ABSTRACT
BACKGROUND: Pulmonary hypertension remains difficult to manage in congenital diaphragmatic hernia (CDH). Prenatal therapy may ameliorate postnatal pulmonary hypertension. We hypothesized that intra-amniotic (IA) injection of either sildenafil, a phosphodiesterase 5 inhibitor, or rosiglitazone, a PPAR-γ agonist, or both late in gestation would decrease the detrimental pulmonary vascular remodeling seen in CDH and improve peripheral pulmonary blood flow. METHODS: Pregnant rats were gavaged with nitrogen on embryonic day (E) 9.5 to induce fetal CDH. Sildenafil and/or rosiglitazone were administered to each fetus via an intra-amniotic injection after laparotomy on the pregnant dam at E19.5, and fetuses delivered at E21.5. Efficacy measures were gross necropsy, histology, peripheral blood flow assessment using intra-cardiac injection of a vascular tracer after delivery, and protein expression analysis. RESULTS: Intra-amniotic injections did not affect fetal survival, the incidence of CDH, or lung weight-to-body weight ratio in CDH fetuses. IA sildenafil injection decreased pulmonary vascular muscularization, and rosiglitazone produced an increase in peripheral pulmonary blood flow distribution. The combination of sildenafil and rosiglitazone decreased pulmonary artery smooth muscle cell proliferation. These intra-amniotic treatments did not show any negative effects in either CDH fetuses or control fetuses. CONCLUSION: IA injection of sildenafil and rosiglitazone late in gestation ameliorates the pulmonary hypertensive phenotype of CDH and may have utility in clinical translation. LEVEL OF EVIDENCE: Not applicable.
Subject(s)
Hernias, Diaphragmatic, Congenital , Hypertension, Pulmonary , Rats, Sprague-Dawley , Rosiglitazone , Sildenafil Citrate , Sildenafil Citrate/administration & dosage , Sildenafil Citrate/therapeutic use , Sildenafil Citrate/pharmacology , Animals , Rosiglitazone/administration & dosage , Rosiglitazone/pharmacology , Rosiglitazone/therapeutic use , Hernias, Diaphragmatic, Congenital/complications , Female , Pregnancy , Rats , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/etiology , Disease Models, Animal , Phenotype , Phosphodiesterase 5 Inhibitors/administration & dosage , Phosphodiesterase 5 Inhibitors/therapeutic use , Phosphodiesterase 5 Inhibitors/pharmacology , Vascular Remodeling/drug effects , Fetal Therapies/methods , Thiazolidinediones/administration & dosage , Thiazolidinediones/therapeutic use , Pulmonary Circulation/drug effectsABSTRACT
Heart failure is a serious clinical and public health problem. Currently there is an unmet demand for effective therapies for heart failure. Herein we reported noninvasive inhalation delivery of nanotherapies to prevent heart failure. Methods: A reactive oxygen species (ROS)-scavenging material (TPCD) was synthesized, which was processed into antioxidative and anti-inflammatory nanoparticles (i.e., TPCD NP). By decoration with a mitochondrial-targeting moiety, a multilevel targeting nanotherapy TTPCD NP was engineered. Pulmonary accumulation of inhaled TPCD NP and underlying mechanisms were examined in mice. In vivo efficacies of nanotherapies were evaluated in mice with doxorubicin (DOX)-induced cardiomyopathy. Further, an antioxidative, anti-inflammatory, and pro-resolving nanotherapy (i.e., ATTPCD NP) was developed, by packaging a peptide Ac2-26. In vitro and in vivo efficacies of ATTPCD NP were also evaluated. Results: TPCD NP alleviated DOX-induced oxidative stress and cell injury by internalization in cardiomyocytes and scavenging overproduced ROS. Inhaled TPCD NP can accumulate in the heart of mice by transport across the lung epithelial and endothelial barriers. Correspondingly, inhaled TPCD NP effectively inhibited DOX-induced heart failure in mice. TTPCD NP showed considerably enhanced heart targeting capability, cellular uptake efficiency, and mitochondrial localization capacity, thereby potentiating therapeutic effects. Notably, TPCD NP can serve as bioactive and ROS-responsive nanovehicles to achieve combination therapy with Ac2-26, affording further enhanced efficacies. Importantly, inhaled TPCD NP displayed good safety at a dose 5-fold higher than the efficacious dose. Conclusions: Inhalation delivery of nanoparticles is an effective, safe, and noninvasive strategy for targeted treatment of heart diseases. TPCD NP-based nanotherapies are promising drugs for heart failure and other acute/chronic heart diseases associated with oxidative stress.
Subject(s)
Heart Failure/prevention & control , Nanoparticles/therapeutic use , Pulmonary Circulation/drug effects , Theranostic Nanomedicine/methods , A549 Cells , Administration, Inhalation , Animals , Anti-Inflammatory Agents/pharmacology , Cardiomyopathies/drug therapy , Cardiomyopathies/metabolism , Cell Line , Doxorubicin/therapeutic use , Drug Delivery Systems , Heart/drug effects , Humans , Inflammation/drug therapy , Lung/drug effects , Mice , Primary Cell Culture , RAW 264.7 Cells , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , beta-CyclodextrinsABSTRACT
Changes in pulmonary microcirculation were studied in isolated perfused rabbit lungs during modelling pulmonary thromboembolism under conditions of acetylcholine infusion against the background of treatment with M1 acetylcholine receptor blocker pirenzepine or blockade of muscarinic acetylcholine receptors with atropine. In the first case, the increase in pulmonary artery pressure was less pronounced than in case of atropine treatment. In response to pulmonary embolism after acetylcholine infusion against the background of pirenzepine pretreatment, the capillary hydrostatic pressure and postcapillary resistance did not change, while after atropine treatment, these parameters increased. In case of pulmonary embolism after acetylcholine infusion combined with selective blockade of M1 muscarinic acetylcholine receptors, the capillary filtration coefficient increased to a greater extent, than in the control and after blockade of muscarinic acetylcholine receptors.
