Abstract 13715: Pathophysiological Role of Dexmedetomidine for Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yohei Yamaguchi ◽  
Susumu Hosokawa ◽  
Yusuke Kajikawa ◽  
Yasuhiro Maejima ◽  
Mitsuaki Isobe ◽  
...  
Keyword(s):  
Survival Rate ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Inflammatory Responses ◽  
Systolic Pressure ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Pulmonary Arterial ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Introduction: The abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs) is one of pathological characteristics of pulmonary arterial hypertension (PAH). Inflammation is thought to play an important role for PASMCs proliferation in PAH. Dexmedetomidine (DEX) is a selective α2-adrenergic receptor agonist that is used as a sedative in clinical settings. It has been reported that DEX regulates certain inflammatory responses. Hypothesis: DEX ameliorates Monocrotaline (MCT)-induced PAH in rats through its anti-inflammatory effect. Methods: In vivo, 6-week-old male Sprague-Dawley rats were injected 60 mg/kg of MCT subcutaneously. At day 14 after MCT injection, continuous infusions of DEX (2μg/kg/hour) by osmotic pumps were started in one group (MCT + DEX group), and not in another group (MCT group). We performed cardiac catheterization to measure right ventricular systolic pressure (RVSP) and prepared rats paraffin embedded lung tissues for Immunohistochemistry at day 23. In vitro, we analyzed the effect of DEX on human PASMCs (hPASMCs) proliferation stimulated with fibroblast growth factor 2 (FGF2). In addition, we examined mRNA levels of proinflammatory cytokines in hPASMCs by FGF2 stimuation with/without DEX. Results: Both RVSP and survival rate markedly improved in MCT + DEX group compared with those in MCT group (RVSP; 34mmHg ± 4mmHg vs. 70mmHg ± 10mmHg, survival rate 42% vs. 0% at day 29). In histological analysis, medial hypertrophy of pulmonary arterioles and phosphorylated-p65 positive PASMCs significantly reduced in MCT + DEX group. DEX also inhibited hPASMCs proliferation dose dependently. Furthermore, IL-6 mRNA expression was suppressed by DEX in hPASMCs stimulated with FGF2. Conclusions: DEX improved MCT-induced PAH in rats by suppressing PASMCs proliferation through the anti-inflammatory effect, which may result from inhibition of NF-κB activation induced by IL-6. DEX can be a new therapeutic tool for PAH.

Abstract 13972: Dexmedetomidine Ameliorates Monocrotaline Induced Pulmonary Arterial Hypertension in Rats

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yusuke Kajikawa ◽  
Susumu Hosokawa ◽  
Kenji Wakabayashi ◽  
Yasuhiro Maejima ◽  
Mitsuaki Isobe ◽  
...  
Keyword(s):  
Survival Rate ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Inflammatory Responses ◽  
Systolic Pressure ◽  
Sprague Dawley ◽  
Apoptosis Resistance ◽  
Ventricular Systolic Pressure ◽  
Significant Difference ◽  
Pulmonary Arterial

[Introduction] Pulmonary arterial hypertension (PAH) is characterized by increased proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Dexmedetomidine (DEX) is a selective α2-aderenergic receptor agonist that is used for sedation in clinical practice. It has been reported that DEX inhibits inflammatory responses through cytokines, such as TNF-alpha, IL-6. Furthermore other reports show that G-protein-coupled receptors (GPCRs) are regulated by β-arrestins, which are also involved with inflammation. [Hypothesis] DEX ameliorates monocrotaline (MCT)-induced PAH in rats by its anti-inflammatory effect. [Methods] We treated 6 weeks-old male Sprague-Dawley rats with a single 60mg/kg intraperitoneal injection of MCT. After 14 days of injection, one group of rats was started to administer dexmedetomidine (dose: 2μg/kg/hour, MCT+DEX group) continuously using osmotic pumps, the other group was not treated with DEX (MCT group). We performed physiological examination and cardiac catheterization to measure right ventricular systolic pressure (RVSP) at day 23. [Results] Both RVSP and survival rate of rats in MCT+DEX group markedly improved compared with those in MCT group (RVSP; 38mmHg±11mmHg vs 91mmHg±6mmHg, survival rate; 42% vs 0% at day 30). In histological analysis, DEX reduced the medial hypertrophy of pulmonary arterioles, and decreased phosphorylated-NF-kB p65 (p-p65) positive PASMCs in MCT+DEX group compared with those of MCT group. In addition, DEX suppressed PASMCs proliferation with PCNA staining, and induced apoptosis of PASMCs with TUNEL assay. Then we examined the involvement of β-arrestins in PAH. It showed that βarrestin1 expressions reduced in MCT group compared with that of MCT+DEX group with western blotting and immunohistochemistry. However β-arrestin2 expressions had no significant difference between the two groups. [Conclusions] DEX ameliorates MCT-induced PAH in rats, one of the mechanism of which may be NF-kB inhibition through β-arrestin1. DEX can be a new therapeutic tool for PAH.

