scholarly journals The Glucagon-Like Peptide-1 Receptor Agonist Liraglutide Improves Hypoxia-Induced Pulmonary Hypertension in Mice Partly via Normalization of Reduced ETB Receptor Expression

2018 ◽  
pp. S175-S184 ◽  
Author(s):  
J. HONDA ◽  
T. KIMURA ◽  
S. SAKAI ◽  
H. MARUYAMA ◽  
K. TAJIRI ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Systolic Pressure ◽  
Receptor Expression ◽  
Vehicle Group ◽  
Ventricular Systolic Pressure ◽  
Etb Receptor ◽  
Mrna And Protein Expression ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Right

The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is an incretin hormone mimetic used in the treatment of diabetes. However, the effects of liraglutide on pulmonary hypertension (PH) and pulmonary endothelin (ET) system are unknown. Eight-week-old C57BL6/J mice were injected liraglutide or vehicle for 5 weeks. One week after injection, the mice were exposed to either room air (normoxia) or chronic hypoxia (10 % O2) for 4 weeks. The right ventricular systolic pressure (RVSP) was significantly higher in hypoxia + vehicle group than in normoxia + vehicle group. ET-1 mRNA expression in the lungs was comparable among all the groups. ETB mRNA and protein expression in the lungs was significantly lower in hypoxia + vehicle group than in normoxia + vehicle group. The above changes were normalized by liraglutide treatment. The expression of phospho-eNOS and phospho-AMPK proteins in the lungs was significantly higher in hypoxia + liraglutide group than in normoxia + vehicle group. We demonstrated for the first time that liraglutide effectively improved RVSP and RV hypertrophy in hypoxia-induced PH mice by activating eNOS through normalization of impaired ETB pathway and augmentation of AMPK pathway. Therefore, GLP-1R agonists can be promising therapeutic agents for PH.

scholarly journals Brain natriuretic peptide inhibits hypoxic pulmonary hypertension in rats

1998 ◽  
Vol 84 (5) ◽  
pp. 1646-1652 ◽  
Author(s):  
James R. Klinger ◽  
Rod R. Warburton ◽  
Linda Pietras ◽  
Nicholas S. Hill
Keyword(s):  
Pulmonary Hypertension ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Systolic Pressure ◽  
High Rate ◽  
Hypoxic Pulmonary Hypertension ◽  
Ventricular Systolic Pressure ◽  
Hypoxic Conditions ◽  
Pulmonary Vasodilator ◽  
The Right

Brain natriuretic peptide (BNP) is a pulmonary vasodilator that is elevated in the right heart and plasma of hypoxia-adapted rats. To test the hypothesis that BNP protects against hypoxic pulmonary hypertension, we measured right ventricular systolic pressure (RVSP), right ventricle (RV) weight-to-body weight (BW) ratio (RV/BW), and percent muscularization of peripheral pulmonary vessels (%MPPV) in rats given an intravenous infusion of BNP, atrial natriuretic peptide (ANP), or saline alone after 2 wk of normoxia or hypobaric hypoxia (0.5 atm). Hypoxia-adapted rats had higher hematocrits, RVSP, RV/BW, and %MPPV than did normoxic controls. Under normoxic conditions, BNP infusion (0.2 and 1.4 μg/h) increased plasma BNP but had no effect on RVSP, RV/BW, or %MPPV. Under hypoxic conditions, low-rate BNP infusion (0.2 μg/h) had no effect on plasma BNP or on severity of pulmonary hypertension. However, high-rate BNP infusion (1.4 μg/h) increased plasma BNP (69 ± 8 vs. 35 ± 4 pg/ml, P < 0.05), lowered RV/BW (0.87 ± 0.05 vs. 1.02 ± 0.04, P < 0.05), and decreased %MPPV (60 vs. 74%, P < 0.05). There was also a trend toward lower RVSP (55 ± 3 vs. 64 ± 2, P = not significant). Infusion of ANP at 1.4 μg/h increased plasma ANP in hypoxic rats (759 ± 153 vs. 393 ± 54 pg/ml, P < 0.05) but had no effect on RVSP, RV/BW, or %MPPV. We conclude that BNP may regulate pulmonary vascular responses to hypoxia and, at the doses used in this study, is more effective than ANP at blunting pulmonary hypertension during the first 2 wk of hypoxia.

