Mean Pulmonary Arterial Blood Pressure Research Articles

A topological data analysis study on murine pulmonary arterial trees with pulmonary hypertension

Pulmonary hypertension (PH), defined by a mean pulmonary arterial blood pressure above 20 mmHg in the main pulmonary artery, is a cardiovascular disease impacting the pulmonary vasculature. PH is accompanied by chronic vascular remodeling, wherein vessels become stiffer, large vessels dilate, and smaller vessels constrict. Some types of PH, including hypoxia-induced PH (HPH), also lead to microvascular rarefaction. This study analyzes the change in pulmonary arterial morphometry in the presence of HPH using novel methods from topological data analysis (TDA). We employ persistent homology to quantify arterial morphometry for control and HPH mice characterizing normalized arterial trees extracted from micro-computed tomography (micro-CT) images. We normalize generated trees using three pruning algorithms before comparing the topology of control and HPH trees.This proof-of-concept study shows that the pruning method affects the spatial tree statistics and complexity. We find that HPH trees are stiffer than control trees but have more branches and a higher depth. Relative directional complexities are lower in HPH animals in the right, ventral, and posterior directions. For the radius pruned trees, this difference is more significant at lower perfusion pressures enabling analysis of remodeling of larger vessels. At higher pressures, the arterial networks include more distal vessels. Results show that the right, ventral, and posterior relative directional complexities increase in HPH trees, indicating the remodeling of distal vessels in these directions. Strahler order pruning enables us to generate trees of comparable size, and results, at all pressure, show that HPH trees have lower complexity than the control trees.Our analysis is based on data from 6 animals (3 control and 3 HPH mice), and even though our analysis is performed in a small dataset, this study provides a framework and proof-of-concept for analyzing properties of biological trees using tools from Topological Data Analysis (TDA). Findings derived from this study bring us a step closer to extracting relevant information for quantifying remodeling in HPH.

Assessment of Inhaled Treprostinil Palmitil, Inhaled and Intravenous Treprostinil, and Oral Selexipag in a Sugen/Hypoxia Rat Model of Pulmonary Arterial Hypertension.

Treprostinil palmitil (TP), a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE), has beneficial effects in a Sugen5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) that compare favorably to the oral phosphodiesterase 5 inhibitor (PDE5) sildenafil. In this study in male Sprague-Dawley rats, a dry powder formulation of TP (TPIP) was compared with inhaled and intravenous TRE and oral selexipag to evaluate inhibition of hemodynamic and pathologic changes in the lungs and heart induced by Su/Hx challenge. Su (20 mg/kg) was injected subcutaneously followed by 3 weeks of Hx (10% O2/balance N2) and then initiation of test article administration over 5 weeks with room air breathing. Hemodynamics and histopathology were measured at the end of the study. Su/Hx challenge approximately doubled the mean pulmonary arterial blood pressure (mPAP) and the Fulton index, decreased cardiac output (CO), doubled the wall thickness and muscularization of the small (10-50 μm) and medium (51-100 μm) sized pulmonary arteries, and increased the percentage of obliterated pulmonary blood vessels. Even though inhaled TRE (65 μg/kg, 4× daily), intravenous TRE (810 ng/kg/min), and oral selexipag (30 mg/kg, twice daily) provided some beneficial effects against the Su/Hx challenge, the overall benefit was generally greater with TPIP at high dose (117 μg/kg, once daily). These results demonstrate that TPIP compares favorably to inhaled and intravenous TRE and oral selexipag with respect to inhibition of the pathophysiological changes induced by Su/Hx challenge in rats. SIGNIFICANCE STATEMENT: Treprostinil palmitil (TP) is a long-acting pulmonary vasodilator prodrug of treprostinil (TRE) formulated for inhaled administration by dry powder [treprostinil palmitil inhalation powder (TPIP)]. Comparison of the activity of TPIP, inhaled and intravenous TRE, and oral selexipag in a Sugen5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension demonstrated that each of these drugs exert protection against the hemodynamic and histopathological changes induced by the Su/Hx challenge, with the greatest effect on these changes produced by TPIP.

