RESUMEN
Introduction: Riociguat, an oral soluble guanylate cyclase stimulator, has been approved for use in adults with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension. However, there is limited data on its therapeutic use in children. Case Presentation: We report the case of two infants with severe suprasystemic pulmonary hypertension who were successfully treated with riociguat after failure to wean off inhaled nitric oxide (iNO) despite combination PAH therapy. Case 1 is a 6-month-old term male with TBX4 deletion who presented with severe hypoxemic respiratory failure and severe PAH immediately after birth. Initial cardiac catheterization showed PVRi 15.5 WU*m2. Marked hypoxemia and PAH persisted despite aggressive therapy with sildenafil, bosentan, intravenous treprostinil, and milrinone. The infant required high doses of inhaled nitric oxide (60â ppm) and manifested significant post-ductal hypoxemia and hemodynamic instability with any attempt at weaning. After discontinuation of sildenafil, initiation, and very slow uptitration of riociguat, the patient was able to maintain hemodynamic stability and wean from nitric oxide over 6 weeks with persistently severe but not worsened pulmonary hypertension. Case 2 is a 4-month-old term male with compound heterozygous SLC25A26 mutation and severe pulmonary hypertension. Initial cardiac catheterization showed PVRi 28.2 WU*m2. After uptitration of sildenafil, bosentan, and IV treprostinil, serial echocardiograms continued to demonstrate near-systemic pulmonary hypertension. He failed multiple attempts to wean off typical doses of iNO (10-20â ppm) over the following weeks with tachypnea, hypoxemia, and worsening pulmonary hypertension on echocardiogram despite continued aggressive combination targeted therapy. After a 24-h sildenafil washout, he was initiated and uptitrated on riociguat with concomitant, successful wean of nitric oxide over one week that was well tolerated. No serious adverse effects in the titration period were observed. Conclusion: Riociguat may be considered as an adjuvant therapeutic agent in selected children with severe PAH who are poorly responsive to sildenafil therapy and unable to wean from iNO.
RESUMEN
In addition to persistent airways disease, survivors of premature birth with chronic lung disease are at risk of cardiovascular sequelae, including pulmonary hypertension, systemic hypertension, left ventricular hypertrophy, and exercise intolerance. The major treatment of pulmonary hypertension is supplemental oxygen, but drugs such as calcium channel blockers may also be required. The use of inhaled nitric oxide for its long term management is being investigated
Asunto(s)
Enfermedades Cardiovasculares/etiología , Enfermedades del Prematuro/terapia , Enfermedades Pulmonares/complicaciones , Administración por Inhalación , Presión Sanguínea/fisiología , Displasia Broncopulmonar/etiología , Enfermedades Cardiovasculares/diagnóstico , Enfermedad Crónica , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/diagnóstico , Enfermedades del Prematuro/fisiopatología , Enfermedades Pulmonares/fisiopatología , Enfermedades Pulmonares/terapia , Óxido Nítrico/administración & dosificación , Oxígeno/sangre , Oxígeno/uso terapéutico , Presión Parcial , Circulación Pulmonar/fisiología , Resistencia Vascular/fisiologíaRESUMEN
We describe a 2-year-old child with severe pulmonary hypertension due to a patent ductus arteriosus (PDA) with plexiform lesions on lung biopsy. Despite high basal pulmonary vascular resistance with minimal responsiveness to inhaled nitric oxide and other vasodilators, and advanced plexogenic arteriopathy on lung biopsy, her pulmonary hypertension completely resolved after PDA ligation and during 8 years of follow-up.