Subject(s)
Muscarinic Antagonists/pharmacology , Pulmonary Circulation/drug effects , Pulmonary Embolism , Acetylcholine/pharmacology , Animals , Atropine/pharmacology , Blood Pressure/drug effects , Disease Models, Animal , Lung/blood supply , Lung/drug effects , Microcirculation/drug effects , Nitroglycerin/pharmacology , Pulmonary Circulation/physiology , Pulmonary Embolism/pathology , Pulmonary Embolism/physiopathology , Rabbits , Receptors, Muscarinic/drug effects , Receptors, Muscarinic/metabolism , Vascular Resistance/drug effects , Vascular Resistance/physiologyABSTRACT
OBJECTIVE: To study the effects of irbesartan on pulmonary artery lesions in a rat model with chronic mountain sickness (CMS) and identify the biomarkers involved. METHODS: In this study, we used a rat model of CMS to evaluate the therapeutic effect of irbesartan by measuring pulmonary artery pressure and evaluating the histopathology of the pulmonary artery. We also used proteomics technology to identify differentially expressed proteins (DEPs) in the serum and performed bioinformatics analysis. Results were then verified by enzyme linked immunosorbent assay (ELISA) and immunohistochemistry (IHC). RESULTS: Irbesartan treatment induced a significant decrease (P < 0.05) in the pulmonary artery pressure of CMS rats. Histopathological and electron microscope further confirmed that high altitude hypoxia induced changes in the structure of the pulmonary artery tissue and caused ultrastructural lesions. Proteomics analysis identified 40 DEPs; bioinformatics analysis further revealed that the cholesterol metabolism pathway plays a crucial role in the occurrence of CMS. ELISA and IHC verified that several DEPs (Apo-A1, Apo-C1, Apo-E, IGF-1, Profilin1, and Col1a1) represent critical biological markers in pulmonary artery disease caused by CMS. CONCLUSIONS: Irbesartan significantly improved pulmonary artery damage in a rat model of CMS possibly by impacting on the cholesterol metabolism pathway and by reducing damage to vascular endothelial cells. Irbesartan also inhibited the expression levels of IGF-1, Profilin1 and Col1a1 to relieve pulmonary artery pressure and improve lung function by inhibiting vascular remodeling. Several proteins were identified as potential biomarkers of CMS, including Apo-A1, Apo-C1, Apo-E, IGF-1, Profilin1, and Col1a1.
Subject(s)
Altitude Sickness/drug therapy , Altitude Sickness/metabolism , Cholesterol/metabolism , Irbesartan/therapeutic use , Protein Interaction Maps/drug effects , Proteomics/methods , Animals , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Chronic Disease/drug therapy , Irbesartan/pharmacology , Protein Interaction Maps/physiology , Pulmonary Artery/drug effects , Pulmonary Artery/metabolism , Pulmonary Circulation/drug effects , Pulmonary Circulation/physiology , Rats , Rats, Sprague-Dawley , Vascular Remodeling/drug effects , Vascular Remodeling/physiologyABSTRACT
Despite the various parenchymal presentation of coronavirus disease 2019 (COVID-19) pneumonia, the involvement of the vascular component, the reduction of perfusion in noninjured part of the lung and secondary right to left shunt play an important role in the genesis of the respiratory insufficiency. We present the case of a 72-year-old woman admitted to Livorno Hospital for severe respiratory insufficiency due to SARS-CoV-2 infection unresponsive to noninvasive in whom administration of nebulized phosphodiesterase 3 (PDE3) inhibitor enoximone was able to improve oxygenation avoiding tracheal intubation. Intravenous infusions of phosphodiesterase inhibitors are commonly used as pulmonary vasodilators in the management of pulmonary hypertension. This is the first case showing that inhaled route administration of PDE3 inhibitor enoximone could be important in the management of COVID-19 hypoxemia, to restore perfusion in noninjured part of the lung, improving oxygenation and avoiding risks of systemic infusion.