Transcatheter radiofrequency pulmonary artery denervation in swine: the evaluation of lesion degree, hemodynamics and pulmonary hypertension inducibility

BackgroundMechanisms of positive effects of pulmonary artery (PA) denervation (PADN) remain poorly understood. The study aimed to evaluate pulmonary hemodynamic changes after PADN and their association with the extent of PA wall damage in an acute thromboxane A2 (TXA2)-induced pulmonary hypertension (PH) model in swine.MethodsIn this experimental sham-controlled study, 17 normotensive male white Landrace pigs (the mean weight 36.2 ± 4.5 kg) were included and randomly assigned to group I (n = 9)—PH modeling before and after PADN, group II (n = 4)—PADN only, or group III (n = 4)—PH modeling before and after a sham procedure. Radiofrequency (RF) PADN was performed in the PA trunk and at the proximal parts of the right and left PAs. PA wall lesions were characterized at the autopsy study using histological and the immunohistochemical examination.ResultsIn groups I and II, no statistically significant changes in the mean pulmonary arterial pressure nor systemic blood pressure were found after PADN (−0.8 ± 3.4 vs 4.3 ± 8.6 mmHg, P = 0.47; and 6.0 ± 15.9 vs -8.3 ± 7.5 mmHg, P = 0.1; correspondingly). There was a trend towards a lower diastolic pulmonary arterial pressure after PADN in group I when compared with group III during repeat PH induction (34.4 ± 2.9 vs 38.0 ± 0.8; P = 0.06). Despite the presence of severe PA wall damage at the RF application sites, S100 expression was preserved in the majority of PA specimens. The presence of high-grade PA lesions was associated with HR acceleration after PADN (ρ = 0.68, p = 0.03). No significant correlation was found between the grade of PA lesion severity and PA pressure after PADN with or without PH induction.ConclusionsExtended PADN does not affect PH induction using TXA2. Significant PA adventitia damage is associated with HR acceleration after PADN. Possible delayed effects of PADN on perivascular nerves and pulmonary hemodynamics require further research in chronic experiments.

Treprostinil palmitil inhibits the hemodynamic and histopathological changes in the pulmonary vasculature and heart in an animal model of pulmonary arterial hypertension

Treprostinil palmitil (TP) is a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE). In this study, TP was delivered by inhalation (treprostinil palmitil inhalation suspension, TPIS) in a rat Sugen 5416 (Su)/hypoxia (Hx) model of pulmonary arterial hypertension (PAH) to evaluate its effects on hemodynamics, pulmonary vascular remodeling, and cardiac performance and histopathology. Male Sprague-Dawley rats received Su (20 mg/kg, s.c), three weeks of Hx (10% O2) and 5 or 10 weeks of normoxia (Nx). TPIS was given during the 5–10 week Nx period after the Su/Hx challenge. Su/Hx increased the mean pulmonary arterial blood pressure (mPAP) and right heart size (Fulton index), reduced cardiac output (CO), stroke volume (SV) and heart rate (HR), and increased the thickness and muscularization of the pulmonary arteries along with obliteration of small pulmonary vessels. In both the 8- and 13-week experiments, TPIS at inhaled doses ranging from 39.6 to 134.1 μg/kg, QD, dose-dependently improved pulmonary vascular hemodynamics, reduced the increase in right heart size, enhanced cardiac performance, and attenuated most of the histological changes induced by the Su/Hx challenge. The PDE5 inhibitor sildenafil, administered at an oral dose of 50 mg/kg, BID for 10 weeks, was not as effective as TPIS. These results in Su/Hx challenged rats demonstrate that inhaled TPIS may have superior effects to oral sildenafil. We speculate that the improvement of the pathobiology in this PAH model induced by TPIS involves effects on pulmonary vascular remodeling due to the local effects of TRE in the lungs.

Identification of the molecular mechanisms underlying brisket disease in Holstein heifers via microbiota and metabolome analyses

Brisket disease (BD) is common among Holstein heifers in high-altitude environments, and this disease may result in serious economic loss. At present, no effective treatment is available for brisket disease. In this study, liver and cecum samples were collected from five heifers with BD and five healthy heifers (HH) for analyses of the metabolome and microbiota. The mean pulmonary arterial pressure and systolic blood pressure were significantly higher in BD heifers, whereas the average breathing rate, blood oxygen saturation, and glucose level were significantly lower in BD group than in the HH group. Further, 16S rDNA data showed that the abundance of Firmicutes was significantly lower and that of Bacteroidetes was significantly higher in BD group than in the HH group. At the genus level, the BD group heifers harbored fewer Ruminococcaceae and Lachnospiraceae than the HH group. Several metabolites, including beta-d-fructose, d-ribose, 1,4-beta-d-glucan, sucrose, and glucose-6-phosphate were present at low levels in BD heifers. Moreover, the mean pulmonary arterial pressure was negatively correlated with beta-d-fructose (r = − 0.74; P = 0.013), d-ribose (r = − 0.72; P = 0.018), and acetyl-tyrosine-ethyl-ester (r = − 0.71; P = 0.022). We also found that mean pulmonary arterial pressure was negatively correlated with most of the genera, including those in the families of Lachnospiraceae and Ruminococcaceae. In summary, the decreased levels of metabolites and microbial genera might affect BD by limiting the energy supply. This study may help us better understand the role of the microbiota in BD and provide new insights into the management of feeding to decrease the rate of BD in Holstein dairy cows in the Qinghai-Tibetan plateau.