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Conducto Arterioso Permeable/complicaciones , Hipertensión Pulmonar/etiología , Preescolar , Conducto Arterioso Permeable/patología , Conducto Arterioso Permeable/fisiopatología , Conducto Arterioso Permeable/cirugía , Femenino , Estudios de Seguimiento , Humanos , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Pulmón/patología , Resultado del Tratamiento , Resistencia VascularAsunto(s)
Displasia Broncopulmonar/embriología , Displasia Broncopulmonar/etiología , Inhibidores de la Angiogénesis/uso terapéutico , Displasia Broncopulmonar/metabolismo , Displasia Broncopulmonar/mortalidad , Displasia Broncopulmonar/patología , Displasia Broncopulmonar/terapia , Factores de Crecimiento Endotelial/análisis , Factores de Crecimiento Endotelial/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Humanos , Indoles/uso terapéutico , Recién Nacido , Linfocinas/análisis , Linfocinas/efectos de los fármacos , Linfocinas/fisiología , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas/efectos de los fármacos , Proteínas Proto-Oncogénicas/fisiología , Pirroles/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/análisis , Proteínas Tirosina Quinasas Receptoras/efectos de los fármacos , Proteínas Tirosina Quinasas Receptoras/fisiología , Respiración Artificial/efectos adversos , Síndrome de Dificultad Respiratoria del Recién Nacido/complicaciones , Síndrome de Dificultad Respiratoria del Recién Nacido/terapia , Factores de Riesgo , Transducción de Señal/fisiología , Factor A de Crecimiento Endotelial Vascular , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Nitric oxide (NO) and prostacyclin (PGI(2)) are potent fetal pulmonary vasodilators, but their relative roles and interactions in the regulation of the perinatal pulmonary circulation are poorly understood. We compared the separate and combined effects of nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition during acute hemodynamic stress caused by brief mechanical compression of the ductus arteriosus (DA) in chronically prepared fetal lambs. Nitro-L-arginine (L-NNA; NOS antagonist), meclofenamate (Mec; COX inhibitor), combined drugs (L-NNA-Mec), or saline (control) was infused into the left pulmonary artery (LPA) before DA compression. In controls, DA compression decreased pulmonary vascular resistance (PVR) by 43% (P < 0.01). L-NNA, but not Mec, treatment completely blocked vasodilation and caused a paradoxical increase in PVR (+31%; P < 0.05). The effects of L-NNA-Mec and L-NNA on PVR were similar. To determine if the vasodilator effect of PGI(2) is partly mediated by NO release, we studied PGI(2)-induced vasodilation before and after NOS inhibition. L-NNA treatment blocked the PGI(2)-induced rise in LPA blood flow by 73% (P < 0.001). We conclude that NO has a greater role than PGs in fetal pulmonary vasoregulation during acute hemodynamic stress and that PGI(2)-induced pulmonary vasodilation is largely mediated by NO release in the fetal lung.
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GMP Cíclico/análogos & derivados , Hemodinámica/fisiología , Pulmón/irrigación sanguínea , Óxido Nítrico/metabolismo , Prostaglandinas/metabolismo , Circulación Pulmonar/fisiología , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , GMP Cíclico/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Interacciones Farmacológicas , Conducto Arterial/fisiología , Femenino , Pulmón/embriología , Ácido Meclofenámico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Nitroarginina/química , Nitroarginina/farmacología , Embarazo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Circulación Pulmonar/efectos de los fármacos , Ovinos , Estrés Mecánico , Resistencia Vascular , VasodilataciónRESUMEN
Prolonged infusions of 17beta-estradiol reduce fetal pulmonary vascular resistance (PVR), but the effects of endogenous estrogens in the fetal pulmonary circulation are unknown. To test the hypothesis that endogenous estrogen promotes pulmonary vasodilation at birth, we studied the hemodynamic effects of prolonged estrogen-receptor blockade during late gestation and at birth in fetal lambs. We treated chronically prepared fetal lambs with ICI-182,780 (ICI, a specific estrogen-receptor blocker, n = 5) or 1% DMSO (CTRL, n = 5) for 7 days and then measured pulmonary hemodynamic responses to ventilation with low- and high-fraction inspired oxygen (FI(O(2))). Treatment with ICI did not change basal fetal PVR or arterial blood gas tensions. However, treatment with ICI abolished the vasodilator response to ventilation with low FI(O(2)) [change in PVR -30 +/- 6% (CTRL) vs. +10 +/- 13%, (ICI), P < 0.05] without reducing the vasodilator response to ventilation with high FI(O(2)) [change in PVR, -73 +/- 3% (CTRL) vs. -77 +/- 4%, (ICI); P = not significant]. ICI treatment reduced prostacyclin synthase (PGIS) expression by 33% (P < 0.05) without altering expression of endothelial nitric oxide synthase or cyclooxygenase-1 and -2. In situ hybridization and immunohistochemistry revealed that PGIS is predominantly expressed in the airway epithelium of late gestation fetal lambs. We conclude that prolonged estrogen-receptor blockade inhibits the pulmonary vasodilator response at birth and that this effect may be mediated by downregulation of PGIS. We speculate that estrogen exposure during late gestation prepares the pulmonary circulation for postnatal adaptation.