Subject(s)
COVID-19 Drug Treatment , Enoximone/administration & dosage , Hypoxia/drug therapy , Lung/blood supply , Phosphodiesterase 3 Inhibitors/administration & dosage , Pulmonary Circulation/drug effects , Administration, Inhalation , Aerosols , Aged , COVID-19/physiopathology , COVID-19/virology , Female , Humans , Hypoxia/physiopathology , Hypoxia/virology , Nebulizers and Vaporizers , Treatment OutcomeABSTRACT
INTRODUCTION: Cocoa flavanols (CF) may exert health benefits through their potent vasodilatory effects, which are perpetuated by elevations in nitric oxide (NO) bioavailability. These vasodilatory effects may contribute to improved delivery of blood and oxygen (O2) to exercising muscle. PURPOSE: Therefore, the objective of this study was to examine how CF supplementation impacts pulmonary O2 uptake ([Formula: see text]) kinetics and exercise tolerance in sedentary middle-aged adults. METHODS: We employed a double-blind cross-over, placebo-controlled design whereby 17 participants (11 male, 6 female; mean ± SD, 45 ± 6 years) randomly received either 7 days of daily CF (400 mg) or placebo (PL) supplementation. On day 7, participants completed a series of 'step' moderate- and severe-intensity exercise tests for the determination of [Formula: see text] kinetics. RESULTS: During moderate-intensity exercise, the time constant of the phase II [Formula: see text] kinetics ([Formula: see text]) was decreased by 15% in CF as compared to PL (mean ± SD; PL 40 ± 12 s vs. CF 34 ± 9 s, P = 0.019), with no differences in the amplitude of [Formula: see text] (A[Formula: see text]; PL 0.77 ± 0.32 l min-1 vs. CF 0.79 ± 0.34 l min-1, P = 0.263). However, during severe-intensity exercise, [Formula: see text], the amplitude of the slow component ([Formula: see text]) and exercise tolerance (PL 435 ± 58 s vs. CF 424 ± 47 s, P = 0.480) were unchanged between conditions. CONCLUSION: Our data show that acute CF supplementation enhanced [Formula: see text] kinetics during moderate-, but not severe-intensity exercise in middle-aged participants. These novel effects of CFs, in this demographic, may contribute to improved tolerance of moderate-activity physical activities, which appear commonly present in daily life. TRIAL REGISTRATION: Registered under ClinicalTrials.gov Identifier no. NCT04370353, 30/04/20 retrospectively registered.
Subject(s)
Cacao/metabolism , Exercise Tolerance/physiology , Flavanones/metabolism , Oxygen Consumption/drug effects , Pulmonary Circulation/drug effects , Sedentary Behavior , Cross-Over Studies , Double-Blind Method , Exercise Test , Female , Humans , Male , Middle Aged , Vasodilation/drug effectsSubject(s)
Fontan Procedure , Phosphodiesterase 5 Inhibitors/pharmacology , Postoperative Complications , Pulmonary Circulation , Univentricular Heart , Vascular Resistance , Fontan Procedure/adverse effects , Fontan Procedure/methods , Hemodynamics/physiology , Homeostasis/physiology , Humans , Models, Cardiovascular , Postoperative Complications/diagnosis , Postoperative Complications/drug therapy , Postoperative Complications/physiopathology , Pulmonary Circulation/drug effects , Pulmonary Circulation/physiology , Treatment Outcome , Univentricular Heart/physiopathology , Univentricular Heart/surgery , Vascular Resistance/drug effects , Vascular Resistance/physiologyABSTRACT
BACKGROUND: Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) predominantly characterized by pulmonary vein and capillary involvement. An association between chemotherapy, in particular mitomycin C (MMC), and PVOD has been reported. RESEARCH QUESTION: What are the characteristics of MMC-induced PVOD, and what is the prognosis for patients with MMC-induced PVOD? STUDY DESIGN AND METHODS: We report the clinical, functional, radiologic, and hemodynamic characteristics at diagnosis and outcomes of patients with PVOD from the French PH Registry after exposure to MMC. The results are expressed as the median (minimum-maximum). RESULTS: From June 2011 to December 2018, 17 incident cases of MMC-induced PVOD were identified. At diagnosis, these patients had severe clinical and functional impairment, with 12 patients having a New York Heart Association (NYHA) functional class of III or IV and a 6-min walk distance of 220 (0-465) m. Right heart catheterization confirmed severe precapillary PH with a mean pulmonary artery pressure of 38 (30-52) mm Hg, a cardiac index of 2.2 (1.5-4) L/(min × m2), and pulmonary vascular resistance of 8.3 (5.1-14.5) Wood units. The diffusing capacity of the lungs for carbon monoxide was markedly decreased at 31% (20%-51%) of the theoretical values associated with severe hypoxemia. MMC was withdrawn for all patients, and 14 patients received specific pulmonary arterial hypertension (PAH) therapies. Among these patients, mild but statistically insignificant improvements were observed in NYHA functional class (P = .10), 6-min walk distance (P = .09), and pulmonary vascular resistance (-4.7 Wood units; P = .052) at reassessment (median delay of 4.8 months). Three patients experienced pulmonary edema requiring the cessation or reduction of PAH treatment. The median overall survival was 20 months, and the 6-, 12-, and 24-month survival rates were 76%, 58%, and 18%, respectively. INTERPRETATION: PVOD after MMC treatment is a rare but life-threatening complication associated with a poor prognosis despite MMC withdrawal and PAH-specific therapy.