scholarly journals Multidisciplinary Team Managements and Clinical Outcomes in Patients With Pulmonary Arterial Hypertension During the Perinatal Period

2021 ◽  
Vol 8 ◽  
Author(s):  
Tingting Shu ◽  
Panpan Feng ◽  
Xiaozhu Liu ◽  
Li Wen ◽  
Huaqiao Chen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Survival Rate ◽  
Pulmonary Arterial Hypertension ◽  
Adverse Events ◽  
Arterial Hypertension ◽  
Clinical Outcomes ◽  
Multidisciplinary Team ◽  
Systolic Pressure ◽  
Perinatal Period ◽  
Pulmonary Arterial

Background: Pulmonary arterial hypertension (PAH) patients with pregnancy have high maternal mortality. This study aimed to provide clinical evidence with multidisciplinary team (MDT) management and to evaluate the clinical outcomes in PAH patients during the perinatal period.Methods: We conducted a retrospective evaluation of PAH patients pregnant at the First Affiliated Hospital of Chongqing Medical University between May 2015 and May 2021.Results: Twenty-two patients (24 pregnancies) were included in this study and received MDT management, and 21 pregnancies chose to continue pregnancy with cesarean section. Nine (37.5%) were first-time pregnancies at 27.78 ± 6.16 years old, and 15 (62.5%) were multiple pregnancies at 30.73 ± 3.71 years old. The average gestational week at hospitalization and delivery were 29.38 ± 8.63 weeks and 32.37 ± 7.20 weeks, individually. Twenty-one (87.5%) pregnancies received single or combined pulmonary vasodilators. The maternal survival rate of PAH patients reached 91.7%. Fifteen (62.5%) pregnancies were complicated with severe adverse events. Patients with complicated adverse events showed lower percutaneous oxygen saturation (SpO2), lower albumin, lower fibrinogen, higher pulmonary artery systolic pressure (PASP), higher blood pressure, longer activated partial thromboplastin time, and longer coagulation time. Fourteen (66.7%) pregnancies with cesarean sections were prematurely delivered and 85.7% newborns who survived after the operation remained alive.Conclusion: The survival rate of parturients with PAH was improved in relation to MDT and pulmonary vasodilator therapy during the perinatal period compared with previous studies. SpO2, albumin, PASP, blood pressure, and coagulation function should be monitored carefully in PAH patients during pregnancy.

scholarly journals Leptin signalling system as a target for pulmonary arterial hypertension therapy

2015 ◽  
Vol 45 (4) ◽  
pp. 1066-1080 ◽  
Author(s):  
Alice Huertas ◽  
Ly Tu ◽  
Raphaël Thuillet ◽  
Morane Le Hiress ◽  
Carole Phan ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Perivascular Inflammation ◽  
Current Therapies ◽  
Pulmonary Arterial ◽  
Anti Inflammatory ◽  
Pulmonary Arterial Hypertension Therapy

Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH.In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages ≤5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH (pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH.We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH.