Asunto(s)
Estradiol/administración & dosificación , Antagonistas de Estrógenos/administración & dosificación , Efectos Tardíos de la Exposición Prenatal , Circulación Pulmonar/efectos de los fármacos , Receptores de Estrógenos/antagonistas & inhibidores , Animales , Animales Recién Nacidos , Western Blotting , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Sistema Enzimático del Citocromo P-450/metabolismo , Esquema de Medicación , Estradiol/análogos & derivados , Femenino , Feto/irrigación sanguínea , Feto/efectos de los fármacos , Feto/fisiología , Fulvestrant , Hemodinámica/efectos de los fármacos , Infusiones Intraarteriales/métodos , Oxidorreductasas Intramoleculares/metabolismo , Isoenzimas/metabolismo , Pulmón/efectos de los fármacos , Pulmón/embriología , Pulmón/enzimología , Óxido Nítrico/metabolismo , Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo III , Especificidad de Órganos , Embarazo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Arteria Pulmonar/embriología , Arteria Pulmonar/fisiología , Circulación Pulmonar/fisiología , Ventilación Pulmonar/efectos de los fármacos , Ovinos , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
Heat exposure early in ovine pregnancy results in placental insufficiency and intrauterine growth restriction (PI-IUGR). We hypothesized that heat exposure in this model disrupts placental structure and reduces placental endothelial nitric oxide synthase (eNOS) protein expression. We measured eNOS protein content and performed immunohistochemistry for eNOS in placentas from thermoneutral (TN) and hyperthermic (HT) animals killed at midgestation (90 days). Placental histomorphometry was compared between groups. Compared with the TN controls, the HT group showed reduced delivery weights (457 +/- 49 vs. 631 +/- 21 g; P < 0.05) and a trend for reduced placentome weights (288 +/- 61 vs. 554 +/- 122 g; P = 0.09). Cotyledon eNOS protein content was reduced by 50% in the HT group (P < 0.03). eNOS localized similarly to the vascular endothelium and binucleated cells (BNCs) within the trophoblast of both experimental groups. HT cotyledons showed a reduction in the ratio of fetal to maternal stromal tissue (1.36 +/- 0.36 vs. 3.59 +/- 1.2; P< or = 0.03). We conclude that eNOS protein expression is reduced in this model of PI-IUGR and that eNOS localizes to both vascular endothelium and the BNC. We speculate that disruption of normal vascular development and BNC eNOS production and function leads to abnormal placental vascular tone and blood flow in this model of PI-IUGR.
Asunto(s)
Retardo del Crecimiento Fetal/enzimología , Óxido Nítrico Sintasa/biosíntesis , Placenta/fisiología , Animales , Western Blotting , Desarrollo Embrionario y Fetal/fisiología , Femenino , Fiebre/enzimología , Edad Gestacional , Calor/efectos adversos , Inmunohistoquímica , Óxido Nítrico Sintasa de Tipo III , Tamaño de los Órganos/fisiología , Placenta/irrigación sanguínea , Placenta/enzimología , Placenta/patología , Insuficiencia Placentaria/enzimología , Embarazo , OvinosRESUMEN
Endothelin (ET)-1 contributes to the regulation of pulmonary vascular tone by stimulation of the ET(A) and ET(B) receptors. Although activation of the ET(A) receptor causes vasoconstriction, stimulation of the ET(B) receptors can elicit either vasodilation or vasoconstriction. To examine the physiological role of the ET(B) receptor in the pulmonary circulation, we studied a genetic rat model of ET(B) receptor deficiency [transgenic(sl/sl)]. We hypothesized that deficiency of the ET(B) receptor would predispose the transgenic(sl/sl) rat lung circulation to enhanced pulmonary vasoconstriction. We found that the lungs of transgenic(sl/sl) rats are ET(B) deficient because they lack ET(B) mRNA in the pulmonary vasculature, have minimal ET(B) receptors as determined with an ET-1 radioligand binding assay, and lack ET-1-mediated pulmonary vasodilation. The transgenic(sl/sl) rats have higher basal pulmonary arterial pressure and vasopressor responses to brief hypoxia or ET-1 infusion. Plasma ET-1 levels are elevated and endothelial nitric oxide synthase protein content and nitric oxide production are diminished in the transgenic(sl/sl) rat lung. These findings suggest that the ET(B) receptor plays a major physiological role in modulating resting pulmonary vascular tone and reactivity to acute hypoxia. We speculate that impaired ET(B) receptor activity can contribute to the pathogenesis of pulmonary hypertension.