Targeting JP2: A New Treatment for Pulmonary Hypertension.

Pulmonary hypertension (PH) is a disease with a complex etiology and high mortality rate. Abnormal pulmonary vasoconstriction and pulmonary vascular remodeling lead to an increase in mean pulmonary arterial blood pressure for which, and there is currently no cure. Junctophilin-2 (JP2) is beneficial for the assembly of junctional membrane complexes, the structural basis for excitation-contraction coupling that tethers the plasma membrane to the sarcoplasmic reticulum/endoplasmic reticulum and is involved in maintaining intracellular calcium concentration homeostasis and normal muscle contraction function. Recent studies have shown that JP2 maintains normal contraction and relaxation of vascular smooth muscle. In some experimental studies of drug treatments for PH, JP2 expression was increased, which improved pulmonary vascular remodeling and right ventricular function. Based on JP2 research to date, this paper summarizes the current understanding of JP2 protein structure, function, and related heart diseases and mechanisms and analyzes the feasibility and possible therapeutic strategies for targeting JP2 in PH.

Higher Incidence of Atrial Fibrillation in Left Ventricular-to-Right Atrial Shunt Patients.

Background: The possible association between atrial fibrillation (AF) and left ventricular-to-right atrial shunt (LVRAS) has never been reported yet. The present study investigated the incidence of AF in LVRAS.Methods: This was a retrospective study of consecutive patients undergoing echocardiography at a single tertiary center. Clinical data, laboratory results and echocardiography parameters such as right atrial area (RAA), right ventricular end diastolic diameter (RVDD) and left atrial diameter (LAD) were compared between LVRAS group and non-LVRAS patients, and between AF and non-AF patients. Propensity score matching was performed to decrease the effect of confounders. Logistic regression analysis and mediation analysis were used to estimate the relationship between LVRAS and AF.Results: A total of 3,436 patients were included, and the incidence of LVRAS was 1.16% (n = 40). The LVRAS group had significantly larger RAA, RVDD and LAD compared with non-LVRAS group. Those who suffered from AF showed larger RAA, RVDD and LAD compared with those who maintained sinus rhythm. Multivariable logistic regression showed that gender (OR: 0.608), age (OR: 1.048), LAD (OR: 1.111), mean pulmonary artery blood pressure (mPAP, OR: 1.023), TR (OR: 2.309) and LVRAS (OR: 12.217) were significant factors for AF. RAA could partially mediate the relationship between LVRAS and AF according to the result of mediation analysis.Conclusions: Our study suggested that LVRAS, TR, LAD, mPAP, age and male were risk factors for AF. RA enlargement might underlie mechanism in the higher incidence of AF in LVRAS patients. These findings should be confirmed in larger prospective studies.

Transcriptomic profiling reveals gene expression kinetics in patients with hypoxia and high altitude pulmonary edema

ObjectiveHigh altitude pulmonary edema (HAPE) is a life threatening condition occurring in otherwise healthy individuals who rapidly ascend to high altitude. However, the molecular mechanisms of its pathophysiology are not well understood. The objective of this study is to evaluate differential gene expression in patients with HAPE during acute illness and subsequent recovery. MethodsTwenty-one individuals who ascended to an altitude of 3780 m were studied, including 12 patients who developed HAPE and 9 matched controls without HAPE. Whole-blood samples were collected during acute illness and subsequent recovery for analysis of the expression of hypoxia-related genes, and physiologic and laboratory parameters, including mean pulmonary arterial pressure (mPAP), heart rate, blood pressure, and arterial oxygen saturation (SpO2), were also measured. ResultsCompared with control subjects, numerous hypoxia-related genes were up-regulated in patients with acute HAPE. Gene network analyses suggested that HIF-1α played a central role in acute HAPE by affecting a variety of hypoxia-related genes, including BNIP3L, VEGFA, ANGPTL4 and EGLN1. Transcriptomic profiling revealed the expression of most HAPE-induced genes was restored to a normal level during the recovery phase except some key hypoxia response factors, such asBNIP3L, EGR1, MMP9 and VEGF, which remained persistently elevated. ConclusionsDifferential expression analysis of hypoxia-related genes revealed distinct molecular signatures of HAPE during acute and recovery phases. This study may help us to better understand HAPE pathogenesis and putative targets for further investigation and therapeutic intervention.