Cystamine Treatment Fails to Prevent the Development of Pulmonary Hypertension in Chronic Hypoxic Rats

2021 ◽  
pp. 1-15
Author(s):  
Lars K. Markvardsen ◽  
Lene D. Sønderskov ◽  
Christine Wandall-Frostholm ◽  
Estéfano Pinilla ◽  
Judit Prat-Duran ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Lung Tissue ◽  
Ventricular Hypertrophy ◽  
Systolic Pressure ◽  
Right Ventricular Hypertrophy ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Arterial ◽  
The Right

<b><i>Introduction:</i></b> Pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary arteries, leading to right ventricular hypertrophy and failure. We have previously found upregulation of transglutaminase 2 (TG2) in the right ventricle of chronic hypoxic rats. The hypothesis of the present study was that treatment with the transglutaminase inhibitor, cystamine, would inhibit the development of pulmonary arterial remodeling, pulmonary hypertension, and right ventricular hypertrophy. <b><i>Methods:</i></b> Effect of cystamine on transamidase activity was investigated in tissue homogenates. Wistar rats were exposed to chronic hypoxia and treated with vehicle, cystamine (40 mg/kg/day in mini-osmotic pumps), sildenafil (25 mg/kg/day), or the combination for 2 weeks. <b><i>Results:</i></b> Cystamine concentration-dependently inhibited TG2 transamidase activity in liver and lung homogenates. In contrast to cystamine, sildenafil reduced right ventricular systolic pressure and hypertrophy and decreased pulmonary vascular resistance and muscularization in chronic hypoxic rats. Fibrosis in the lung tissue decreased in chronic hypoxic rats treated with cystamine. TG2 expression was similar in the right ventricle and lung tissue of drug and vehicle-treated hypoxic rats. <b><i>Discussion/Conclusions:</i></b> Cystamine inhibited TG2 transamidase activity, but cystamine failed to prevent pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial muscularization in the chronic hypoxic rat.

Abstract 70: Novel Multi-target Compound, Agonist of Adenosine Receptor and Inhibitor of Phosphodiesterase 5, Ameliorates Monocrotaline-induced Pulmonary Hypertension in Rats

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Gisele Zapata-Sudo ◽  
Allan K Alencar ◽  
Jaqueline S da Silva ◽  
Eliezer J Barreiro ◽  
Carlos A Fraga ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Exercise Capacity ◽  
Systolic Pressure ◽  
Premature Death ◽  
Treated Group ◽  
Exercise Intolerance ◽  
Vehicle Group ◽  
Ventricular Systolic Pressure ◽  
Phosphodiesterase 5