Asunto(s)
Endotelina-1/metabolismo , Hipoxia/metabolismo , Pulmón/metabolismo , Receptores de Endotelina/deficiencia , Vasoconstricción/fisiología , Animales , Animales Modificados Genéticamente , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Dopamina beta-Hidroxilasa/genética , Endotelina-1/farmacología , Hipertensión Pulmonar/genética , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/etiología , Hibridación in Situ , Técnicas In Vitro , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo III , Regiones Promotoras Genéticas , Arteria Pulmonar/fisiología , Circulación Pulmonar/efectos de los fármacos , Circulación Pulmonar/genética , ARN Mensajero/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas , Receptor de Endotelina B , Receptores de Endotelina/genética , Receptores de Endotelina/metabolismo , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/genética , Vasoconstricción/efectos de los fármacosRESUMEN
To determine whether type II nitric oxide synthase (NOS II) contributes to the NO-mediated fall in pulmonary vascular resistance (PVR) at birth, we studied the effects of selective NOS II antagonists N-(3-aminomethyl) benzylacetamidine dihydrochloride (1400W) and aminoguanidine (AG) and a nonselective NOS antagonist, nitro-L-arginine (L-NA), during mechanical ventilation with low FIO(2) (<10%), high FIO(2) (100%), and inhaled NO (20 ppm) in 23 near-term fetal lambs. Intrapulmonary infusions of AG, 1400W, and L-NA increased basal PVR before delivery (P<0.05). In control animals, ventilation with low and high FIO(2) decreased PVR by 62% and 85%, respectively. Treatment with AG and 1400W attenuated the fall in PVR by 50% during ventilation with low and high FIO(2) (control versus treatment, P<0.05 for each intervention). L-NA treatment attenuated the fall in PVR during ventilation with low and high FIO(2) to a similar degree as the NOS II antagonists. To test the selectivity of the NOS II antagonists, we studied the effects of acetylcholine and inhaled NO in each study group. Acetylcholine-induced pulmonary vasodilation remained intact after treatment with selective NOS II antagonists but not after treatment with nonselective NOS blockade with L-NA. In contrast, the response to inhaled NO was similar between treatment groups. We conclude that selective NOS II inhibition is as effective as nonselective NOS blockade in attenuating pulmonary vasodilation at birth and speculate that NOS II activity contributes to NO-mediated pulmonary vasodilation at birth. We additionally speculate that stimulation of the airway epithelium by rhythmic distension and increased FIO(2) may activate NOS II release at birth.
Asunto(s)
Trabajo de Parto/fisiología , Pulmón/irrigación sanguínea , Óxido Nítrico Sintasa/fisiología , Circulación Pulmonar/fisiología , Resistencia Vascular/fisiología , Acetilcolina/farmacología , Administración por Inhalación , Amidinas/farmacología , Animales , Bencilaminas/farmacología , Inhibidores Enzimáticos/farmacología , Femenino , Feto , Guanidinas/farmacología , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Pulmón/efectos de los fármacos , Pulmón/embriología , Óxido Nítrico/administración & dosificación , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II , Nitroarginina/farmacología , Oxígeno/administración & dosificación , Embarazo , Circulación Pulmonar/efectos de los fármacos , Respiración Artificial , Ovinos , Resistencia Vascular/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Vasodilatadores/farmacologíaRESUMEN
Monitoring lung volume is important in the treatment of acute hypoxemic respiratory failure. However, there are no tools available for lung volume measurement to guide ventilator management during high-frequency oscillatory ventilation (HFOV) and during dynamic changes in conventional ventilation (CV). We studied the performance of a new respiratory inductive plethysmograph (RIP) with modified software. We measured Delta changes in lung volume above end-expiratory volume (V(RIP)) during HFOV and studied whether changes in V(RIP) parallel changes in mean airway pressure. Calibration of the plethysmograph was made by serial injections of a known gas volume in six term (140 d gestation) and eight preterm (125 d gestation) lambs. Linear regression analysis of the relationship between injected gas volume and V(RIP) showed strong correlation (r(2) = 0.93-1.00 term animals, r(2) = 0.86-1.00 preterm animals). The pressure volume curves from the calibration with the injected gas volumes also correlated well with the pressure volume curves extrapolated from changes in V(RIP). Lung hysteresis was clearly demonstrated with RIP after changes in mean airway pressure during HFOV and after changes in positive end-expiratory pressure during CV. We conclude that measurements of lung volume in term and preterm lambs by use of modified RIP correlate well with changes in mean airway pressure during HFOV, with static pressure volume curves and with changes in positive end-expiratory pressure during CV. We speculate that this technique may provide clinically useful information about changes in lung volume during HFOV and CV. However, evaluation of the precision and chronic stability of RIP measurements over prolonged periods will require further studies.