Comparison of hemodynamic effects of inhaled milrinone and inhaled nitroglycerin in patients with pulmonary hypertension undergoing mitral valve surgery

Introduction Pulmonary hypertension (PH) frequently complicates the perioperative management of patients undergoing mitral valve surgery and has been shown to be a significant independent predictor of postoperative morbidity and mortality. The aim of this work is to compare the effects of inhaled milrinone and inhaled nitroglycerin on pulmonary and systemic hemodynamic responses in patients with PH undergoing mitral valve surgery. Patients and methods A total of 50 patients with PH were randomly divided into two groups with 25 patients in each group: group I patients received inhaled nitroglycerin (5 mg, 1 mg/ml) over 15 min and group II patients received inhaled milrinone (5 mg, 1 mg/ml) over 15 min through an ultrasonic nebulizer connected to the inspiratory limb of the ventilator circuit near the endotracheal tube immediately after separation from cardiopulmonary bypass. Hemodynamic parameters were measured after induction of anesthesia (T1), immediately after the end of cardiopulmonary bypass (T2), 30 min after the start of treatment, and 90 min after the start of treatment (T4). The hemodynamic variables were as follows: heart rate, mean arterial blood pressure (MAP), mean pulmonary artery blood pressure (MPAP), cardiac index (CI), systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), and right ventricular stroke work index (RVSWI). Results At 30 min after the start of treatment, both groups showed a significant comparable decrease in MPAP, PVRI, and RVSWI, with no significant changes in MAP, CI, and SVRI. At 90 min after the start of treatment, MPAP, PVRI, and RVSWI returned to their values in the inhaled nitroglycerin group but remained at significantly lower values in the inhaled milrinone group. Conclusion Inhalation of nitroglycerin and milrinone produces a comparable decrease in MPAP, PVRI, and RVSWI without significant changes in heart rate, MAP, CI, and SVRI. Inhaled milrinone has a longer duration of action than inhaled nitroglycerin.

Correlations between physiological parameters related with kidney function and minute-by-minute urine output.

Recently, devices capable of measuring minute-by-minute urine output (UOm) have become available. It is not known how UOm correlates with physiological parameters in normal conditions and in disease states characterized by vascular dysfunction. This paper analyzes correlations between UOm and physiological parameters related to kidney perfusion to provide some insight about UOm pathophysiological interpretation and its relationship with renal blood flow. We studied 14 male pigs were anesthetized, tracheostomized, and mechanically ventilated. Mean systemic blood pressure (PART ), mean pulmonary artery blood pressure (PPA ), carotid artery blood flow (QCA ), as well as total (QREN ), cortical (QCOR ) and medullary (QMED ) renal blood flows, and the renal resistive index (RRI) were measured or calculated. Animals received an intravenous dose of live E. coli for the induction of sepsis (septic group), or an equivalent amount of normal saline (nonseptic group). Three groups were studied: nonseptic (n = 6) and septic (n = 4), both receiving for resuscitation NaCl 0.9% at 4 mL/kg per h; and septic (n = 4), receiving for resuscitation NaCl 0.9% at 17 mL/kg per h. Animals were monitored for 5 h after the induction of sepsis. In septic animals, UOm was strongly positively correlated with QREN (Kendall's τ = 0.770, P < 0.05), QCOR (τ = -0.566, P < 0.05) and QMED (τ = 0.632, P < 0.05); and negatively correlated with PPA (τ = -0.524, P < 0.05) and RRI (τ = -0.672, P < 0.05). Control animals exhibited weaker correlations. UOm is a good physiological surrogate marker of total and regional renal blood flows and vascular resistance, particularly under septic conditions, probably reflecting glomerulo-tubular dysfunction in sepsis.

Chronic Normobaric Hypoxia Induces Pulmonary Hypertension in Rats: Role of NF-κB.

To investigate whether nuclear factor-kappa B (NF-κB) activation is involved in chronic normobaric hypoxia-induced pulmonary hypertension (PH), rats were treated with saline or an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC, 150 mg/kg, sc, twice daily), and exposed to normoxia or chronic normobaric hypoxia with a fraction of inspired oxygen of ∼0.1 for 14 days. Lung tissue levels of NF-κB activity, and interleukin (IL)-1β, IL-6, and cyclooxygenase-2 mRNAs, were determined, and mean pulmonary arterial pressure, right ventricular hypertrophy, and right heart function were evaluated. Compared to the normoxia exposure group, rats exposed to chronic normobaric hypoxia showed an increased NF-κB activity, measured by increased nuclear translocation of p50 and p65 proteins, an increased inflammatory gene expression in the lungs, elevated mean pulmonary arterial blood pressure and mean right ventricular pressure, right ventricular hypertrophy, as assessed by right ventricle-to-left ventricle plus septum weight ratio, and right heart dysfunction. Treatment of hypoxia-exposed rats with PDTC inhibited NF-κB activity, decreased pulmonary arterial blood pressure and right ventricular pressure, and ameliorated right ventricular hypertrophy and right heart dysfunction. Hypoxia exposure increased protein kinase C activity and promoted pulmonary artery smooth muscle cell proliferation in vitro. Our data suggest that NF-κB activation may contribute to chronic normobaric hypoxia-induced PH.