Aims: Pulmonary hypertension (PH) is a disease that results in right ventricular (RV) dysfunction and premature death. This work investigated the effects of LASSBio-1386, a compound with dual target, activation of the adenosine A 2A receptor and inhibition of phosphodiesterase 5 in rats with monocrotaline (MCT)-induced PH. Methods and Results: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. Male Wistar rats received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Experimental groups were: control, MCT + vehicle (DMSO), MCT + LASSBio-1386 (100 μmol/kg/day p.o.) and MCT + Sildenafil (100 μmol/kg/day p.o.). Animals were treated with vehicle or drug for 14 days after the onset of disease (n = 6 per group). Treadmill test and transthoracic echocardiography were performed to access exercise capacity and cardiac function, respectively. Right ventricular systolic pressure (RVSP) and ratio between RV and body weight (RV/BW) were analyzed. Exercise capacity (m.kg) was reduced from 1336.2 ± 82.2(control) to 479.7 ± 75.5 (MCT+ vehicle) and recovered to 1357.0 ± 87.8 and 1221.0 ± 96.8 after treatment with LASSBio-1386 and sildenafil, respectively. Pulmonary acceleration time (PAT) (ms) was reduced from 45.3 ± 0.8 (control) to 21.9 ± 0.3 in MCT + vehicle group ( P < 0.05) and restored to 42.9 ± 0.7 in MCT + LASSBio-1386 group, but it was only partially restored to 37.8 ± 1.3 (ms) in MCT + Sildenafil-treated group. RVSP (mmHg) was increased from 27.1 ± 0.7 (control) to 52.9 ± 1.5 in the PH rats and was reduced to 29.1 ± 1.0 and to 31.8 ± 0.6 after treatment with LASSBio-1386 and sildenafil. PH induced an increase of RV/BW (mg/g) from 0.62 ± 0.03 (control) to 1.81 ± 0.20 which was reduced to 0.70 ± 0.07 after administration of LASSBio-1386. Sildenafil treatment did not reverse the RV hypertrophy in PH rats (RV/BW = 1.52 ± 0.10 mg/g). Conclusions: LASSBio-1386 was effective to prevent RV dysfunction and exercise intolerance indicating important implications for ongoing clinical evaluation of multi-target drugs for the treatment of PAH.

Serotonin transporter is not required for the development of severe pulmonary hypertension in the Sugen hypoxia rat model

2015 ◽  
Vol 309 (10) ◽  
pp. L1164-L1173 ◽  
Author(s):  
Michiel Alexander de Raaf ◽  
Yvet Kroeze ◽  
Anthonieke Middelman ◽  
Frances S. de Man ◽  
Helma de Jong ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Serotonin Transporter ◽  
Rat Model ◽  
Systolic Pressure ◽  
Serum Levels ◽  
Normal Function ◽  
Ventricular Systolic Pressure ◽  
Serotonin System ◽  
Pulmonary Arterial

Increased serotonin serum levels have been proposed to play a key role in pulmonary arterial hypertension (PAH) by regulating vessel tone and vascular smooth muscle cell proliferation. An intact serotonin system, which critically depends on a normal function of the serotonin transporter (SERT), is required for the development of experimental pulmonary hypertension in rodents exposed to hypoxia or monocrotaline. While these animal models resemble human PAH only with respect to vascular media remodeling, we hypothesized that SERT is likewise required for the presence of lumen-obliterating intima remodeling, a hallmark of human PAH reproduced in the Sugen hypoxia (SuHx) rat model of severe angioproliferative pulmonary hypertension. Therefore, SERT wild-type (WT) and knockout (KO) rats were exposed to the SuHx protocol. SERT KO rats, while completely lacking SERT, were hemodynamically indistinguishable from WT rats. After exposure to SuHx, similar degrees of severe angioproliferative pulmonary hypertension and right ventricular hypertrophy developed in WT and KO rats (right ventricular systolic pressure 60 vs. 55 mmHg, intima thickness 38 vs. 30%, respectively). In conclusion, despite its implicated importance in PAH, SERT does not play an essential role in the pathogenesis of severe angioobliterative pulmonary hypertension in rats exposed to SuHx.

Evaluation of glucagon-like peptide-1 receptor expression in non-diabetic and diabetic atherosclerotic mice using PET tracer 68Ga-NODAGA-exendin-4