Subject(s)
Hypertension, Pulmonary , Lung , Mitomycin , Pulmonary Veno-Occlusive Disease , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/adverse effects , Cardiac Catheterization/methods , Cardiac Catheterization/statistics & numerical data , Female , France/epidemiology , Functional Status , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/physiopathology , Lung/blood supply , Lung/diagnostic imaging , Male , Middle Aged , Mitomycin/administration & dosage , Mitomycin/adverse effects , Patient Care Management/methods , Pharmacovigilance , Prognosis , Pulmonary Circulation/drug effects , Pulmonary Veno-Occlusive Disease/chemically induced , Pulmonary Veno-Occlusive Disease/diagnosis , Pulmonary Veno-Occlusive Disease/mortality , Pulmonary Veno-Occlusive Disease/physiopathology , Pulmonary Wedge Pressure , Registries/statistics & numerical data , Survival Analysis , Withholding TreatmentABSTRACT
Changes in pulmonary microhemodynamics during modelling of pulmonary thromboembolism against the background of nebivolol and mirabegron pretreatment were studied in isolated perfused rabbit lungs. In both cases, the pulmonary artery pressure and precapillary and pulmonary vascular resistance increased to a greater extent than in control animals, but the increase in capillary hydrostatic pressure was less pronounced. The postcapillary resistance did not change in pulmonary embolism against the background of nebivolol administration and increased in case of mirabegron pretreatment; capillary filtration coefficient after nebivolol pretreatment increased less markedly than after mirabegron administration. The increase in capillary filtration coefficient after activation of ß3-adrenoceptors with the specified drugs depended on the ratio of constriction of pulmonary veins, capillary hydrostatic pressure, and endothelial permeability.
Subject(s)
Acetanilides/pharmacology , Isoproterenol/pharmacology , Nebivolol/pharmacology , Propranolol/pharmacology , Pulmonary Embolism/metabolism , Receptors, Adrenergic, beta/metabolism , Thiazoles/pharmacology , Adrenergic beta-1 Receptor Agonists/pharmacology , Adrenergic beta-3 Receptor Agonists/pharmacology , Adrenergic beta-Agonists/pharmacology , Adrenergic beta-Antagonists/pharmacology , Animals , Blood Pressure/drug effects , Capillary Permeability/drug effects , Capillary Permeability/physiology , Disease Models, Animal , Lung/drug effects , Lung/physiology , Pulmonary Circulation/drug effects , Pulmonary Circulation/physiology , Pulmonary Embolism/pathology , Rabbits , Vascular Resistance/drug effects , Vascular Resistance/physiologyABSTRACT
BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) is a reaction of the pulmonary vasculature upon hypoxia, diverting blood flow into ventilated areas to preserve oxygenation. It is impaired in endotoxemia or ARDS. Voltage gated potassium channels have been shown to play a key role in the regulation of HPV. The aim of the study was to identify a voltage gated potassium channel involved in dysregulated HPV during endotoxemia. METHODS: Lungs of male C57BL/6 mice with and without endotoxemia (n = 6 ea. group) were analyzed for Kv3.4 gene and protein expression. HPV was examined in isolated perfused lungs of mice with and without endotoxemia and with and without selective Kv3.4 blocker BDS-I (n = 7 ea. group). Pulmonary artery pressure (PAP) and pressure-flow curves were measured during normoxic (FiO2 0.21) and hypoxic (FiO2 0.01) ventilation. HPV was quantified as the increase in perfusion pressure in response to hypoxia in percent of baseline perfusion pressure (ΔPAP) in the presence and absence of BDS-I. RESULTS: Kv3.4 gene (3.2 ± 0.5-fold, p < 0.05) and protein (1.5 ± 0.1-fold p < 0.05) expression levels were increased in endotoxemic mouse lungs. Endotoxemia reduced HPV (∆PAP control: 121.2 ± 8.7% vs. LPS 19.5 ± 8.0%, means ± SEM) while inhibition of Kv3.4 with 50 nM BDS-I augmented HPV in endotoxemic but not in control lungs (∆PAP control BDS-I: 116.6 ± 16.0% vs. LPS BDS-I 84.4 ± 18.2%, means ± SEM). CONCLUSIONS: Kv3.4 gene and protein expressions are increased in endotoxemic mouse lungs. Selective inhibition of Kv3.4 augments HPV in lungs of endotoxemic mice, but not in lungs of control mice.
Subject(s)
Endotoxemia/metabolism , Hypoxia/metabolism , Lung/metabolism , Shaw Potassium Channels/biosynthesis , Vasoconstriction/physiology , Animals , Endotoxemia/pathology , Hypoxia/pathology , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Lung/blood supply , Lung/drug effects , Male , Mice , Mice, Inbred C57BL , Organ Culture Techniques , Perfusion , Pulmonary Artery/drug effects , Pulmonary Artery/physiopathology , Pulmonary Circulation/drug effects , Shaw Potassium Channels/antagonists & inhibitors , Vasoconstriction/drug effectsABSTRACT
AIMS: The angiotensin receptor and neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) is recommended for the treatment of patients with heart failure in New York Heart Association (NYHA) class II-III and left ventricular ejection fraction (LVEF) 35% or less. We examined the effects of sacubitril/valsartan on cardiac remodeling and their correlation with heart failure duration in patients enrolled in our heart failure clinic from March 2017 to December 2019. METHODS: Echocardiographic and clinical/laboratory data were collected at baseline and at 6-month and 12-month follow-up visits in 69 patients (age 67â±â12 years, disease duration 8.4â±â5.8 years, 93% men). RESULTS: At both time points, mean NYHA class, NT-proBNP level, LVEF, LV end-systolic volume, and estimated systolic pulmonary pressure significantly (Pâ<â0.05) improved versus baseline, as did the proportion of patients with diastolic dysfunction grade 3 or functional mitral regurgitation grade 3-4. In the subgroup with mean disease duration less than 8.5 years (nâ=â40), there was a significant improvement in all variables at both time points; in this group, a recovery of right ventricular function was also seen at the 12-month follow-up. On the contrary, patients with heart failure duration of at least 8.5 years (nâ=â29) showed only a slight improvement in LVEF and mitral regurgitation at 12 months. There were no significant changes in renal function and/or potassium levels in all patients. CONCLUSION: In patients with a relatively short disease duration, sacubitril/valsartan was associated with a strong favorable remodeling of the left ventricle and improvement in pulmonary circulation.