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Pulmón/anatomía & histología , Pletismografía/métodos , Animales , Calibración , Oxígeno/análisis , Respiración , OvinosRESUMEN
Calcium-sensitive potassium (K(Ca)) channels play a critical role in mediating perinatal pulmonary vasodilation. Because infants with persistent pulmonary hypertension of the newborn (PPHN) have blunted vasodilator responses to birth-related stimuli, we hypothesized that lung K(Ca) channel gene expression is decreased in PPHN. To test this hypothesis, we measured K(Ca) channel gene expression in distal lung homogenates from both fetal lambs with severe pulmonary hypertension caused by prolonged compression of the ductus arteriosus and age-matched, sham-operated animals (controls). After at least 9 days of compression of the ductus arteriosus, fetal lambs were killed. To determine lung K(Ca) channel mRNA levels, primers were designed against the known sequence of the K(Ca) channel and used in semiquantitative RT-PCR, with lung 18S rRNA content as an internal control. Compared to that in control lambs, lung K(Ca) channel mRNA content in the PPHN group was reduced by 26 +/- 6% (P < 0.02), whereas lung voltage-gated K(+) 2.1 mRNA content was unchanged. We conclude that lung K(Ca) channel mRNA expression is decreased in an ovine model of PPHN. Decreased K(Ca) channel gene expression may contribute to the abnormal pulmonary vascular reactivity associated with PPHN.
Asunto(s)
Hipertensión Pulmonar/embriología , Pulmón/embriología , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/genética , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Canales de Potasio de Tipo Rectificador Tardío , Femenino , Humanos , Hipertensión Pulmonar/genética , Datos de Secuencia Molecular , Canales de Potasio/química , Embarazo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Homología de Secuencia de Aminoácido , OvinosRESUMEN
Endothelin (ET)-1 contributes to regulation of pulmonary vascular tone and structure in the normal ovine fetus and in models of perinatal pulmonary hypertension. The hemodynamic effects of ET-1 are due to activation of its receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, whereas the ET(B) receptor mediates vasodilation. In a lamb model of chronic intrauterine pulmonary hypertension, ET(B) receptor activity and gene expression are decreased. To determine whether prolonged ET(B) receptor blockade causes pulmonary hypertension, we studied the hemodynamic effects of selective ET(B) receptor blockade with BQ-788. Animals were treated with an infusion of either BQ-788 or vehicle for 7 days. Prolonged BQ-788 treatment increased pulmonary arterial pressure and pulmonary vascular resistance (P < 0.05). The pulmonary vasodilator response to sarafotoxin 6c, a selective ET(B) receptor agonist, was attenuated after 7 days of BQ-788 treatment, demonstrating pharmacological blockade of the ET(B) receptor. Animals treated with BQ-788 had greater right ventricular hypertrophy and muscularization of small pulmonary arteries (P < 0. 05). Lung ET-1 levels were threefold higher in the animals treated with BQ-788 (P < 0.05). We conclude that prolonged selective ET(B) receptor blockade causes severe pulmonary hypertension and pulmonary vascular remodeling in the late-gestation ovine fetus.
Asunto(s)
Endotelina-1/fisiología , Hemodinámica/efectos de los fármacos , Hipertensión Pulmonar/embriología , Oligopéptidos/farmacología , Piperidinas/farmacología , Receptores de Endotelina/fisiología , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Dióxido de Carbono/sangre , Antagonistas de los Receptores de Endotelina , Femenino , Edad Gestacional , Hemodinámica/fisiología , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/fisiopatología , Oxígeno/sangre , Embarazo , Circulación Pulmonar/efectos de los fármacos , Circulación Pulmonar/fisiología , Receptor de Endotelina A , Receptor de Endotelina B , Valores de Referencia , Ovinos , Resistencia Vascular/efectos de los fármacosRESUMEN
OBJECTIVE: Conventional mechanical ventilatory support (CV) contributes to lung injury in premature lambs with respiratory distress syndrome, a disease that is characterized by progressive deterioration of gas exchange and increased lung inflammation. Lung recruitment strategies, such as high-frequency oscillatory ventilation (HFOV) and partial liquid ventilation (PLV), improve gas exchange and attenuate lung inflammation when instituted immediately after birth. However, whether these recruitment strategies are effective as rescue treatment after established lung injury is unknown. To determine the separate and combined effects of HFOV and PLV when initiated after the establishment of acute lung injury in severe respiratory distress syndrome, we studied the effects of these strategies on gas exchange and histologic signs of acute lung injury in premature lambs. DESIGN: Animals were intubated, treated with surfactant and ventilated with 1.00 FIO2 for 4 hrs. After 2 hrs, animals were either continued on CV (controls) or treated with one of three strategies: HFOV; CV + PLV; or HFOV + PLV. The response to low-dose inhaled nitric oxide (5 ppm) was measured in each group at the end of the study. SETTING: An animal laboratory affiliated with University of Colorado School of Medicine. SUBJECTS: A total of 20 premature lambs at 115-118 days of gestation (term = 147 days). MEASUREMENTS AND MAIN RESULTS: In comparison with control animals, each of the rescue therapies improved PaO2 after 1 hr of treatment. The HFOV and HFOV + PLV groups had higher PaO2 than CV + PLV or CV alone (p < .05). Mean airway pressure (Paw) was lower in the PLV groups during CV or HFOV compared with their controls (p < .05). Inhaled NO improved PaO2 in all groups; however, the increase in PaO2 was greatest in the HFOV + PLV group (p < .05). Histologic examination and myeloperoxidase assay were not different between groups. CONCLUSION: We conclude that each lung recruitment strategy improved oxygenation in premature lambs with established lung injury.