2021 ◽  
Author(s):  
Mia Ståhle ◽  
Sanna Hellberg ◽  
Jenni Virta ◽  
Heidi Liljenbäck ◽  
Olli Metsälä ◽  
...  
Keyword(s):  
Vessel Wall ◽  
Vascular Inflammation ◽  
Tracer Uptake ◽  
Receptor Expression ◽  
Atherosclerotic Lesions ◽  
Pet Tracer ◽  
Positron Emission ◽  
Healthy Control ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Activation of glucagon-like peptide-1 receptor (GLP-1R) signaling attenuates development of atherosclerosis and vascular inflammation. However, the expression of GLP-1R in atherosclerotic arteries remains uncertain. We evaluated whether a positron emission tomography (PET) tracer 68Ga-NODAGA-exendin-4 enables detection and imaging of GLP-1R expression in the mouse atherosclerotic aorta. Hypercholesterolemic (LDLR-/-ApoB100/100), hypercholesterolemic and diabetic (IGF-II/LDLR-/-ApoB100/100) as well as healthy control (C57BL/6N) mice were utilized in the study. The uptake of 68Ga-NODAGA-exendin-4 in atherosclerotic lesions was studied by autoradiography of tissue sections followed by immunofluorescence evaluation of inflammatory and vascular cell markers and GLP-1R. A subset of mice was imaged with 68Ga-NODAGA-exendin-4 PET/computed tomography (CT). The aortas of both LDLR-/-ApoB100/100 and IGF-II/LDLR-/-ApoB100/100 mice contained prominent, macrophage-rich atherosclerotic lesions. Diabetic mice demonstrated hyperglycemia and glucose intolerance. We found that by autoradiography, 68Ga-NODAGA-exendin-4 uptake was focally increased in macrophage-rich lesion areas compared with corresponding healthy vessel wall (lesion-to-wall ratio 1.6 ± 0.10, p<0.0001) in both non-diabetic and diabetic hypercholesterolemic mice. Pre-injection of unlabeled exendin-4 peptide significantly reduced cellular uptake of 68Ga-NODAGA-exendin-4. Furthermore, PET/CT imaging showed 68Ga-NODAGA-exendin-4 accumulation in the atherosclerotic aorta. Immunofluorescence stainings demonstrated co-localization of GLP-1R with macrophage-rich areas in atherosclerotic lesions. Tracer uptake was low in the healthy vessel wall of C57BL/6N mice coupled with negative GLP-1R staining. In conclusion, 68Ga-NODAGA-exendin-4 detects GLP-1R expression in atherosclerotic lesions in both non-diabetic and diabetic hypercholesterolemic mice. These results provide evidence that GLP-1R expression is mainly localized in macrophage-rich area in atherosclerotic lesions and may have implications for studies of pharmacological modification of GLP-1R signaling in atherosclerosis.

Abstract 15388: Persistent Pulmonary Hypertension After Transcatheter Aortic Valve Implantation: Impact on Mortality

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Maria Drakopoulou ◽  
Konstantinos Stathogiannis ◽  
Konstantinos Toutouzas ◽  
George Latsios ◽  
Andreas Synetos ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Aortic Stenosis ◽  
Pulmonary Artery ◽  
Severe Aortic Stenosis ◽  
Systolic Pressure ◽  
Right Atrial ◽  
Pulmonary Artery Systolic Pressure ◽  
End Point ◽  
The Right ◽  
The Impact

Objective: Severe aortic stenosis leads to increased pulmonary arterial systolic pressure. A controversy still remains regarding the impact of persistent pulmonary hypertension (PHT) on prognosis of patients undergoing transcatheter aortic valve implantation (TAVI). We sought to investigate the impact of persistent PHT on 2-year all-cause mortality of patients with severe aortic stenosis following TAVI. Methods: Patients with severe and symptomatic aortic stenosis (effective orifice area [EOA]≤1 cm 2 ) who were scheduled for TAVI with a self-expanding valve at our institution were prospectively enrolled. Prospectively collected echocardiographic data before and after TAVI were retrospectively analyzed in all patients. Pulmonary artery systolic pressure was estimated as the sum of the right ventricular to the right atrial gradient during systole and the right atrial pressure. PHT following TAVI was classified as absent if <35 mmHg and persistent if ≥35 mmHg. Primary clinical end-point was 2-year all-cause mortality defined according to the criteria proposed by the Valve Academic Research Consortium-2. Results: Hundred and forty patients (mean age: 82±9 years) were included in the study. The primary clinical end point occurred in 17 patients (12%) during a median follow-up period of 2 years. Mean pulmonary artery systolic pressure was reduced in all patients following TAVI (45±9 versus 41±6 mmHg, p<0.01). Mortality rate was higher in patients with persistent PHT compared to patients with normal pulmonary artery systolic pressure following TAVI (26% versus 14 %, p<0.01). Patients that reached the primary clinical end point had a higher post procedural mean systolic pulmonary pressure (43±9 versus 39±6 mmHg, p=0.02). In multivariate regression analysis, persistence of PHT (OR: 2.51, 95% CI: 1.109-7.224, p=0.01) was an independent predictor of long-term mortality. Conclusions: The persistence of pulmonary hypertension after TAVI is associated with long term mortality. Identifying the population that will clearly benefit from TAVI is still need to be validated by larger trials.

