemodynamic and hormonal response to haemorrhage during either anaesthetic protocol. CONCLUSIONS AND CLINICAL RELEVANCE: Selective ET(A) receptor blockade with atrasentan did not impair the haemodynamic and hormonal compensation of acute haemorrhage during X/R or I/R anaesthesia in dogs.


Assuntos
Anestesia/veterinária , Anestésicos Inalatórios , Anestésicos Intravenosos , Doenças do Cão/fisiopatologia , Antagonistas do Receptor de Endotelina A , Hemodinâmica/efeitos dos fármacos , Hemorragia/veterinária , Isoflurano , Piperidinas , Pirrolidinas/farmacologia , Xenônio , Anestesia/métodos , Anestesia por Inalação/métodos , Anestesia por Inalação/veterinária , Anestesia Intravenosa/métodos , Anestesia Intravenosa/veterinária , Animais , Atrasentana , Perda Sanguínea Cirúrgica/fisiopatologia , Perda Sanguínea Cirúrgica/veterinária , Catecolaminas/sangue , Cães , Endotelina-1/sangue , Epinefrina/sangue , Feminino , Hemorragia/fisiopatologia , Norepinefrina/sangue , Remifentanil , Fatores de Tempo , Resistência Vascular/efeitos dos fármacos , Vasopressinas/sangue
14.
Vet J ; 183(2): 228-31, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19026579

RESUMO

This study investigated the applicability of two human radio-immunoassays (RIA) to detect epinephrine (EPI), norepinephrine (NE), and their O-methylated metabolites metanephrine (MN) and normetanephrine (NMN) in canine plasma. The analysis yielded a positive correlation between metabolites and their respective parent compounds: EPI and MN (r=0.63), NE and NMN (r=0.47), as well as between parent compounds, EPI and NE (r=0.48), and between metabolites MN and NMN (r=0.71). Moreover, EPI (r=0.99) and NE (r=0.77) concentrations determined by RIA did correlate positively with high pressure liquid chromatography (HPLC). However, there was limited agreement between both methods. It was concluded that complete validation tests for accuracy, precision and agreement are needed before this RIA can be applied to quantify catecholamines, metanephrine, and normetanephrine in canine plasma. The assay may prove to be a potential alternative to HPLC or tandem mass spectrometry in the work-up of pheochromocytoma and the detection of overall sympathetic activity in dogs.


Assuntos
Catecolaminas/sangue , Cães/sangue , Metanefrina/sangue , Radioimunoensaio/veterinária , Animais , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão/veterinária , Feminino , Estudos de Validação como Assunto
15.
Am J Physiol Lung Cell Mol Physiol ; 292(1): L178-84, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16936246

RESUMO

Acute hypoxic pulmonary vasoconstriction can be inhibited by high doses of the carbonic anhydrase inhibitor acetazolamide. This study aimed to determine whether acetazolamide is effective at dosing relevant to human use at high altitude and to investigate whether its efficacy against hypoxic pulmonary vasoconstriction is dependent on carbonic anhydrase inhibition by testing other potent heterocyclic sulfonamide carbonic anhydrase inhibitors. Six conscious dogs were studied in five protocols: 1) controls, 2) low-dose intravenous acetazolamide (2 mg.kg(-1).h(-1)), 3) oral acetazolamide (5 mg/kg), 4) benzolamide, a membrane-impermeant inhibitor, and 5) ethoxzolamide, a membrane-permeant inhibitor. In all protocols, unanesthetized dogs breathed spontaneously during the first hour (normoxia) and then breathed 9-10% O(2) for the next 2 h. Arterial oxygen tension ranged between 35 and 39 mmHg during hypoxia in all protocols. In controls, mean pulmonary artery pressure increased by 8 mmHg and pulmonary vascular resistance by 200 dyn.s.cm(-5) (P <0.05). With intravenous acetazolamide, mean pulmonary artery pressure and pulmonary vascular resistance remained unchanged during hypoxia. With oral acetazolamide, mean pulmonary artery pressure increased by 5 mmHg (P < 0.05), but pulmonary vascular resistance did not change during hypoxia. With benzolamide and ethoxzolamide, mean pulmonary artery pressure increased by 6-7 mmHg and pulmonary vascular resistance by 150-200 dyn.s.cm(-5) during hypoxia (P < 0.05). Low-dose acetazolamide is effective against acute hypoxic pulmonary vasoconstriction in vivo. The lack of effect with two other potent carbonic anhydrase inhibitors suggests that carbonic anhydrase is not involved in the mediation of hypoxic pulmonary vasoconstriction and that acetazolamide acts on a different receptor or channel.


Assuntos
Acetazolamida/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Hipóxia/tratamento farmacológico , Hipóxia/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Acetazolamida/administração & dosagem , Equilíbrio Ácido-Base/efeitos dos fármacos , Doença da Altitude/tratamento farmacológico , Doença da Altitude/fisiopatologia , Animais , Benzolamida/farmacologia , Inibidores da Anidrase Carbônica/administração & dosagem , Modelos Animais de Doenças , Cães , Etoxzolamida/farmacologia , Feminino , Humanos , Rim/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologia
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