Abstract 13535: The Synergistic Effects of Incretin-related Drugs for the Treatment of Pulmonary Arterial Hypertension

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Susumu Hosokawa ◽  
Go Haraguchi ◽  
Yasuhiro Maejima ◽  
Shozaburo Doi ◽  
Mitsuaki Isobe
Keyword(s):  
T Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Synergistic Effects ◽  
Cell Activity ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Dipeptidyl Peptidase 4 ◽  
Caveolin 1 ◽  
Pulmonary Arterial

Introduction: A growing body of evidence suggests that inflammation plays a crucial role in the development of pulmonary arterial hypertension (PAH). Dipeptidyl peptidase-4 (DPP-4; also known as CD26), a protease which degrades incretin hormones such as glucagon-like peptide-1 (GLP-1), modulates inflammatory processes by regulating activity of T cells through co-stimulatory pathway. Hypothesis: Incretin-related drugs, including both DPP-4 inhibitors and GLP-1 receptor agonists, suppress the progression of PAH by attenuating inflammatory response of PA. Methods: Sprague Dawley rats were injected monocrotaline to induce PAH (N=80). After 14 days from PAH induction, these rats were treated with alogliptin, a DPP-4 inhibitor (M+A, N=20), liraglutide, a GLP-1 receptor agonist (M+L, N=20), both of these drugs (M+A+L, N=20), or vehicle (M, N=20). Results: A significant increase of survival was observed on days 30 after PAH induction both in the M+A and M+L compared to the M (M+A: 45%* vs. M+L: 60%* vs. M: 5%, * p <0.05). Both alogliptin and liraglutide markedly improved right ventricular pressure (M+A: 33±4.1mmHg* vs. M+L: 26±1.9mmHg* vs. M: 85.9±1.2mmHg, * p <0.05). mRNA levels of both CD28 and CD86, co-stimulators of T cells, significantly decreased and the level of caveolin-1 markedly increased in lung tissues of the M+A compared to those in the M. mRNA levels of both Tissue Factor (TF) and PAI-1 significantly decreased in lung tissues of the M+L than those in the M. Consistently, survival of rats in the M+A+L was the highest (65%) among all of the groups of PAH rats. Coimmunoprecipitation assays revealed that CD26 in T cells physically interacted with caveolin-1 in rat pulmonary vascular smooth muscle cells (rPASMCs). Immunoblot analyses showed that alogliptin suppressed caveolin-1 phosphorylation in rPASMCs. Furthermore, reporter gene assays demonstrated that alogliptin significantly inhibited the transcriptional activity of NF-κB. Conclusions: These results suggest that DPP-4 inhibition and stimulation of GLP-1 receptors synergistically mediate salutary effects on monocrotaline-induced PAH by modulating T cell activity and TF-associated signaling pathway. Thus, incretin-related drugs have a potential as a novel therapeutic tool for PAH.

Fli1 deficiency induces endothelial adipsin expression, contributing to the onset of pulmonary arterial hypertension in systemic sclerosis

Rheumatology ◽  
2019 ◽  
Vol 59 (8) ◽  
pp. 2005-2015
Author(s):  
Takuya Miyagawa ◽  
Takashi Taniguchi ◽  
Ryosuke Saigusa ◽  
Maiko Fukayama ◽  
Takehiro Takahashi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Vascular Involvement ◽  
Enzyme Linked Immunosorbent Assay ◽  
Complement Factor ◽  
Mrna Levels ◽  
Small Vessels ◽  
Pulmonary Arterial

Abstract Objectives Adipsin, or complement factor D, is a serine proteinase catalysing complement factor C3 breakdown, leading to the production of opsonin (C3b), membrane attack complex (C5b–C9) and anaphylatoxins (C3a and C5a). Since adipsin is potentially associated with pulmonary arterial hypertension in SSc, we investigated adipsin expression in dermal small vessels of SSc-involved skin, the mechanism regulating adipsin expression in endothelial cells, and the correlation of serum adipsin levels with SSc clinical symptoms. Methods Adipsin expression was assessed by immunohistochemistry with skin sections of SSc and healthy subjects. mRNA levels of target genes and transcription factor binding to the ADIPSIN promoter were evaluated by quantitative reverse transcription PCR and chromatin immunoprecipitation, respectively. Serum adipsin levels were determined by enzyme-linked immunosorbent assay. Results Adipsin expression was remarkably increased in dermal small vessels of SSc-involved skin as compared with those of healthy control skin. Consistent with the notion that Fli1 deficiency induces SSc-like phenotypes in various types of cells, FLI1 siRNA enhanced adipsin expression at protein and mRNA levels and Fli1 bound to the ADIPSIN promoter in human dermal microvascular endothelial cells. Serum adipsin levels were significantly lower in diffuse cutaneous SSc patients than in limited cutaneous SSc patients and healthy controls, and were associated positively with elevated right ventricular systolic pressure and inversely with interstitial lung disease by multivariate regression analysis. Conclusion Adipsin is up-regulated at least partially by Fli1 deficiency in endothelial cells, potentially contributing to the development of pulmonary vascular involvement in SSc.