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Productos Biológicos , Broncodilatadores/uso terapéutico , Ventilación de Alta Frecuencia , Óxido Nítrico/uso terapéutico , Síndrome de Dificultad Respiratoria/terapia , Algoritmos , Animales , Animales Recién Nacidos , Análisis de los Gases de la Sangre , Hemodinámica , Respiración con Presión Positiva , Intercambio Gaseoso Pulmonar , Surfactantes Pulmonares/uso terapéutico , OvinosRESUMEN
To determine whether angiogenesis is necessary for normal alveolarization, we studied the effects of two antiangiogenic agents, thalidomide and fumagillin, on alveolarization during a critical period of lung growth in infant rats. Newborn rats were treated with daily injections of fumagillin, thalidomide, or vehicle during the first 2 wk of life. Compared with control treatment, fumagillin and thalidomide treatment reduced lung weight-to-body weight ratio and pulmonary arterial density by 20 and 36%, respectively, and reduced alveolarization by 22%. Because these drugs potentially have nonspecific effects on lung growth, we also studied the effects of Su-5416, an inhibitor of the vascular endothelial growth factor receptor known as kinase insert domain-containing receptor/fetal liver kinase (KDR/flk)-1. As observed with the other antiangiogenic agents, Su-5416 treatment decreased alveolarization and arterial density. We conclude that treatment with three different antiangiogenic agents attenuated lung vascular growth and reduced alveolarization in the infant rat. We speculate that angiogenesis is necessary for alveolarization during normal lung development and that injury to the developing pulmonary circulation during a critical period of lung growth can contribute to lung hypoplasia.
Asunto(s)
Animales Recién Nacidos/crecimiento & desarrollo , Neovascularización Fisiológica/fisiología , Alveolos Pulmonares/crecimiento & desarrollo , Inhibidores de la Angiogénesis/farmacología , Animales , Sulfato de Bario/administración & dosificación , Peso Corporal/efectos de los fármacos , Ciclohexanos , Ácidos Grasos Insaturados/farmacología , Gelatina/administración & dosificación , Corazón/anatomía & histología , Indoles/farmacología , Inyecciones Intraarteriales , Pulmón/anatomía & histología , Pulmón/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Alveolos Pulmonares/anatomía & histología , Alveolos Pulmonares/efectos de los fármacos , Arteria Pulmonar/anatomía & histología , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptores de Factores de Crecimiento/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular , Sesquiterpenos , Talidomida/farmacologíaRESUMEN
Antenatal administration of glucocorticoids has been shown to improve postnatal lung function after preterm birth in the ovine fetus. Mechanisms of steroid-induced lung maturation include increased surfactant production and altered parenchymal lung structure. Whether steroid treatment also affects lung vascular function is unclear. Because nitric oxide contributes to the fall in pulmonary vascular resistance at birth, we hypothesized that the improvement of postnatal lung function of preterm lambs after treatment with prenatal glucocorticoids may be in part caused by an increase in endothelial nitric oxide synthase (eNOS) activity. To determine whether glucocorticoid treatment increases lung eNOS expression, we measured eNOS protein content by Western blot analysis of distal lung homogenates and immunostaining of formalin-fixed lungs from ovine fetuses delivered at preterm and term gestation after prenatal administration of glucocorticoids. Treatment protocols were followed in which ewes were treated with intramuscular betamethasone (0.5 mg/kg) at single or multiple doses at weekly intervals, and fetuses were delivered at 125, 135, or 145 d gestation. All groups were compared with saline-treated controls. Western blot analysis of whole lung homogenates demonstrated a 4-fold increase in eNOS protein content in lambs treated with repetitive doses of glucocorticoids and delivery at term (145 d; p < 0.002). In addition, a small increase in lung eNOS protein content was seen in lambs treated with a single dose of betamethasone at 128 d gestation with delivery at 135 d gestation. In comparison with control animals, there were no differences in lung eNOS content from the remaining lambs treated with glucocorticoids when delivery occurred at preterm ages (125 and 135 d). Immunostaining showed eNOS predominantly in the vascular endothelium in all vessel sizes. Pattern of staining was not altered by treatment with antenatal glucocorticoids. We conclude that maternal treatment with glucocorticoids increases lung eNOS content after multiple doses and delivery at term gestation. We speculate that antenatal glucocorticoids may up-regulate eNOS but that the timing and duration of steroid administration appears to be critical to this response.
