RESUMO
BACKGROUND: Ideally, vasodilator therapies for pulmonary arterial hypertension (PAH) should have a favorable impact on markers of vascular dysfunction, in addition to their known effects on hemodynamics, cardiac function, and patient's physical capacity. METHODS: We analyzed circulating (plasma) markers of endothelial and platelet activation/dysfunction (enzyme-linked immunoassays) in the specific setting of advanced PAH associated with congenital heart disease, during the course of sildenafil and tadalafil therapies. Thirty-one patients were enrolled (age 10-54 years), most of them with chronic hypoxemia and elevated hematocrit. Drugs were administered orally for 6 months (sildenafil [n = 16], 20 mg t.i.d.; tadalafil [n = 15], single daily dose of 40 mg). Measurements were performed at baseline, and 90 and 180 days. RESULTS: Compared to controls, patients had elevated baseline ß-thromboglobulin (ß-TG, P = .002), P-selectin (P = .027), tissue-type plasminogen activator (t-PA, P = .009), and von Willebrand factor antigen (VWF:Ag, P = .010). Thrombomodulin was importantly reduced (TM, P < .001), while soluble CD40 Ligand was not changed (P = .320). Tadalafil administration was associated with improvement of ß-TG (P = .004), t-PA (P = .003) and TM (P = .046) levels, while P-selectin was improved by sildenafil treatment only (P = .034). VWF:Ag improved transiently in the sildenafil group (P = .019). Both therapies were associated with improvement of the physical capacity (functional class and distance walked during the 6-minute test, P < .05), hematocrit and hemoglobin level (P < .05), and health-related quality of life (physical and mental components, P < .05). CONCLUSION: In PAH associated with congenital heart disease, phosphodiesterase 5 inhibitors seem to have beneficial actions at microcirculatory level, beyond the proposed effects as vasodilators.
Assuntos
Cardiopatias Congênitas/tratamento farmacológico , Hipertensão Pulmonar/tratamento farmacológico , Microcirculação/efeitos dos fármacos , Circulação Pulmonar/fisiologia , Pressão Propulsora Pulmonar/fisiologia , Citrato de Sildenafila/administração & dosagem , Tadalafila/administração & dosagem , Adolescente , Adulto , Cateterismo Cardíaco , Criança , Relação Dose-Resposta a Droga , Ecocardiografia , Feminino , Seguimentos , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Imagem Cinética por Ressonância Magnética , Masculino , Microcirculação/fisiologia , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 5/administração & dosagem , Circulação Pulmonar/efeitos dos fármacos , Pressão Propulsora Pulmonar/efeitos dos fármacos , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Hypoxia-induced pulmonary hypertension is characterized by progressive remodeling of the pulmonary artery (PA) system and loss of the transcription factor, cAMP response element binding protein (CREB) in PA smooth muscle cells (SMCs). Previous in vitro studies suggested that platelet-derived growth factor, a mitogen produced in the hypoxic arterial wall, elicits loss of CREB in medial SMCs via the PI3K/Akt pathway. These events trigger switching of SMCs from a quiescent, contractile phenotype to a proliferative, migratory, dedifferentiated, and synthetic phenotype, which contributes to PA thickening. Here, we investigated whether inhibition of PI3K or Akt could attenuate arterial remodeling in the lung and prevent CREB loss in PA medial SMCs in rats subjected to chronic hypoxia. Inhibition of either enzyme-blunted hypoxia-induced PA remodeling and SMC CREB depletion and diminished SMC proliferation and collagen deposition. Inhibition of Akt, but not PI3K, suppressed muscularization of distal arterioles and blunted right ventricular hypertrophy. Interestingly, mean PA pressure was elevated equally by hypoxia in untreated and inhibitor-treated groups but was normalized acutely by the Rho kinase inhibitor, Fasudil. We conclude that PI3K and Akt inhibitors can attenuate hypoxia-induced PA remodeling and SMC CREB depletion but fail to block the development of pulmonary hypertension because of their inability to repress Rho kinase-mediated vasoconstriction.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/agonistas , Hipertensão Pulmonar/prevenção & controle , Músculo Liso Vascular/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Artéria Pulmonar/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/metabolismo , Arteríolas/patologia , Proliferação de Células/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Inibidores Enzimáticos/uso terapêutico , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Hipertensão Pulmonar/etiologia , Hipertrofia Ventricular Direita/etiologia , Hipertrofia Ventricular Direita/prevenção & controle , Hipóxia/fisiopatologia , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Estabilidade Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Circulação Pulmonar/efeitos dos fármacos , Ratos , Ratos Endogâmicos WKY , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Quinases Associadas a rho/metabolismoRESUMO
We determined whether store-operated channels (SOC) are involved in neonatal pulmonary artery function under conditions of acute and chronic hypoxia, using newborn sheep gestated and born either at high altitude (HA, 3,600 m) or low altitude (LA, 520 m). Cardiopulmonary variables were recorded in vivo, with and without SOC blockade by 2-aminoethyldiphenylborinate (2-APB), during basal or acute hypoxic conditions. 2-APB did not have effects on basal mean pulmonary arterial pressure (mPAP), cardiac output, systemic arterial blood pressure, or systemic vascular resistance in both groups of neonates. During acute hypoxia 2-APB reduced mPAP and pulmonary vascular resistance in LA and HA, but this reduction was greater in HA. In addition, isolated pulmonary arteries mounted in a wire myograph were assessed for vascular reactivity. HA arteries showed a greater relaxation and sensitivity to SOC blockers than LA arteries. The pulmonary expression of two SOC-forming subunits, TRPC4 and STIM1, was upregulated in HA. Taken together, our results show that SOC contribute to hypoxic pulmonary vasoconstriction in newborn sheep and that SOC are upregulated by chronic hypoxia. Therefore, SOC may contribute to the development of neonatal pulmonary hypertension. We propose SOC channels could be potential targets to treat neonatal pulmonary hypertension.
