Right Ventricular Systolic Pressure and Pulmonary Artery Diameter in Pulmonary Arterial Hypertension Associated With Scleroderma

CHEST Journal ◽  
2014 ◽  
Vol 146 (4) ◽  
pp. 836A
Author(s):  
Julianne Nichols ◽  
Electra Kaloudis ◽  
D. Datta ◽  
Raymond Foley
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Diameter

scholarly journals Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension

2021 ◽  
Author(s):  
Takanori Watanabe ◽  
Mariko Ishikawa ◽  
Kohtaro Abe ◽  
Tomohito Ishikawa ◽  
Satomi Imakiire ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Uric Acid ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Pressure Increase ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

Involvement of CFTR in the pathogenesis of pulmonary arterial hypertension

2021 ◽  
pp. 2000653
Author(s):  
Hélène Le Ribeuz ◽  
Lucie To ◽  
Maria-Rosa Ghigna ◽  
Clémence Martin ◽  
Chandran Nagaraj ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Arterial Hypertension ◽  
Animal Models ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Right Ventricular Systolic Pressure ◽  
Vascular Cell ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

IntroductionA reduction in pulmonary artery (PA) relaxation is a key event in pulmonary arterial hypertension (PAH) pathogenesis. CFTR dysfunction in airway epithelial cells plays a central role in cystic fibrosis (CF); CFTR is also expressed in PAs and has been shown to control endothelium-independent relaxation.Aim and objectivesWe aimed to delineate the role of CFTR in PAH pathogenesis through observational and interventional experiments in human tissues and animal models.Methods and resultsRT-Q-PCR, confocal imaging and electron microscopy showed that CFTR expression was reduced in PAs from patients with idiopathic PAH (iPAH) and in rats with monocrotaline-induced pulmonary hypertension (PH). Moreover, using myograph on human, pig and rat PAs, we demonstrated that CFTR activation induces PAs relaxation. CFTR-mediated PA relaxation was reduced in PAs from iPAH patients and rats with monocrotaline- or chronic hypoxia-induced PH. Long-term in vivo CFTR inhibition in rats significantly increased right ventricular systolic pressure, which was related to exaggerated pulmonary vascular cell proliferation in situ and vessel neomuscularization. Pathologic assessment of lungs from patients with severe CF (F508del-CFTR) revealed severe PA remodeling with intimal fibrosis and medial hypertrophy. Lungs from homozygous F508delCftr rats exhibited pulmonary vessel neomuscularization. The elevations in right ventricular systolic pressure and end diastolic pressure in monocrotaline-exposed rats with chronic CFTR inhibition were more prominent than those in vehicle-exposed rats.ConclusionsCFTR expression is strongly decreased in PA smooth muscle and endothelial cells in human and animal models of PH. CFTR inhibition increases vascular cell proliferation and strongly reduces PA relaxation.

scholarly journals Temporal hemodynamic and histological progression in Sugen5416/hypoxia/normoxia-exposed pulmonary arterial hypertensive rats

2014 ◽  
Vol 306 (2) ◽  
pp. H243-H250 ◽  
Author(s):  
Michie Toba ◽  
Abdallah Alzoubi ◽  
Kealan D. O'Neill ◽  
Salina Gairhe ◽  
Yuri Matsumoto ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Male Rats ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Time Points ◽  
Pulmonary Arterial ◽  
Time Point