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Betametasona/farmacología , Glucocorticoides/farmacología , Pulmón/embriología , Pulmón/enzimología , Óxido Nítrico Sintasa/metabolismo , Animales , Animales Recién Nacidos , Betametasona/administración & dosificación , Cesárea , Esquema de Medicación , Femenino , Edad Gestacional , Inmunohistoquímica , Inyecciones Intramusculares , Pulmón/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III , Embarazo , Valores de Referencia , OvinosAsunto(s)
Hipoxia/tratamiento farmacológico , Óxido Nítrico/administración & dosificación , Administración por Inhalación , Factores de Edad , Ecocardiografía , Edad Gestacional , Humanos , Recién Nacido , Recien Nacido Prematuro , Selección de Paciente , Respiración Artificial , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
As observed with nitric oxide (NO), carbon monoxide (CO) binds and may activate soluble guanylate cyclase and increase cGMP levels in smooth muscle cells in vitro. Because inhaled NO (I(NO)) causes potent and sustained pulmonary vasodilation, we hypothesized that inhaled CO (I(CO)) may have similar effects on the perinatal lung. To determine whether I(CO) can lower pulmonary vascular resistance (PVR) during the perinatal period, we studied the effects of I(CO) on late-gestation fetal lambs. Catheters were placed in the main pulmonary artery, left pulmonary artery (LPA), aorta, and left atrium to measure pressure. An ultrasonic flow transducer was placed on the LPA to measure blood flow to the left lung. After baseline measurements, fetal lambs were mechanically ventilated with a hypoxic gas mixture (inspired O(2) fraction < 0.10) to maintain a constant fetal arterial PO(2). After 60 min (baseline), the lambs were treated with I(CO) [5-2,500 parts/million (ppm)]. Comparisons were made with I(NO) (5 and 20 ppm) and combined I(NO) (5 ppm) and I(CO) (100 and 2,500 ppm). We found that I(CO) did not alter left lung blood flow or PVR at any of the study doses. In contrast, low-dose I(NO) decreased PVR by 47% (P < 0.005). The combination of I(NO) and I(CO) did not enhance the vasodilator response to I(NO). To determine whether endogenous CO contributes to vascular tone in the fetal lung, zinc protoporphyrin IX, an inhibitor of heme oxygenase, was infused into the LPA in three lambs. Zinc protoporphyrin IX had no effect on baseline PVR, aortic pressure, or the pressure gradient across the ductus arteriosus. We conclude that I(CO) does not cause vasodilation in the near-term ovine transitional circulation, and endogenous CO does not contribute significantly to baseline pulmonary vascular tone or ductus arteriosus tone in the late-gestation ovine fetus.
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Monóxido de Carbono/farmacología , Feto/fisiología , Circulación Pulmonar/efectos de los fármacos , Vasodilatación , Administración por Inhalación , Animales , Presión Sanguínea/efectos de los fármacos , Edad Gestacional , Hemodinámica/efectos de los fármacos , Inyecciones Intraarteriales , Protoporfirinas/farmacología , Arteria Pulmonar/efectos de los fármacos , Ovinos/embriología , Resistencia Vascular/efectos de los fármacosRESUMEN
Mechanisms that regulate endothelin (ET) in the perinatal lung are complex and poorly understood, especially with regard to the role of ET before and after birth. We hypothesized that the ET system is developmentally regulated and that the balance of ET(A) and ET(B) receptor activity favors vasoconstriction. To test this hypothesis, we performed a series of molecular and physiological studies in the fetal lamb, newborn lamb, and adult sheep. Lung preproET-1 mRNA levels, tissue ET peptide levels, and cellular localization of ET-1 expression were determined by Northern blot analysis, peptide assay, and immunohistochemistry in distal lung tissue from fetal lambs between 70 and 140 days (term = 145 days), newborn lambs, and ewes. Lung mRNA expression for the ET(A) and ET(B) receptors was also measured at these ages. We found that preproET-1 mRNA expression increased from 113 to 130 days gestation. Whole lung ET protein content was highest at 130 days gestation but decreased before birth in the fetal lamb lung. Immunolocalization of ET-1 protein showed expression of ET-1 in the vasculature and bronchial epithelium at all gestational ages. ET(A) receptor mRNA expression and ET(B) receptor mRNA increased from 90 to 125 and 135 days gestation. To determine changes in activity of the ET(A) and ET(B) receptors, we studied the effect of selective antagonists to the ET(A) or ET(B) receptors at 120, 130, and 140 days of fetal gestation. ET(A) receptor-mediated vasoconstriction increased from 120 to 140 days, whereas blockade of the ET(B) receptor did not change basal fetal pulmonary vascular tone at any age examined. We conclude that the ET system is developmentally regulated and that the increase in ET(A) receptor gene expression correlates with the onset of the vasodilator response to ET(A) receptor blockade. Although ET(B) receptor gene expression increases during late gestation, the balance of ET receptor activity favors vasoconstriction under basal conditions. We speculate that changes in ET receptor activity play important roles in regulation of pulmonary vascular tone in the ovine fetus.