The expression changes of peripheral endothelial progenitor cells and Ang-1/Tie2 in patients with pulmonary arterial hypertension

Objective To observe the expression changes of peripheral endothelial progenitor cells(EPCs) and Ang-1/Tie2 in patients with pulmonary arterial hypertension (PAH). Methods From Jun 2011 to Dec 2012, 45 patients with PAH charged in Affiliated Hospital of Hangzhou Normal University were divided into 3 groups according to mean pulmonary arterial blood pressure (15 per group): mild(Group L), moderate(Group M), and severe(Group S), with another 15 normal people as control group(Group C). The EPCs were isolated from peripheral blood of every patient, number counting using fluorescence activated cell sorter (FACS), function test using cell culture in vitro. Expression of Ang-1 and Tie2 in the peripheral EPCs were measured by RT-PCR or Western-blot. Non normal data was analyzed by non parametric statistical test. Results The statistical discrepancy existed among Group L, M, S and the control in the number of EPCs [32.0 (27.0, 37.0), 26.0 (19.0, 31.0), 24.0 (22.0, 26.0) vs 40.0 (37.0, 51.0), P<0.05]. The ability of migration [32.1(26.5, 37.5), 26.8(22.4, 35.4), 21.0(17.8, 34.0) vs 39.0(33.3, 42.4), P<0.05] and adhesion of the EPCs [57.1(50.9, 61.8), 51.8(45.2, 58.7), 46.0(37.2, 55.1) vs 64.1(56.2, 75.0), P<0.05] among study groups and control group was different in statistic, the same with the proliferation activity of EPCs in different groups [0.6(0.5, 0.7), 0.5(0.4, 0.6), 0.4(0.3, 0.5) vs 0.7(0.6, 0.8), P<0.05 ]. The mRNA expression of Ang-1 and Tie2 in Group M & S were significantly reduced compared with control [4.33(2.49, 4.62)and 2.89(2.39, 3.44) vs 5.31(3.78, 6.22), P<0.05], Tie2 mRNA[1.32(1.23, 1.34)and 1.23(1.08, 1.42)vs 1.49(1.25, 1.66), P<0.05], and the protein expression of the phosphorylated Tie 2 in Group M &S were decreased[0.16(0.15, 0.24)and 0.12(0.08, 0.18)vs 0.22(0.19, 0.28), P<0.05]. No significant difference of Ang-1 and Tie2 expression was observed between Group L and control[5.42(4.72, 5.95), 1.54(1.43, 1.66) and 0.23(0.19, 0.33), P=0.674, 0.867 and 0.674]. Conclusion With the severity of PAH, the number and function of circulating EPCs decreased, as consistent with Ang-1 and Tie2 expression changes, suggesting that function decrease of EPCs in patients with PAH may be associated with the decrease of Ang-1/Tie2 expression. Key words: Hypertension, pulmonary; Endothelial progenitor cells; Angiopoietin-1; Receptor, TIE-2

Maternal Outcome in Pregnancy Complicated With Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH), including Eisenmenger syndrome, has a risk of mortality in pregnancy of 10-40%. The aim of this study was to investigate whether pulmonary artery blood pressure (PABP) is a prognostic factor for pregnancy outcome in patients with PAH. The subjects were 42 patients with PAH during pregnancy. Severe and mild cases were defined by PABP before and during the first 14 weeks of pregnancy, with severe cases having mean PABP >40 mmHg by catheterization or systolic PABP >50 mmHg on echocardiography. Eighteen women chose termination of pregnancy before 14 weeks, leaving 24 women (10 mild, 14 severe) for analysis. The women with severe PAH delivered earlier (35.4 vs. 31.5 weeks, P<0.05) and had higher rates of small-for-gestational-age infants (0/10 vs. 7/14, P<0.01). Among the women with severe PAH, the New York Heart Association class dropped by 1 in 9 cases, by 2 in 3 cases, and remained the same in 2 cases as pregnancy progressed, whereas among the women with mild PAH, the class dropped by 1 in 1 case and 9 women remained in the same class. Among the severe cases, 1 woman died and there was 1 fetal death; PABP markedly increased in later pregnancy from 54 to 74 mmHg (catheter measurement) and from 78 to 93 mmHg (echocardiography) (P<0.05). The level of PABP before or in the early stage of pregnancy is an important predictor of pregnancy outcome.