Assuntos
Altitude , Canais Iônicos/fisiologia , Circulação Pulmonar/fisiologia , Carneiro Doméstico/fisiologia , Doença da Altitude/sangue , Doença da Altitude/complicações , Doença da Altitude/genética , Doença da Altitude/fisiopatologia , Animais , Animais Recém-Nascidos , Compostos de Boro/farmacologia , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos , Hipóxia/sangue , Hipóxia/complicações , Hipóxia/genética , Hipóxia/fisiopatologia , Recém-Nascido , Canais Iônicos/sangue , Canais Iônicos/genética , Síndrome da Persistência do Padrão de Circulação Fetal/sangue , Síndrome da Persistência do Padrão de Circulação Fetal/etiologia , Síndrome da Persistência do Padrão de Circulação Fetal/fisiopatologia , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar/efeitos dos fármacos , Carneiro Doméstico/sangue , Carneiro Doméstico/genética , Canais de Cátion TRPC/sangue , Canais de Cátion TRPC/fisiologia , Vasoconstrição/fisiologiaRESUMO
Lowland mammals at high altitude constrict the pulmonary vessels, augmenting vascular resistance and developing pulmonary arterial hypertension. In contrast, highland mammals, like the llama, do not present pulmonary arterial hypertension. Using wire myography, we studied the sensitivity to norepinephrine (NE) and NO of small pulmonary arteries of fetal llamas and sheep at high altitudes. The sensitivity of the contractile responses to NE was decreased whereas the relaxation sensitivity to NO was augmented in the llama fetus compared to the sheep fetus. Altogether these data show that the fetal llama has a lower sensitivity to a vasoconstrictor (NE) and a higher sensitivity to a vasodilator (NO), than the fetal sheep, consistent with a lower pulmonary arterial pressure found in the neonatal llama in the Andean altiplano. Additionally, we investigated carbon monoxide (CO) in the pulmonary circulation in lowland and highland newborn sheep and llamas. Pulmonary arterial pressure was augmented in neonatal sheep but not in llamas. These sheep had reduced soluble guanylate cyclase and heme oxygenase expression and CO production than at lowland. In contrast, neonatal llamas increased markedly pulmonary CO production and HO expression at high altitude. Thus, enhanced pulmonary CO protects against pulmonary hypertension in the highland neonate. Further, we compared pulmonary vascular responses to acute hypoxia in the adult llama versus the adult sheep. The rise in pulmonary arterial pressure was more marked in the sheep than in the llama. The llama pulmonary dilator strategy may provide insights into new treatments for pulmonary arterial hypertension of the neonate and adult.
Assuntos
Altitude , Animais Recém-Nascidos/fisiologia , Camelídeos Americanos/fisiologia , Feto/fisiologia , Circulação Pulmonar/fisiologia , Carneiro Doméstico/fisiologia , Animais , Pressão Sanguínea/fisiologia , Monóxido de Carbono/metabolismo , Heme Oxigenase-1/metabolismo , Hipertensão Pulmonar/fisiopatologia , Hipóxia/fisiopatologia , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiologia , Circulação Pulmonar/efeitos dos fármacos , Resistência Vascular/fisiologia , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
BACKGROUND: APVT is an invasive method recommended for symptomatic patients with PAH that permits the identification of the minority of patients (<20%) that may benefit from long-term calcium channel blockers. Adenosine has been indicated in guidelines as a vasodilator agent of choice for APVT, although it has not been directly compared with iNO, the gold standard for this test. The objective of the study was to compare adenosine with inhaled nitric oxide (iNO) for acute pulmonary vasoreactivity testing (APVT) in pulmonary arterial hypertension (PAH), in order to determine the efficacy and safety of the first in the clinical setting. METHODS: The measurements of cardiac output, pulmonary and systemic resistance were done in the basal state and with a stepwise increase of the dose of each drug until either maximum dosage (adenosine: 500 microg/kg/min or iNO: 80 ppm) or side effects observed or a positive response were reached, according to current guidelines. The order of drugs used in each test was consecutively alternated during the study. RESULTS: Six of the 39 studied patients (15%) presented a positive response to iNO; none to adenosine (p = 0.047, McNemar's test). Twenty-three patients (59%) did not reach the maximum dose of adenosine due to side effects, including bronchospasm, thoracic pain and bradycardia. CONCLUSIONS: APVT testing with adenosine was not able to detect PAH patients responsive to iNo and provoked frequent adverse effects. Adenosine should not be used as a vasodilator drug in APVT.