We have investigated the temporal relationship between the hemodynamic and histological/morphological progression in a rat model of pulmonary arterial hypertension that develops pulmonary arterial lesions morphologically indistinguishable from those in human pulmonary arterial hypertension. Adult male rats were injected with Sugen5416 and exposed to hypoxia for 3 wk followed by a return to normoxia for various additional weeks. At 1, 3, 5, 8, and 13 wk after the Sugen5416 injection, hemodynamic and histological examinations were performed. Right ventricular systolic pressure reached its maximum 5 wk after Sugen5416 injection and plateaued thereafter. Cardiac index decreased at the 3∼5-wk time point, and tended to further decline at later time points. Reflecting these changes, calculated total pulmonary resistance showed a pattern of progressive worsening. Acute intravenous fasudil markedly reduced the elevated pressure and resistance at all time points tested. The percentage of severely occluded small pulmonary arteries showed a similar pattern of progression to that of right ventricular systolic pressure. These small vessels were occluded predominantly with nonplexiform-type neointimal formation except for the 13-wk time point. There was no severe occlusion in larger arteries until the 13-wk time point, when significant numbers of vessels were occluded with plexiform-type neointima. The Sugen5416/hypoxia/normoxia-exposed rat shows a pattern of chronic hemodynamic progression similar to that observed in pulmonary arterial hypertension patients. In addition to vasoconstriction, nonplexiform-type neointimal occlusion of small arteries appears to contribute significantly to the early phase of pulmonary arterial hypertension development, and plexiform-type larger vessel occlusion may play a role in the late deterioration.

scholarly journals Dual-Functional MN-08 Attenuated Pulmonary Arterial Hypertension Through Vasodilation and Inhibition of Pulmonary Arterial Remodeling

Hypertension ◽  
2021 ◽  
Vol 77 (5) ◽  
pp. 1787-1798
Author(s):  
Fangcheng Luo ◽  
Liangmiao Wu ◽  
Guoqing Xie ◽  
FangFang Gao ◽  
Zhixiang Zhang ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Pulmonary Vascular Disease ◽  
Arterial Remodeling ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Dual Functional ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a rare, progressive pulmonary vascular disease with limited therapeutic options. Pulmonary circulation resistance, pulmonary vascular remodeling, and over-activated NMDARs (N-methyl-d-aspartate receptors) play vital roles in the pathogenesis of PAH. In the present study, we aimed to evaluate the efficacy and molecular mechanism of MN-08, a dual-functional memantine nitrate derivative, in experimental animal models of PAH. MN-08 showed a high degree of accumulation in the lungs and dilated pulmonary arterial rings ex vivo by releasing nitric oxide. MN-08 did not lower systemic blood pressure. MN-08 attenuated right ventricular systolic pressure and right ventricular hypertrophy, inhibited pulmonary arterial remodeling, alleviated glutamate-NMDARs dysregulation, and improved survival rates in monocrotaline-induced PAH rats. More importantly, the therapeutic benefit of MN-08 for PAH was greater than that of sildenafil. Moreover, MN-08 can reduce right ventricular systolic pressure in U46619-induced acute PAH rats. Mechanistically, MN-08 suppressed proliferation of pulmonary arterial smooth muscle cells exposed to human platelet-derived growth factor-BB by regulating the cell cycle and expression of NMDAR1, AKT (serine/threonine kinase Akt), and ERK (extracellular signal-regulated kinase) 1/2. In conclusion, our studies demonstrated that MN-08 may be a promising therapeutic agent for PAH.