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Endotelinas/metabolismo , Pulmón/embriología , Ovinos/embriología , Animales , Northern Blotting , Desarrollo Embrionario y Fetal , Endotelina-1 , Endotelinas/genética , Feto/metabolismo , Feto/fisiología , Hemodinámica/efectos de los fármacos , Inmunohistoquímica , Pulmón/citología , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , ARN Mensajero/metabolismo , Receptor de Endotelina A , Receptor de Endotelina B , Receptores de Endotelina/genéticaRESUMEN
Dexamethasone (Dex) treatment during a critical period of lung development causes lung hypoplasia in infant rats. However, the effects of Dex on the pulmonary circulation are unknown. To determine whether Dex increases the risk for development of pulmonary hypertension, we treated newborn Sprague-Dawley rats with Dex (0.25 microg/day, days 3-13). Litters were divided equally between Dex-treated and vehicle control (ethanol) rats. Rats were raised in either room air until 10 wk of age (normoxic groups) or room air until 7 wk of age and then in a hypoxia chamber (inspired O(2) fraction = 0.10; hypoxic groups) for 3 wk to induce pulmonary hypertension. Compared with vehicle control rats, Dex treatment of neonatal rats reduced alveolarization (by 42%; P < 0.05) and barium-filled pulmonary artery counts (by 37%; P < 0.05) in 10-wk-old adults. Pulmonary arterial pressure and the ratio of right ventricle to left ventricle plus septum weights (RV/LV+S) were higher in 10-wk-old Dex-treated normoxic rats compared with those in normoxic control rats (by 16 and 16% respectively; P < 0.05). Small pulmonary arteries of adult normoxic Dex-treated rats showed increased vessel wall thickness compared with that in control rats (by 15%; P < 0.05). After 3 wk of hypoxia, RV/LV+S values were 36% higher in rats treated with Dex in the neonatal period compared with those in hypoxic control rats (P < 0.05). RV/LV+S was 42% higher in hypoxic control rats compared with those in normoxic control rats (P < 0.05). We conclude that Dex treatment of neonatal rats caused sustained lung hypoplasia and increased pulmonary arterial pressures and augmented the severity of hypoxia-induced pulmonary hypertension in adult rats.
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Animales Recién Nacidos/fisiología , Dexametasona/farmacología , Glucocorticoides/farmacología , Hipertensión Pulmonar/etiología , Angiografía , Animales , Presión Sanguínea , Peso Corporal/efectos de los fármacos , Tabiques Cardíacos/patología , Hipertrofia Ventricular Derecha/patología , Pulmón/diagnóstico por imagen , Pulmón/patología , Miocardio/patología , Tamaño de los Órganos/efectos de los fármacos , Alveolos Pulmonares/patología , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Ratas , Ratas Sprague-Dawley , Factores de RiesgoRESUMEN
We hypothesized that disrupted alveolarization and lung vascular growth caused by brief perinatal hypoxia would predispose infant rats to higher risk for developing pulmonary hypertension when reexposed to hypoxia. Pregnant rats were exposed to 11% inspired oxygen fraction (barometric pressure, 410 mmHg; inspired oxygen pressure, 76 mmHg) for 3 days before birth and were maintained in hypoxia for 3 days after birth. Control rats were born and raised in room air. At 2 wk of age, rats from both groups were exposed to hypoxia for 1 wk or kept in room air. We found that brief perinatal hypoxia resulted in a greater increase in right ventricular systolic pressure and higher ratio of right ventricle to left ventricle plus septum weights after reexposure to hypoxia after 2 wk of age. Moreover, perinatal hypoxic rats had decreased radial alveolar counts and reduced pulmonary artery density. We conclude that brief perinatal hypoxia increases the severity of pulmonary hypertension when rats are reexposed to hypoxia. We speculate that disrupted alveolarization and lung vascular growth following brief perinatal hypoxia may increase the risk for severe pulmonary hypertension with exposure to adverse stimuli later in life.