scholarly journals Rosuvastatin ameliorates the development of pulmonary arterial hypertension in the transgenic (mRen2)27 rat

2009 ◽  
Vol 297 (3) ◽  
pp. H1128-H1139 ◽  
Author(s):  
Vincent G. DeMarco ◽  
Javad Habibi ◽  
Adam T. Whaley-Connell ◽  
Rebecca I. Schneider ◽  
James R. Sowers ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Proliferation ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
No Synthase ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Pulmonary Arterial

We have recently reported that transgenic (mRen2)27 rats (Ren2 rats) exhibit pulmonary arterial hypertension (PAH), which is, in part, mediated by oxidative stress. Since 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exhibit beneficial vascular effects independent of cholesterol synthesis, we hypothesized that rosuvastatin (RSV) treatment ameliorates PAH and pulmonary vascular remodeling in Ren2 rats, in part, by reducing oxidative stress. Six-week-old male Ren2 and Sprague-Dawley rats received RSV (10 mg·kg−1·day−1 ip) or vehicle for 3 wk. After treatment, right ventricular systolic pressure (RVSP) and mean arterial pressure (MAP) were measured. To evaluate treatment effects on pulmonary arteriole remodeling, morphometric analyses were performed to quantitate medial thickening and cell proliferation, whereas whole lung samples were used to quantitate the levels of 3-nitrotyrosine, superoxide, stable nitric oxide (NO) metabolites [nitrates and nitrites (NO x)], and expression of NO synthase isoforms. In the Ren2 rat, RVSP is normal at 5 wk of age, PAH develops between 5 and 7 wk of age, and the elevated pressure is maintained with little variation through 13 wk. At 8 wk of age, left ventricular function and blood gases were normal in the Ren2 rat. Ren2 rats exhibited elevations in medial hypertrophy due to smooth muscle cell proliferation, 3-nitrotyrosine, NO x, NADPH oxidase activity, and endothelial NO synthase expression compared with Sprague-Dawley rats. RSV significantly blunted the increase in RVSP but did not reduce MAP in the Ren2 rat; additionally, RSV significantly attenuated the elevated parameters examined in the Ren2 rat. These data suggest that statins may be a clinically viable adjunct treatment of PAH through reducing peroxynitrite formation.

scholarly journals Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats

2016 ◽  
Vol 310 (11) ◽  
pp. L1088-L1097 ◽  
Author(s):  
C. M. Happé ◽  
M. A. de Raaf ◽  
N. Rol ◽  
I. Schalij ◽  
A. Vonk-Noordegraaf ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Endothelial Cell Proliferation ◽  
Pulmonary Vasculature ◽  
Hypoxic Exposure ◽  
Sprague Dawley ◽  
Pulmonary Arterial ◽  
Severe Pulmonary Arterial Hypertension

The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6. Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature.

Beta3-adrenergic stimulation restores endothelial mitochondrial dynamics and prevents pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Oliver ◽  
S.F Rocha ◽  
M Spaczynska ◽  
D.V Lalama ◽  
M Gomez ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Therapeutic Strategy ◽  
Mitochondrial Dynamics ◽  
Systolic Pressure ◽  
Funding Source ◽  
Pulmonary Arterial