Abstract 329: Oral Administration of New Calcium Channel Antagonist Reverses Right Ventricular Dysfunction in Rats With Pulmonary Arterial Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Sharlene L Pereira ◽  
Allan K Alencar ◽  
Arthur E Kummerle ◽  
Emanuelle B Ferraz ◽  
José Nascimento ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Calcium Channel Antagonist ◽  
Ventricular Dysfunction ◽  
Systolic Pressure ◽  
Right Ventricular Dysfunction ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, endothelial injury and vascular remodeling, right ventricular hypertrophy and increased right ventricular systolic pressure. This work investigated the effects of LASSBio-1289, a new calcium channel antagonist, in rats with PAH induced by monocrotaline (MCT). METHODS: Male Wistar rats (200 - 250 g) received a single MCT i.p. injection (60 mg/kg) for induction of PAH. The experimental groups were: control, MCT, MCT + vehicle, MCT + LASSBio-1289 (50 mg/kg p.o.). Animals were treated either with vehicle or LASSBio-1289 for 14 days after the onset of disease. The following parameters were analyzed: right ventricular systolic pressure (RVSP), RV contractility (dp/dtmax), RV relaxation (dp/dtmin)and RV weight / left ventricle + septum weight (RV/LV+S). Echocardiography was performed to determine RV area and wall thickness. The protocols used in the present study were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. Results: RVSP (mmHg) increased from 25.3 ± 1.9 (control) to 49.0 ± 6.2 (P < 0.05) and 52.7 ± 6.2 (P < 0.05) in MCT and MCT + vehicle groups, respectively. When MCT-injected rats were treated with LASSBio-1289, RVSP was decreased to 36.4 ± 2.0 mm Hg (P < 0.05). RV/LV+S increased from 0.24 ± 0.02 to 0.56 ± 0.04 (P < 0.05) and 0.49 ± 0.03 in the MCT and MCT + vehicle groups (P < 0.05) and reduced to 0.30 ± 0.03 (P < 0.05) after treatment with LASSBio-1289. The dp/dtmax (mmHg/s) was 1179 ± 137, 2180 ± 238, 2482 ± 371 and 1134 ± 131 for control, MCT, MCT + vehicle and MCT + LASSBio-1289 groups. In addition to this, the dp/dtmin (mmHg/s) increased from -702 ± 83 to -1359 ± 120, -1720 ± 243 in the MCT and MCT + vehicle groups. In contrast, treatment with LASSBio-1289 reduced this parameter to -701 ± 122 (P < 0.05). RV area (mm2) was increased from 8.2 ± 0.5 to 17.8 ± 1.4 and 18.7 ± 1.0 in the PAH groups. RV area was reduced in LASSBio-1289-treated rats to 9.4 ± 0.9 (P < 0.05). PAH increased the RV wall thickness (cm) from 0.089 ± 0.002 to 0.125 ± 0.006 (P < 0.05) and was reduced to 0.098 ± 0.006 after treatment with LASSBio-1289. Conclusions: LASSBio-1289 effectively reversed right ventricular dysfunction and hypertrophy in rats with monocrotaline-induced PAH.

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.

scholarly journals Baicalin prevents pulmonary arterial remodeling in vivo via the AKT/ERK/NF-κB signaling pathways

2019 ◽  
Vol 9 (4) ◽  
pp. 204589401987859 ◽  
Author(s):  
Guosen Yan ◽  
Jinxia Wang ◽  
Tao Yi ◽  
Junfen Cheng ◽  
Haixu Guo ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Signaling Pathways ◽  
Vascular Remodeling ◽  
Systolic Pressure ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial

Pulmonary arterial hypertension is a rapidly progressive and often fatal disease. As the pathogenesis of pulmonary arterial hypertension remains unclear, there is currently no good drug for pulmonary arterial hypertension and new therapy is desperately needed. This study investigated the effects and mechanism of baicalin on vascular remodeling in rats with pulmonary arterial hypertension. A rat pulmonary arterial hypertension model was constructed using intraperitoneal injection of monocrotaline, and different doses of baicalin were used to treat these rats. The mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured with a right heart catheter. Moreover, the hearts were dissected to determine the right ventricular hypertrophy index (RVHI). The lung tissues were stained with H&E and Masson's staining to estimate the pulmonary vascular remodeling and collagen fibrosis, and the expression of proteins in the AKT, ERK, and NF-κB p65 phosphorylation (p-AKT, p-ERK, p-p65) was examined by Western blot analysis. We found that compared with untreated pulmonary arterial hypertension rats, baicalin ameliorated pulmonary vascular remodeling and cardiorespiratory injury, inhibited p-p65 and p-ERK expression, and promoted p-AKT and p-eNOS expression. In conclusion, baicalin interfered with pulmonary vascular remodeling and pulmonary arterial hypertension development in rats through the AKT/eNOS, ERK and NF-κB signaling pathways.

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