Abstract 15193: Pulmonary Hypertension in Pregnancy: WHO Group 1 Outcomes Improved, Time to Focus on WHO Group 2

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
William H Marshall ◽  
Stephen Gee ◽  
Woobeen Lim ◽  
Elisa A Bradley ◽  
Lauren Lastinger ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Post Partum ◽  
Systolic Pressure ◽  
Adverse Outcomes ◽  
Cardiac Events ◽  
Ventricular Systolic Pressure ◽  
Group 5 ◽  
Group 2 ◽  
In Pregnancy ◽  
Group 1

Introduction: Pregnancy is contraindicated in women with pulmonary hypertension (PH), yet many still decide to pursue pregnancy. Hypothesis: We hypothesized improved maternal mortality with PH at our center’s cardio-obstetrics program and sought to identify factors to estimate the risk of major adverse cardiac events (MACE). Methods: Pregnant women with right ventricular systolic pressure (RVSP) ≥35 mmHg or tricuspid regurgitant velocity > 2.8 m/s on transthoracic echocardiogram (TTE) were identified. Women with intermediate to high probability PH by ESC criteria (TTE or catheterization, n = 70) were classified using the 6 th World Society of PH definitions. Results: In 70 women with PH (30 ± 6 years-old, RVSP 52 ± 16 mmHg) there were 12 (17%) with WHO Group 1 PH, 45 (64%) with Group 2 PH, 4 (6%) with Group 3 PH and 9 (13%) with Group 5 PH (Figure A). Baseline characteristics were similar except: Group 1 PH had 83% on prostacyclin (PC) therapy, higher RVSP (78 ± 20 mmHg vs. Groups 2 (46 ± 9), 3 (44 ± 2 mmHg) and 5 PH (48 ± 10mmHg), p<0.01), and compared to Group 2 PH, more Group 1 PH women were diagnosed pre-pregnancy (9 (75%) vs. 12 (27%), p = 0.01) and had cardio-obstetrics care (10 (83%) vs. 16 (36%), p < 0.01) (Figure B - E). There were no peripartum deaths, however 3 (4.3%) women with Group 2 PH had late mortality (7 ± 4 months post-partum). MACE occurred in 24 (34%) women and was more likely in those with: NYHA FC ≥ 2 (95% CI 4.7-57, p < 0.01), pre-eclampsia (95% CI 1.2-13, p = 0.03), RVSP >50 mmHg (95% CI 1.3-10, p = 0.02) and LVEF <50% (95% CI 1.1-8.8, p = 0.04) (Figure F). Preterm birth occurred in 32 (49%) pregnancies, with no neonatal mortality. Conclusion: To conclude, in a large single center cohort we report 100% 1-year survival in Groups 1, 3, and 5 PH, with most Group 1 PH patients on PC therapy and under cardio-obstetrics care. We identify Group 2 PH as an under-recognized group for adverse outcomes in pregnancy, with NYHA FC, pre-eclampsia, RVSP >50 mmHg and LVEF <50% associated with increased MACE.