Abstract Background Endothelial dysfunction is one of the most important hallmarks of pulmonary arterial hypertension (PAH). This leads to anomalous production of vasoactive mediators that are responsible for a higher vascular tone and a subsequent increase in pulmonary artery pressure (PAP), and to an increased vascular permeability that favors perivascular inflammation and remodeling, thus worsening the disease. Therefore, preservation of the endothelial barrier could become a relevant therapeutic strategy. Purpose In previous studies, others and we have suggested the pharmacological activation of the β3-adrenergic receptor (AR) as a potential therapeutic strategy for pulmonary hypertension (PH) due to left heart disease. However, its potential use in other forms of PH remain unclear. The aim of the present study was to elucidate whether the β3-AR agonist mirabegron could preserve pulmonary endothelium function and be a potential new therapy in PAH. Methods For this purpose, we have evaluated the effect of mirabegron (2 and 10 mg/kg·day) in different animal models, including the monocrotaline and the hypoxia-induced PAH models in rats and mice, respectively. Additionally, we have used a transgenic mouse model with endothelial overexpression of human β3-AR in a knockout background, and performed in vitro experiments with human pulmonary artery endothelial cells (HPAECs) for mechanistic experiments. Results Our results show a dose dependent effect of mirabegron in reducing mean PAP and Right Ventricular Systolic Pressure in both mice and rats. In addition, the use of transgenic mice has allowed us to determine that pulmonary endothelial cells are key mediators of the beneficial role of β3-AR pathway in ameliorating PAH. Mechanistically, we have shown in vitro that activation of β3-AR with mirabegron protects HPAECs from hypoxia-induced ROS production and mitochondrial fragmentation by restoring mitochondrial fission/fusion dynamics. Conclusions This protective effect of mirabegron would lead to endothelium integrity and preserved pulmonary endothelial function, which are necessary for a correct vasodilation, avoiding increased permeability and remodeling. Altogether, the current study demonstrates a beneficial effect of the β3-AR agonist mirabegron that could open new therapeutic avenues in PAH. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Programa de Atracciόn de Talento, Comunidad de Madrid

Abstract 532: New Agonist of A2a Receptor Reduces Ventricular and Vascular Dysfunction in Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Allan K Alencar ◽  
Sharlene L Pereira ◽  
Arthur E Kummerle ◽  
Sharon S Langraf ◽  
Celso Caruso-Neves ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Systolic Pressure ◽  
Pulmonary Tissue ◽  
A2a Receptor ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance with subsequent remodeling and right ventricular hypertrophy. Vascular reactivity and ventricular function were investigated in rats with monocrotaline-induced PAH and treated with a new N-acylhydrazone derivative named as LASSBio-1359. METHODS: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. Male Wistar rats received a single i.p. injection of monocrotaline (MCT) (60 mg/kg) for PAH induction and were randomly divided in groups which were treated with: saline, vehicle and LASSBio-1359 (50 mg/kg p.o.). After 14 days of treatment, some parameters were evaluated: pulmonary acceleration time (PAT); right ventricular systolic pressure (RVSP); vascular reactivity to acetylcholine; expression of iNOS in pulmonary tissue; wall thickness of pulmonary artery (PAWT). Results: PAT (ms) was increased from 26.2 ± 2.8 to 41.3 ± 3.9 in PAH group treated with vehicle (n=8, p<0.05) and was reduced to 24.2 ± 1.7 when PAH group was treated with LASSBio-1359. RVSP (mmHg) increased from 26.0 ± 2.0 to 55.2 ± 2.3 in PAH group (p<0.05) but was similar to control after treatment with LASSBio-1359 (31.8 ± 2.3 mm Hg). Ratio of right ventricle and body weight (mg/g) was 0.66 ± 0.02, 1.63 ± 0.16 and 0.87 ± 0.10 for control, vehicle- and LASSBio-1359-treated PAH groups, respectively. PAH promoted ventricular dysfunction which was reduced by LASSBio-1359. The pulmonary artery maximum relaxation (%) was 57.3 ± 5.5, 43.6 ± 1.2 and 61.4 ± 8.4 for control, vehicle and LASSBio-1359-treated groups indicating that PAH promoted endothelium injury which was recovered by LASSBio-1359. iNOS expression in pulmonary tissue was increased from 0.48 ± 1.31 to 0.98 ± 3.14 in PAH group and reduced to 0.53 ± 1.83 in rats treated with LASSBio-1359. The PAWT (%) were increased from 74.1 ± 1.3 to 90.2 ± 2.7 in PAH group (p<0.05) but was 74.4 ± 1.3 when treated with LASSBio-1359. This compound showed an in vitro vasodilatory activity mediated by activation of adenosinergic A2A receptor. Conclusion: LASSBio-1359 reduced ventricular and vascular dysfunction in monocrotaline-induced PAH in rats indicating a possible new alternative to treat PAH.

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