Urantide alleviates monocrotaline induced pulmonary arterial hypertension in Wistar rats

Pulmonary arterial hypertension (PAH) is a serious disorder with poor prognosis. Urotensin II (UII) has been confirmed to be powerful vasoconstrictor than endothelin-1, which may play an important role in PAH development. The aim of this study is to observe the effects of urantide, a UII receptor antagonist， on monocrotaline (MCT) induced PAH in rats. 60 male Wistar rats were divided into six groups. For early treatment experiment, rats were divided into normal control group, MCT 4w model group (MCT + saline × 3wks from the 8th day of MCT injection) and urantide early treatment group (MCT + urantide 10 μg/kg/d × 3wks, 1 week after MCT injection once). For late treatment experiment, rats were divided as controls, MCT 6w model group (MCT + saline × 2wks, 4 weeks after MCT injection once) and urantide late treatment group (MCT + urantide 10 μg/kg/d × 2wks, 4 weeks after MCT injection once). At the end of experiments, mean pulmonary arterial pressures (mPAP) and mean blood pressure (MBP) of rats in each group were measured by catheterization. Right ventricular weight ratio was also weighed. Relaxation effects of urantide on intralobar pulmonary arterial rings of normal control and MCT 4w model rats were investigated. Pulmonary artery remodeling was detected by hematoxylin and eosin (HE) staining and immunohistochemistry analysis. Serum nitric oxide (NO) levels in all six groups were assayed by ELISA kits. Urantide markedly reduced the mPAP levels of MCT induced PAH in both early and late treatment groups. It didn’t change the MBP. Urantide dose-dependently relaxed the pulmonary arterial rings of normal control and MCT 4w model rats. Moreover, N G-Nitro- l-arginine Methyl Ester ( l-NAME) blocked the dilation response induced by urantide. In addition, urantide inhibited the pulmonary vascular remodeling remarkably. Serum NO level elevated in both early and late treatment rats with urantide infusion. These results suggest that urantide effectively alleviated MCT induced rats PAH may through relaxing pulmonary arteries and inhibiting pulmonary vascular remodeling. NO pathway might be one of the mechanisms in urantide induced pulmonary artery dilation. Thus, it is expected that urantide may be a novel therapy for PAH.

Elevated inflammatory mediators and pulmonary hypertension after applying an extracorporeal circuit in a neonatal sepsis model

We aimed to study the changes in cytokines, oxidative mediators, and pulmonary blood pressure in a neonatal sepsis model when applying an extracorporeal circuit (ECC). Of 28 anesthetized and mechanically ventilated 3-day-old piglets, 14 underwent cecal ligation and perforation (CLP), of which 7 underwent ECC for 3 h from 3 to 6 h after CLP. The remaining 14 were sham, of which 7 underwent ECC. Serum interleukin (IL)-6, IL-10, tumor necrosis factor (TNF), interferon gamma (IFN-γ), total hydroperoxide (TH), nitric oxide metabolites (NOx), and mean pulmonary arterial blood pressure (mPAP)/mean arterial blood pressure (mABP) ratio were measured at pre-CLP and at 3, 6, and 9 h in the CLP groups, and continued in the sham groups at 12, 15, 18, and 24 h. The CLP group with ECCs compared to the CLP group without it showed higher levels of serum IL-6, IL-10, and NOx at 6 h and higher levels of serum TH at 6 and 9 h. The sham group with ECCs compared to the one without it showed higher levels of serum IL-6 and IL-10 at 12, 15, and 18 h, TH at 6 and 9 h, TNF at 6 h, and IFN-γ at 9 h. The mPAP/mABP ratios in the CLP group with ECCs were higher compared to the CLP group without it at 6 and 9 h. Applying ECCs provoked a window of cytokines, free radicals elevation, and pulmonary hypertension which could be hazardous in critically ill newborns.