Right ventricular pressure response to +GZ acceleration stress

1982 ◽  
Vol 53 (4) ◽  
pp. 908-913 ◽  
Author(s):  
J. E. Whinnery ◽  
M. H. Laughlin
Keyword(s):  
Right Ventricular ◽  
Diastolic Pressure ◽  
Vena Cava ◽  
Systolic Pressure ◽  
Ventricular Pressure ◽  
Miniature Swine ◽  
Right Ventricular Systolic Pressure ◽  
Ventricular Systolic Pressure ◽  
The Right ◽  
Acceleration Stress

Measurements of right ventricular pressure in miniature swine were made at +Gz levels from +1 through +9 Gz. Polyethylene catheters were chronically placed in the cranial vena cava of five 2-yr-old female miniature swine (35–50 kg). The catheters were large enough to allow the introduction of a Millar pressure transducer into the venous system for placement in the right heart. The animals were fitted with an abdominal anti-G suit, restrained in a fiberglass couch, and exposed to the various +Gz levels on a centrifuge while fully conscious and unanesthetized. Right ventricular pressure and heart rate were measured during and for 2 min following 30-s exposures to each level of +Gz stress. The maximum right ventricular systolic pressure observed during +Gz was 200 Torr at +5 Gz with the maximum diastolic pressure being 88 Torr observed at +5 Gz. Mean heart rates were 200–210 beats/min at all levels of +Gz greater than or equal to +3 Gz when the animal remained stable. Mean maximum right ventricular pressures during +Gz stress were observed to increase through +5 Gz (85 Torr) and to decrease at higher levels of +Gz, indicating that through +5 Gz there is at least a partial compensation during acceleration stress. Decompensation in response to the stress began to occur during acceleration above +5 Gz with all animals decompensating during +9 Gz.

scholarly journals Glucagon-like peptide-1 receptor expression after myocardial infarction: Imaging study using 68Ga-NODAGA-exendin-4 positron emission tomography

2018 ◽  
Vol 27 (6) ◽  
pp. 2386-2397 ◽  
Author(s):  
Mia Ståhle ◽  
Ville Kytö ◽  
Max Kiugel ◽  
Heidi Liljenbäck ◽  
Olli Metsälä ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Positron Emission Tomography ◽  
Smooth Muscle Actin ◽  
Receptor Expression ◽  
Emission Tomography ◽  
Sham Operation ◽  
Alpha Smooth Muscle Actin ◽  
Positron Emission ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Background Activation of glucagon-like peptide-1 receptor (GLP-1R) signaling protects against cardiac dysfunction and remodeling after myocardial infarction (MI). The aim of the study was to evaluate 68Ga-NODAGA-exendin-4 positron emission tomography (PET) for assessment of GLP-1R expression after MI in rats. Methods and Results Rats were studied at 3 days, 1 and 12 weeks after permanent coronary ligation or a sham-operation. Rats were injected with 68Ga-NODAGA-exendin-4 and scanned with PET and contrast-enhanced computed tomography (CT) followed by digital autoradiography and histology of left ventricle tissue sections. 68Ga-NODAGA-exendin-4 PET/CT showed focally increased tracer uptake in the infarcted regions peaking at 3 days and continuing at 1 week after MI. Pre-treatment with an unlabeled exendin-4 peptide significantly reduced 68Ga-NODAGA-exendin-4 uptake. By autoradiography, 68Ga-NODAGA-exendin-4 uptake was 8.6-fold higher in the infarcted region and slightly increased also in the remote, non-infarcted myocardium at 1 week and 12 weeks post-MI compared with sham. Uptake of 68Ga-NODAGA-exendin-4 correlated with the amount of CD68-positive macrophages in the infarcted area and alpha-smooth muscle actin staining in the remote myocardium. Conclusions 68Ga-NODAGA-exendin-4 PET detects up-regulation of cardiac GLP-1R expression during healing of MI in rats and may provide information on the activated repair mechanisms after ischemic myocardial injury.

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