Subject(s)
Aminobutyrates/therapeutic use , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Biphenyl Compounds/therapeutic use , Heart Failure/drug therapy , Protease Inhibitors/therapeutic use , Stroke Volume/drug effects , Valsartan/therapeutic use , Ventricular Function, Left/drug effects , Ventricular Remodeling/drug effects , Adult , Aged , Aged, 80 and over , Aminobutyrates/adverse effects , Angiotensin II Type 1 Receptor Blockers/adverse effects , Biphenyl Compounds/adverse effects , Drug Combinations , Female , Heart Failure/diagnostic imaging , Heart Failure/physiopathology , Humans , Male , Middle Aged , Mitral Valve/diagnostic imaging , Mitral Valve/drug effects , Mitral Valve/physiopathology , Mitral Valve Insufficiency/diagnostic imaging , Mitral Valve Insufficiency/drug therapy , Mitral Valve Insufficiency/physiopathology , Neprilysin/antagonists & inhibitors , Protease Inhibitors/adverse effects , Pulmonary Circulation/drug effects , Recovery of Function , Retrospective Studies , Time Factors , Treatment Outcome , Valsartan/adverse effects , Ventricular Function, Right/drug effectsABSTRACT
BACKGROUND: Dysregulated nitric oxide (NO) signaling contributes to chronic hypoxia (CH)-induced pulmonary hypertension (PH). NO signaling is improved and pulmonary vascular resistance (PVR) is reduced in CH piglets treated with the l-arginine-NO precursor, l-citrulline. We hypothesized that l-citrulline might cause structural changes in the pulmonary circulation that would contribute to the reduction in PVR and that the l-citrulline-induced structural changes would be accompanied by alterations in vascular endothelial growth factor (VEGF) signaling. METHODS: We evaluated small pulmonary arterial (PA) wall thickness, lung capillary density, and protein abundances of VEGF, VEGFR2, and phospho (p)-VEGFR2 in PA and peripheral lung samples of piglets raised in the lab in CH (10%-12% O2 ) from the day of life (DOL) 2 until DOL 11 to 12 or raised in room air (normoxia) by the vendor and studied on arrival to the lab on DOL 11 to 12. Some CH piglets were treated with oral l-citrulline (1-1.5 g/kg/d) starting on the third day of hypoxia. RESULTS: PA wall thickness was 32% less and lung capillary formation was nearly doubled in l-citrulline treated than untreated CH piglets. Both of these l-citrulline-induced structural changes in the pulmonary circulation were accompanied by altered amounts of VEGF protein but not by altered amounts of either VEGFR2 or p-VEGFR2 proteins. CONCLUSIONS: Alterations in the structure of the pulmonary circulation in CH piglets by l-citrulline are unlikely to be mediated by overall VEGF signaling. Nonetheless, l-citrulline- induced structural changes should reduce PVR and thereby contribute to the amelioration of CH-induced PH.
Subject(s)
Citrulline/pharmacology , Hypoxia/physiopathology , Pulmonary Circulation/drug effects , Animals , Animals, Newborn , Capillaries/drug effects , Capillaries/physiology , Lung/drug effects , Lung/metabolism , Lung/physiology , Pulmonary Artery/drug effects , Pulmonary Artery/physiology , Swine , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Rationale: Antenatal inflammation with placental dysfunction is strongly associated with high bronchopulmonary dysplasia (BPD) risk in preterm infants. Whether antenatal or postnatal HIF (hypoxia-inducible factor) augmentation can preserve lung structure and function and prevent pulmonary hypertension after intrauterine inflammation is controversial.Objectives: To determine whether antenatal or postnatal prolyl-hydroxylase inhibitor (PHi) therapy increases lung HIF expression, preserves lung growth and function, and prevents pulmonary hypertension in a rat model of chorioamnionitis-induced BPD caused by antenatal inflammation.Methods: Endotoxin (ETX) was administered to pregnant rats by intraamniotic injection at Embryonic Day 20, and pups were delivered by cesarean section at Embryonic Day 22. Selective PHi drugs, dimethyloxalylglycine or GSK360A, were administered into the amniotic space at Embryonic Day 20 or after birth by intraperitoneal injection for 2 weeks. Placentas and lung tissue were collected at birth for morphometric and Western blot measurements of HIF-1a, HIF-2a, VEGF (vascular endothelial growth factor), and eNOS (endothelial nitric oxide synthase) protein contents. At Day 14, lung function was assessed, and tissues were harvested to determine alveolarization by radial alveolar counts, pulmonary vessel density, and right ventricle hypertrophy (RVH).Measurements and Main Results: Antenatal PHi therapy preserves lung alveolar and vascular growth and lung function and prevents RVH after intrauterine ETX exposure. Antenatal administration of PHi markedly upregulates lung HIF-1a, HIF-2a, VEGF, and eNOS expression after ETX exposure.Conclusions: HIF augmentation improves lung structure and function, prevents RVH, and improves placental structure following antenatal ETX exposure. We speculate that antenatal or postnatal PHi therapy may provide novel strategies to prevent BPD due to antenatal inflammation.