Assuntos
Adenosina/uso terapêutico , Débito Cardíaco/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Óxido Nítrico/uso terapêutico , Circulação Pulmonar/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Administração por Inalação , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Sinergismo Farmacológico , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Propofol is an alternative to thiopental for induction of general anaesthesia for cesarean section. It crosses the placenta and induces vasodilatation of isolated vessels and may therefore alter fetal placental vascular resistance. The direct effect of propofol on the fetal placental circulation was studied in vitro. The actions of propofol on vasoconstrictive effects induced by angiotensin II (Ang II), bradykinin (BK), prostaglandin F(2alpha) (PGF(2alpha)) and potassium chloride (KCl) were evaluated. METHODS: Full-term healthy human placentas (n=48) were perfused with modified Tyrode's solution using a pulsatile pump. Placental perfusion pressure was measured in response to injection of Ang II, BK, KCl and PGF(2alpha) before and after perfusion with propofol (1.7 x 10(-5) and 5.6 x 10(-5) M). RESULTS: BK, Ang II, KCl and PGF(2alpha) induced a dose-dependent increase in placental perfusion pressure. Propofol induced a concentration-dependent decrease in placental perfusion pressure, but this was not observed with the propofol solvent (Intralipid). Propofol, but not Intralipid, reduced the vasoconstrictor effects of BK, KCl and PGF(2alpha), while the effect of Ang II was not changed. The effect of KCl was abolished in placentas perfused with Ca(2+)-free solution, while the effect of Ang II was not altered. CONCLUSIONS: Propofol induced vasodilatation and inhibited the vasoconstrictive effects of BK and PGF(2alpha), in the human placenta. These findings suggest that propofol may not reduce fetal placental blood flow. Since propofol reduced the vasoconstricting effect of KCl but not that of AngII, we propose that the vasodilatory effect of propofol in the human placenta involves inhibition of Ca(2+) channels.
Assuntos
Anestésicos Intravenosos/efeitos adversos , Feto/irrigação sanguínea , Placenta/irrigação sanguínea , Propofol/efeitos adversos , Adulto , Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/efeitos dos fármacos , Dinoprosta/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Técnicas In Vitro , Cloreto de Potássio/farmacologia , Gravidez , Circulação Pulmonar/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacosRESUMO
Pulmonary embolism (PE) is a common condition. The central aim of this study was to describe the use of volumetric capnography (VCap) before and after fibrinolytic treatment of major PE. Lung scintigraphy was used as a base of comparison for the results of this treatment. We describe the cases of two conscious and spontaneously breathing patients (20- and by 24-year-old women) with major PE undergoing thrombolysis. Curves of CO(2) were obtained VCap and associated with arterial blood gas analysis and D-dimer. The pattern of VCap was compared with the VCap of health volunteers. Parameters also calculated were: P(a-et)CO(2) gradient, alveolar dead space fraction (AVDSf ), late dead space fraction (fDlate), and slope phase III (Slp III). The VCap results before and after thrombolysis for patients 1 and 2 were, respectively, P(a-et)CO(2): 12.6 to 5.8 and 7.9 to 1.6 (mmHg); AVDSf: 0.46 to 0.18 and 0.25 to 0.05; fDlate: 0.46 to 0.21 and 0.24 to 0.04; Slp III: 1.75 to 5.10 and 1.21 to 5.61 (mmHg/L). Lung scintigraphy was used to compare VCap results from the two subjects with VCap results from healthy volunteers and pigs before and after treatment associated with arterial blood gas, D-dimer, and showed satisfactory agreement.