Beneficial effect of a hydrogen sulphide donor (sodium sulphide) in an ovine model of burn‐ and smoke‐induced acute lung injury

The present study investigated whether the pathophysiological changes induced by burn and smoke inhalation are modulated by parenteral administration of Na(2)S, a H(2)S donor. The study used a total of 16 chronically instrumented, adult female sheep. Na(2)S was administered 1 h post injury, as a bolus injection at a dose of 0.5 mg.kg(-1) and subsequently, as a continuous infusion at a rate of 0.2 mg.kg(-1).h(-1) for 24 h. Cardiopulmonary variables (mean arterial and pulmonary arterial blood pressure, cardiac output, ventricular stroke work index, vascular resistance) and arterial and mixed venous blood gases were measured. Lung wet-to-dry ratio and myeloperoxidase content and protein oxidation and nitration were also measured. In addition, lung inducible nitric oxide synthase expression and cytochrome c were measured in lung homogenates via Western blotting and enzyme-linked immunosorbent assay (elisa) respectively. The H(2)S donor decreased mortality during the 96 h experimental period, improved pulmonary gas exchange and lowered further increase in inspiratory pressure and fluid accumulation associated with burn- and smoke-induced acute lung injury. Further, the H(2)S donor treatment reduced the presence of protein oxidation and 3-nitrotyrosine formation following burn and smoke inhalation injury. Parenteral administration of the H(2)S donor ameliorated the pulmonary pathophysiological changes associated with burn- and smoke-induced acute lung injury. Based on the effect of H(2)S observed in this clinically relevant model of disease, we propose that treatment with H(2)S or its donors may represent a potential therapeutic strategy in managing patients with acute lung injury.

N-acetylcysteine inhibits hypoxic pulmonary hypertension most effectively in the initial phase of chronic hypoxia

Exposure to chronic hypoxia results in hypoxic pulmonary hypertension (HPH). In rats HPH develops during the first two weeks of exposure to hypoxia, then it stabilizes and does not increase in severity. We hypothesize that free radical injury to pulmonary vascular wall is an important mechanism in the early days of the hypoxic exposure. Thus antioxidant treatment just before and at the beginning of hypoxia should be more effective in reducing HPH than antioxidant therapy of developed pulmonary hypertension. We studied adult male rats exposed for 4 weeks to isobaric hypoxia (F iO2 = 0.1) and treated with the antioxidant, N-acetylcysteine (NAC, 20 g/l in drinking water). NAC was given “early” (7 days before and the first 7 days of hypoxia) or “late” (last two weeks of hypoxic exposure). These experimental groups were compared with normoxic controls and untreated hypoxic rats (3-4 weeks hypoxia). All animals kept in hypoxia had significantly higher mean pulmonary arterial blood pressure (PAP) than normoxic animals. PAP was significantly lower in hypoxic animals with early (27.1 ± 0.9 mmHg) than late NAC treatment (30.5 ± 1.0 mmHg, P < 0.05; hypoxic without NAC 32.6 ± 1.2 mmHg, normoxic controls 14.9 ± 0.7 mmHg). Early but not late NAC treatment inhibited hypoxia-induced increase in right ventricle weight and muscularization of distal pulmonary arteries assessed by quantitative histology. We conclude that release of free oxygen radicals in early phases of exposure to hypoxia induces injury to pulmonary vessels that contributes to their structural remodeling and development of HPH.

Magnitude and patterns of ruminal hydrogen sulfide production, blood thiamine concentration, and mean pulmonary arterial pressure in feedlot steers consuming water of different sulfate concentrations

Twenty-seven single-source, yearling crossbred steers (713 lb; 324 kg) were used to evaluate the effect of water sulfate concentration on the patterns and magnitude of ruminal gas cap hydrogen sulfide, blood thiamine concentration and mean pulmonary arterial blood pressure (mPAP). Target water sulfate concentrations were 125, 500 and 2000 mg sulfate/L of drinking water, while the observed water sulfate concentrations were 136, 583 and 2,360 mg/L. Ruminal gas cap hydrogen sulfide concentrations were measured three times per week for 10 weeks, then once a week for seven additional weeks. On days 29 and 113, whole-blood samples were collected and analyzed for thiamine concentration. Pulmonary arterial blood pressures were measured on day 100. Ruminal gas cap hydrogen sulfide concentrations decreased to day 15, then increased and peaked by day 31, and finally decreased and remained relatively stable. The peak in hydrogen sulfide concentration was associated with an event of polioencephalomalacia in the treatment group consuming water with 2,360 mg/L sulfate, and the greatest frequency of polioencephalomalacia events in cattle in an adjacent commercial feedlot consuming water with a similar sulfate concentration. Ruminal hydrogen sulfide concentration increased with increasing water sulfate concentration (P&lt;0.05). A treatment effect on blood thiamine concentration was not detected (P=0.29). Mean pulmonary arterial pressure increased linearly with increasing water sulfate concentration (P&lt;0.05). Ruminal gas cap hydrogen sulfide concentrations greater than 1000 ppm provide evidence of excessive sulfur consumption. Pathological concentrations of ruminal sulfides appear central to the pathogenesis of sulfur-associated polioencephalomalacia.