Subject(s)
Bronchopulmonary Dysplasia/drug therapy , Hypoxia-Inducible Factor 1/metabolism , Lung/drug effects , Peptide PHI/pharmacology , Pregnancy, Animal , Amino Acids, Dicarboxylic/pharmacology , Animals , Animals, Newborn , Blotting, Western , Bronchopulmonary Dysplasia/metabolism , Bronchopulmonary Dysplasia/pathology , Disease Models, Animal , Endotoxins/adverse effects , Endotoxins/pharmacology , Female , Hypoxia-Inducible Factor 1/drug effects , Immunohistochemistry , In Vitro Techniques , Injections, Intralesional , Lung/embryology , Pregnancy , Prenatal Care , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/growth & development , Pulmonary Circulation/drug effects , Random Allocation , Rats , Rats, Sprague-Dawley , Reference Values , Respiratory Function Tests , Tissue Culture TechniquesABSTRACT
Red Bull energy drink is popular among athletes, students and drivers for stimulating effects or enhancing physical performance. In previous work, Red Bull has been shown to exert manifold cardiovascular effects at rest and during exercise. Red Bull with caffeine as the main ingredient increases blood pressure in resting individuals, probably due to an increased release of (nor)-epinephrine. Red Bull has been shown to alter heart rate or leaving it unchanged. Little is known about possible effects of caffeinated energy drinks on pulmonary ventilation/perfusion distribution at sea level or at altitude. Here, we hypothesized a possible alteration of pulmonary blood flow in ambient air and in hypoxia after Red Bull consumption. We subjected eight anesthetized piglets in normoxia (FiO2 = 0.21) and in hypoxia (FiO2 = 0.13), respectively, to 10 mL/kg Red Bull ingestion. Another eight animals served as controls receiving an equivalent amount of saline. In addition to cardiovascular data, ventilation/perfusion distribution of the lung was assessed by using the multiple inert gas elimination technique (MIGET). Heart rate increased in normoxic conditions but was not different from controls in acute short-term hypoxia after oral Red Bull ingestion in piglets. For the first time, we demonstrate an increased fraction of pulmonary shunt with unchanged distribution of pulmonary blood flow after Red Bull administration in acute short-term hypoxia. In summary, these findings do not oppose moderate consumption of caffeinated energy drinks even at altitude at rest and during exercise.
Subject(s)
Altitude , Caffeine/administration & dosage , Caffeine/pharmacology , Central Nervous System Stimulants/administration & dosage , Central Nervous System Stimulants/pharmacology , Energy Drinks , Heart Rate/drug effects , Performance-Enhancing Substances , Pulmonary Circulation/drug effects , Pulmonary Ventilation/drug effects , Animals , Blood Pressure/drug effects , Models, Animal , Norepinephrine/metabolism , SwineABSTRACT
Ductal stenting (DS) palliates duct-dependent lesions using coronary stents. Sirolimus-eluting stents have replaced bare-metal stents in coronary interventions. Concerns exist about sirolimus levels in neonates. Therapeutic immunosuppressive sirolimus level is 5-15 ng/ml. After neonatal DS, drug levels were assessed at 24 h, 7 days and monthly thereafter till they were undetectable. Clinical course, ductal patency till their final corrective surgery was analyzed. The exact quantity of sirolimus in each stent was known. Twelve neonates with median age of 5.5 days received sirolimus-eluting stents, one stent in nine and two in the rest. The lesions were pulmonary atresia intact ventricular septum(PAIVS) in four, univentricular lesions with pulmonary atresia in four, biventricular lesions with pulmonary atresia in three and right ventricular rhabdomyoma in one neonate. If single stents up to 22 mm length, 24-h drug levels were less than 5 ng/ml. Even though 24-h levels were above 5 ng/ml in patients with single longer stent or two stents, it reduced to very low levels by seventh day. Two hospital deaths included rhabdomyoma with complete heart block and post-valvotomy cardiac failure for PAIVS. Stent patency after valvotomy for PAIVS exceeded three years. Patency was retained for 8-27 months till their elective corrective surgery in others. Sirolimus levels were acceptable at 24 h in all neonates receiving single stent under 22 mm length. In patients needing two stents, drug levels were in immunosuppressive range at 24 h but reduced rapidly within 7 days. The palliation provided by sirolimus-eluting DS was sufficiently long to provide clinical benefit.