Assuntos
Capnografia , Dióxido de Carbono/sangue , Circulação Pulmonar/efeitos dos fármacos , Embolia Pulmonar/tratamento farmacológico , Espaço Morto Respiratório/efeitos dos fármacos , Terapia Trombolítica , Relação Ventilação-Perfusão/efeitos dos fármacos , Doença Aguda , Animais , Biomarcadores/sangue , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Modelos Biológicos , Imagem de Perfusão , Embolia Pulmonar/sangue , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/fisiopatologia , Suínos , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To evaluate the respiratory and the pulmonary circulatory effects of norepinephrine in newborn infants with persistent pulmonary hypertension (PPHN)-induced cardiac dysfunction. STUDY DESIGN: Inclusion criteria were: 1) Newborn infants >35 weeks gestational age; 2) PPHN treated with inhaled nitric oxide; and 3) symptoms of circulatory failure despite adequate fluid resuscitation. Lung function and pulmonary hemodynamic variables assessed with Doppler echocardiography were recorded prospectively before and after starting norepinephrine. RESULTS: Eighteen newborns were included (gestational age: 37 +/- 3 weeks; birth weight: 2800 +/- 700 g). After starting norepinephrine, systemic pressure and left ventricular output increased respectively from 33 +/- 4 mm Hg to 49 +/- 4 mm Hg and from 172 +/- 79 mL/kg/min to 209+/-90 mL/kg/min (P < .05). Although the mechanical ventilatory variables have not been changed, the post-ductal transcutaneous arterial oxygen saturation increased from 89% +/- 1% to 95% +/- 4%, whereas the oxygen need decreased from 51% +/- 24% to 41% +/- 20% (P < .05). The pulmonary/systemic pressure ratio decreased from 0.98 +/- 0.1 to 0.87 +/- 0.1 (P < .05). Mean left pulmonary artery blood flow velocity increased by 20% (P < .05). CONCLUSION: Norepinephrine may improve lung function in newborn infants with PPHN through a decrease in pulmonary/systemic artery pressure ratio and improved cardiac performance.
Assuntos
Agonistas alfa-Adrenérgicos/uso terapêutico , Hipertensão Pulmonar/fisiopatologia , Norepinefrina/uso terapêutico , Circulação Pulmonar/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/administração & dosagem , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Seguimentos , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Recém-Nascido , Infusões Intravenosas , Norepinefrina/administração & dosagem , Oximetria , Estudos Prospectivos , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar/fisiologia , Pressão Propulsora Pulmonar/efeitos dos fármacos , Resultado do TratamentoRESUMO
Sildenafil is a pulmonary vasodilator shown to be effective in neonates, but conflicting data exist regarding its effect on arterial oxygenation. To address this issue, we tested the sildenafil effect on the piglet's hypoxic pulmonary vasoconstriction (HPV) response. A segmental lung atelectasis was created by obstructing the corresponding bronchus. Total pulmonary and specific flows to the atelectatic and contra-lateral lobes were measured by magnetic resonance (MR) before and 30-min post sildenafil (0.2 and 1 mg/kg i.v.) or saline administration. Flow was reduced (p < 0.01) in the atelectatic and increased in the contra-lateral lobe indicating an effective HPV response. Sildenafil at both doses significantly (p < 0.01) increased flow solely to the atelectatic lobe. At a dose of 1 mg/kg, sildenafil induced a decrease in Pao2 from 285 +/- 37 to 161 +/- 22 mm Hg (p < 0.01). We conclude that the HPV response in the newborn is capable of almost completely reducing blood flow to nonventilated lung units and is reversed following sildenafil i.v. administration in a dose-dependent manner. In the presence of lung parenchymal disease, the use of i.v. sildenafil as a pulmonary vasodilator may worsen arterial oxygenation by reversing the HPV response in nonventilated lung units.
Assuntos
Hipóxia/fisiopatologia , Pulmão/irrigação sanguínea , Piperazinas/farmacologia , Atelectasia Pulmonar/fisiopatologia , Sulfonas/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Infusões Intravenosas , Imageamento por Ressonância Magnética , Piperazinas/administração & dosagem , Circulação Pulmonar/efeitos dos fármacos , Circulação Pulmonar/fisiologia , Ventilação Pulmonar/fisiologia , Purinas/administração & dosagem , Purinas/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Citrato de Sildenafila , Sulfonas/administração & dosagem , Suínos , Vasoconstrição/fisiologia , Vasodilatadores/administração & dosagemRESUMO
Bupropion is a non-nicotinic drug used in smoking cessation therapy. However, its acute effects remain unclear. In this study, we investigated the effects of bupropion on hemodynamic parameters in pentobarbital-anesthetized mongrel dogs. Bupropion administered either in bolus injections (3 or 6 mg/kg, i.v.) or in cumulative doses of 0.01, 0.1, 1, 3 and 10 mg/kg showed, in both studies, a significant increase of mean pulmonary arterial pressure and pulmonary vascular resistance index. These results show that bupropion can elevate the pulmonary pressure. Further investigations should be done to test this effect in smokers with chronic obstructive pulmonary disease.