Pharmacological criteria for ventricular assist device insertion following postcardiotomy shock: experience with the Abiomed BVS system.

The traditional approach to postcardiotomy shock includes inotropic support followed by the application of an intra-aortic balloon pump (IABP). Consideration toward insertion of a ventricular assist device (VAD) becomes necessary when these maneuvers fail to restore hemodynamic stability. The definition of maximal inotropic support, however, is lacking such that a standard formula for VAD insertion remains problematic. The purpose of this paper is to define the pharmacological thresholds for VAD implantation in the setting of postcardiotomy cardiogenic shock. The medical records of all adult open-heart operations performed at Hahnemann University Hospital, Philadelphia, PA, from 1 July 1996 through 1 July 1999 were reviewed. Specific data were collected on the hemodynamics and inotrope levels upon separation from cardiopulmonary bypass (CPB). The hospital course was reviewed with attention toward documenting hospital mortality. Cardiogenic shock was defined as systolic blood pressure (SBP) < 100 mmHg, mean pulmonary artery blood pressure (mPAP) > 25 mmHg, central venous pressure (CVP) > 15 mmHg, and cardiac index (CI) < 2.0 L/min/per m2. Inotrope dosages were defined as low, moderate, and high according to assigned values. A formula for VAD insertion was established if cardiogenic shock parameters were present in the setting of two or more high dose inotropes. Early VAD insertion was defined as implantation within three hours of the first attempt to wean from CPB. The VAD recipients were divided into two groups. Group A were VADs placed in conjunction with the formula. Group B was VADs placed in violation (excess) of the formula. The results of these two groups were compared. [table: see text] From 1 July 1996 to 1 July 1999, there were 3462 adult open-heart operations performed at Hahnemann University Hospital, Philadelphia, Pa. The hospital mortality for patients successfully separating from CPB on no inotropes, low-dose, moderate-dose, one high-dose, two high-dose, and three high-dose inotropes were approximately 2.0%, 3.0%, 7.5%, 21%, 42%, and 80% respectively. During this time there were 29 patients supported with the Abiomed BVS (Danvers, Mass) system for postcardiotomy cardiogenic shock. For the entire group of VAD recipients, there were 18 (62%) who were successfully weaned and 8 (28%) who were discharged from the hospital. For the 20 VAD recipients in group A, there were 16 (80%) who were successfully weaned and 8 (40%) who were discharged from the hospital. For the nine VAD recipients in group B, there were two (22%) who were successfully weaned and zero (0%) who were discharged from the hospital. Multiple organ system failure occurred in three (15%) in group A versus seven (78%) in group B patients, respectively. Early VAD insertion was accomplished in 17 (85%) group A patients and 2 (22%) group B patients. Hospital mortality correlates with the number and level of inotropic support necessary to separate from CPB following adult open heart surgery. The application of a standard pharmacological formula together with hemodynamic criteria for VAD insertion after postcardiotomy cardiogenic shock results in earlier insertion, lower incidence of postoperative MOSF, and improved wean and discharge rates.

Haemodynamic effects of ATP in dogs during hypoxia-induced pulmonary hypertension.

Pulmonary hypertension may result from an increase in vascular resistance caused by persistent hypoxia. We have investigated the effects of adenosine triphosphate (ATP), administered into the pulmonary artery, on haemodynamic changes occurring in anaesthetized adult dogs subjected to acute hypoxic pulmonary vasoconstriction. Hypoxia alone (ventilation with 10% O2/90% N2) caused significant increases in mean pulmonary arterial blood pressure (PAP), central venous pressure (CVP), and cardiac index (CI) by 71, 102 and 38%, respectively. ATP (0.03-3.0 micromol/kg/min approximately 0.02-1.65 mg/kg/min), when infused under hypoxic conditions, significantly reduced both mean PAP and systemic arterial blood pressure (ABP) in a dose-dependent manner. The maximum decrease in mean PAP amounted to 20%; mean ABP, on the other hand, was decreased by up to 52% (P<0.01). Heart rate, CI, CVP and pulmonary occlusion pressure were not dose-dependently affected by ATP. Our data indicate that while pulmonary arterial administration of ATP in mature dogs during hypoxic pulmonary hypertension causes dilation in the pulmonary vascular bed, it is even more effective in dilating the systemic vasculature. This result suggests a need for further evaluation and warrants cautious use of ATP in the treatment of hypoxic pulmonary hypertension in adult dogs.