Subject(s)
Drug-Eluting Stents , Ductus Arteriosus, Patent/drug therapy , Pulmonary Circulation/drug effects , Sirolimus/blood , Sirolimus/therapeutic use , Chromium , Cobalt , Ductus Arteriosus, Patent/surgery , Female , Heart Ventricles/physiopathology , Humans , Immunosuppressive Agents , Infant, Newborn , Male , Prospective Studies , Prosthesis Implantation , Pulmonary Atresia/surgery , Treatment Outcome , Ventricular SeptumABSTRACT
Pulmonary Hypertension (PH) is a pathophysiological condition, defined by a mean pulmonary arterial pressure exceeding 25 mm Hg at rest, as assessed by right heart catheterization. A broad spectrum of diseases can lead to PH, differing in their etiology, histopathology, clinical presentation, prognosis, and response to treatment. Despite significant progress in the last years, PH remains an uncured disease. Understanding the underlying mechanisms can pave the way for the development of new therapies. Animal models are important research tools to achieve this goal. Currently, there are several models available for recapitulating PH. This protocol describes a two-hit mouse PH model. The stimuli for PH development are hypoxia and the injection of SU5416, a vascular endothelial growth factor (VEGF) receptor antagonist. Three weeks after initiation of Hypoxia/SU5416, animals develop pulmonary vascular remodeling imitating the histopathological changes observed in human PH (predominantly Group 1). Vascular remodeling in the pulmonary circulation results in the remodeling of the right ventricle (RV). The procedures for measuring RV pressures (using the open chest method), the morphometrical analyses of the RV (by dissecting and weighing both cardiac ventricles) and the histological assessments of the remodeling (both pulmonary by assessing vascular remodeling and cardiac by assessing RV cardiomyocyte hypertrophy and fibrosis) are described in detail. The advantages of this protocol are the possibility of the application both in wild type and in genetically modified mice, the relatively easy and low-cost implementation, and the quick development of the disease of interest (3 weeks). Limitations of this method are that mice do not develop a severe phenotype and PH is reversible upon return to normoxia. Prevention, as well as therapy studies, can easily be implemented in this model, without the necessity of advanced skills (as opposed to surgical rodent models).
Subject(s)
Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/pathology , Indoles/pharmacology , Pyrroles/pharmacology , Animals , Cell Hypoxia/drug effects , Disease Models, Animal , Fibrosis , Heart Ventricles/drug effects , Heart Ventricles/physiopathology , Humans , Hydrogen-Ion Concentration , Hypertension, Pulmonary/complications , Hypertension, Pulmonary/physiopathology , Hypertrophy, Right Ventricular/complications , Male , Mice , Pulmonary Artery/drug effects , Pulmonary Artery/physiopathology , Pulmonary Circulation/drug effects , Vascular Endothelial Growth Factor A/metabolism , Vascular Remodeling/drug effects , Ventricular Remodeling/drug effectsABSTRACT
PURPOSE: Nicorandil is a hybrid between nitrates and KATP channel opener activators. The aim of this study was to evaluate the nicorandil's effects on ischemia-reperfusion (IR) lung injury and examine the mechanism of its effects. METHODS: Isolated rat lungs were divided into 6 groups. In the sham group, the lungs were perfused and ventilated for 150 min. In the IR group, after perfusion and ventilation for 30 min, they were interrupted (ischemia) for 60 min, and then resumed for 60 min. In the nicorandil (N) + IR group, nicorandil 6 mg was added before ischemia (nicorandil concentration was 75 µg ml-1). In the glibenclamide + N + IR group, the L-NAME (Nω-Nitro-L-arginine methyl ester) + N + IR group and ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) + N + IR group, glibenclamide 3 µM, L-NAME 100 µM, and ODQ 30 µM were added 5 min before nicorandil administration, respectively. We measured the coefficient of filtration (Kfc) of the lungs, total pulmonary vascular resistance, and the wet-to-dry lung weight ratio (WW/DW ratio). RESULTS: Kfc was significantly increased after 60 min reperfusion compared with baseline in the IR group, but no change in the sham group. An increase in Kfc was inhibited in the N + IR group compared with the IR group (0.92 ± 0.28 vs. 2.82 ± 0.68 ml min-1 mmHg-1 100 g-1; P < 0.01). Also, nicorandil attenuated WW/DW ratio was compared with IR group (8.3 ± 0.41 vs. 10.9 ± 2.5; P < 0.05). Nicorandil's inhibitory effect was blocked by glibenclamide and ODQ (P < 0.01), but not by L-NAME. CONCLUSIONS: Nicorandil attenuated IR injury in isolated rat lungs. This protective effect appears to involve its activation as KATP channel opener as well as that of the sGC-cGMP pathway.
Subject(s)
KATP Channels/agonists , Lung Injury/prevention & control , Lung/blood supply , Lung/drug effects , Membrane Transport Modulators/pharmacology , Nicorandil/pharmacology , Reperfusion Injury/prevention & control , Animals , Capillary Permeability/drug effects , Cyclic GMP/metabolism , KATP Channels/metabolism , Lung/metabolism , Lung/pathology , Lung Injury/metabolism , Lung Injury/pathology , Male , Perfusion , Pulmonary Circulation/drug effects , Pulmonary Edema/metabolism , Pulmonary Edema/pathology , Pulmonary Edema/prevention & control , Rats, Sprague-Dawley , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Signal Transduction , Soluble Guanylyl Cyclase/metabolism , Vascular Resistance/drug effectsABSTRACT
In heart transplantation, pulmonary hypertension and increased pulmonary vascular resistance followed by donor right ventricular dysfunction remain a major cause of perioperative morbidity and mortality. In lung transplantation, primary graft dysfunction remains a major obstacle because it can cause bronchiolitis obliterans and mortality. Pulmonary vasodilators have been used as an adjunct therapy for heart or lung transplantation, mainly to treat pulmonary hypertension, right ventricular failure, and associated refractory hypoxemia. Among pulmonary vasodilators, inhaled nitric oxide is unique in that it is selective in pulmonary circulation and causes fewer systemic complications such as hypotension, flushing, or coagulopathy. Nitric oxide is expected to prevent or attenuate primary graft dysfunction by decreasing ischemia-reperfusion injury in lung transplantation. However, when considering the long-term benefit of these medications, little evidence supports their use in heart or lung transplantation. Current guidelines endorse inhaled vasodilators for managing immediate postoperative right ventricular failure in lung or heart transplantation, but no guidance is offered regarding agent selection, dosing, or administration. This review presents the current evidence of inhaled nitric oxide in lung or heart transplantation as well as comparisons with other pulmonary vasodilators including cost differences in consideration of economic pressures to contain rising pharmacy costs.
Subject(s)
Heart Transplantation/methods , Lung Transplantation/methods , Vasodilator Agents/administration & dosage , Administration, Inhalation , Cost-Benefit Analysis , Heart Transplantation/economics , Humans , Hypertension, Pulmonary/drug therapy , Hypertension, Pulmonary/etiology , Lung Transplantation/economics , Nitric Oxide/administration & dosage , Nitric Oxide/economics , Primary Graft Dysfunction/prevention & control , Pulmonary Circulation/drug effects , Vasodilator Agents/economics , Ventricular Dysfunction, Right/drug therapy , Ventricular Dysfunction, Right/etiologyABSTRACT
BACKGROUND: Elevated pulmonary vascular resistance (PVR) is common following repair of truncus arteriosus. Inhaled nitric oxide (iNO) is an effective yet costly therapy that is frequently implemented postoperatively to manage elevated PVR. OBJECTIVES: We aimed to describe practice patterns of iNO use in a multicenter cohort of patients who underwent repair of truncus arteriosus, a lesion in which recovery is often complicated by elevated PVR. We also sought to identify patient and center factors that were more commonly associated with the use of iNO in the postoperative period. DESIGN: Retrospective cohort study. SETTING: 15 tertiary care pediatric referral centers. PATIENTS: All infants who underwent definitive repair of truncus arteriosus without aortic arch obstruction between 2009 and 2016. INTERVENTIONS: Descriptive statistics were used to demonstrate practice patterns of iNO use. Bivariate comparisons of characteristics of patients who did and did not receive iNO were performed, followed by multivariable mixed logistic regression analysis using backward elimination to identify independent predictors of iNO use. MAIN RESULTS: We reviewed 216 patients who met inclusion criteria, of which 102 (46%) received iNO in the postoperative period: 69 (68%) had iNO started in the operating room and 33 (32%) had iNO initiated in the ICU. Median duration of iNO use was 4 days (range: 1-21 days). In multivariable mixed logistic regression analysis, use of deep hypothermic circulatory arrest (odds ratio: 3.2; 95% confidence interval: 1.2, 8.4) and center (analyzed as a random effect, p = .02) were independently associated with iNO use. CONCLUSIONS: In this contemporary multicenter study, nearly half of patients who underwent repair of truncus arteriosus received iNO postoperatively. Use of iNO was more dependent on individual center practice rather than patient characteristics. The study suggests a need for collaborative quality initiatives to determine optimal criteria for utilization of this important but expensive therapy.
Subject(s)
Cardiac Surgical Procedures/adverse effects , Nitric Oxide/administration & dosage , Postoperative Care/trends , Practice Patterns, Physicians'/trends , Pulmonary Circulation/drug effects , Truncus Arteriosus, Persistent/surgery , Vascular Resistance/drug effects , Vasodilator Agents/administration & dosage , Administration, Inhalation , Female , Humans , Infant, Newborn , Male , Nitric Oxide/adverse effects , Retrospective Studies , Risk Factors , Time Factors , Treatment Outcome , Truncus Arteriosus, Persistent/diagnostic imaging , Truncus Arteriosus, Persistent/physiopathology , United States , Vasodilator Agents/adverse effectsABSTRACT
Background: Perfusion of intrapulmonary arteriovenous anastomoses (IPAVA) is increased during exercise and in hypoxia and is associated with variations in oxygen saturation (SPO2), resulting in blood bypassing the pulmonary microcirculation. Sildenafil is a pulmonary vasodilator that improves SPO2 and endurance performance in hypoxia. The purpose of this study was to determine if 50 mg sildenafil would reduce IPAVA perfusion (QIPAVA) and if the decrement in maximal exercise capacity (VO2max) in hypoxia is related to QIPAVA. We hypothesized that during progressive levels of hypoxia at rest (FIO2 = 0.21, 0.14, 0.12), sildenafil would increase SPO2 and reduce bubble score (estimate of QIPAVA) compared to placebo, and that the decrement in VO2max in hypoxia would be positively correlated with bubble score at rest in hypoxia. Materials and Methods: Fourteen endurance-trained men performed a graded maximal exercise test at sea level and at a simulated altitude of 3000 m, followed by two experimental visits where, after randomly ingesting sildenafil or placebo, they underwent agitated saline contrast echocardiography during progressive levels of hypoxia at rest. Results: All participants experienced a decrement in power output in hypoxia that ranged from 9% to 19% lower than sea level values. Compared to normoxia, bubble score increased significantly in hypoxia (p < 0.001) with no effect of sildenafil (p = 0.580). There was a negative correlation between SPO2 and bubble score (p < 0.001). The decrement in peak power output at VO2max in hypoxia was unrelated to IPAVA perfusion in resting hypoxia (p = 0.32). Several participants demonstrated QIPAVA greater than zero in room air, indicating that arterial hypoxemia may not be the sole mechanism for QIPAVA. Conclusion: These results indicate that the VO2max decrement caused by hypoxia is not related to QIPAVA and that sildenafil does not improve VO2max in hypoxia through modulation of QIPAVA.