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.

Activation of the right ventricular endothelin (ET) system in the monocrotaline model of pulmonary hypertension: response to chronic ETA receptor blockade

2003 ◽  
Vol 105 (6) ◽  
pp. 647-653 ◽  
Author(s):  
Jean-François JASMIN ◽  
Peter CERNACEK ◽  
Jocelyn DUPUIS
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Right Ventricular Hypertrophy ◽  
Lower Percentage ◽  
Receptor Blockade ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
The Right

Although activation of the endothelin (ET) system contributes to pulmonary hypertension, modifications of the cardiopulmonary ET system and its responses to chronic ET receptor blockade are not well known. To investigate this, rats were injected with monocrotaline (60 mg/kg intraperitoneal) or saline, followed with treatment with the selective ETA receptor antagonist LU135252 (LU; 50 mg·kg-1·day-1) or with saline. After 3 weeks, haemodynamics, cardiac hypertrophy, ET-1 levels and cardiopulmonary ET-receptor-binding profile were evaluated. Monocrotaline (n=7) elicited marked pulmonary hypertension and right ventricular hypertrophy compared with controls (n=8). Both variables were substantially attenuated by LU therapy (n=8; P<0.05 for both). After monocrotaline, right ventricular ET-1 levels were more significantly increased than in the left ventricle (+198% compared with +127%; P<0.05). ETB receptor density was augmented (3-fold) in the right ventricle, whereas that of ETA receptors was not affected. LU treatment also significantly attenuated these alterations (P<0.05). In the lungs, ET-1 levels were not increased after monocrotaline, whereas the balance of ETB to ETA receptors was altered, with a trend toward a lower percentage of ETB than in the control rats. LU treatment did not affect these variables in the lungs. Therefore monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy are associated with the up-regulation of ET-1 and ETB receptors in the right ventricle. These alterations are attenuated with the reduction of pulmonary hypertension and right ventricular hypertrophy after chronic blockade of the ETA receptors, supporting the role of the ET system in right ventricular hypertrophy.

Lung vascular smooth muscle as a determinant of pulmonary hypertension at high altitude

1975 ◽  
Vol 228 (3) ◽  
pp. 762-767 ◽  
Author(s):  
A Tucker ◽  
IF McMurtry ◽  
JT Reeves ◽  
AF Alexander ◽  
DH Will ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Right Ventricular ◽  
High Altitude ◽  
Ventricular Hypertrophy ◽  
Mammalian Species ◽  
Systolic Pressure ◽  
Right Ventricular Hypertrophy ◽  
Ventricular Systolic Pressure

The pulmonary hypertensive response to chronic hypoxia varies markedly among mammalian species. An explanation for this variability was sought by exposing seven species to hypobaric hypoxia (PB equal to 435 mmHg) for 19-48 days. Control animals were studied at 1,600 m (PB equal to 630 mmHg). The pulmonary hypertension that developed varied in the following order of decreasing severity: calf and pig (severe); rat and rabbit (moderate); sheep, guinea pig, and dog (mild). Right ventricular hypertrophy developed in proportion to the elevation in right ventricular systolic pressure. These interspecies variations in response were not correlated with the degree of arterial hypoxemia, degree of polycythemia, elevation in heart rate, or postnatal age. However, the medial thickness of the small pulmonary arteries in control animals was highly correlated with the development of pulmonary hypertension and right ventricular hypertrophy in hypoxic animals. Thus, the amount of lung vascular smooth muscle inherent within each species is a major determinant of the pulmonary hypertensive response to high altitude and contributes to the interspecies variability in this response.

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.

Transient severe isolated right ventricular hypertrophy in neonates

2003 ◽  
Vol 13 (4) ◽  
pp. 384-386 ◽  
Author(s):  
Munesh Tomar ◽  
Sitaraman Radhakrishnan ◽  
Savitri Shrivastava
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Ventricular Function ◽  
Ventricular Hypertrophy ◽  
Pressure Overload ◽  
Posterior Wall ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Vasculature ◽  
Normal Thickness ◽  
The Right

We report two instances of transient isolated right-sided myocardial hypertrophy in patients with an intact ventricular septum, normal thickness of the posterior wall of the left ventricle, and normal ventricular function, diagnosed by echocardiography on the third day of life. The two neonates, born at 36 and 38 weeks gestation respectively, had perinatal distress. Both were diagnosed as having isolated right ventricular hypertrophy with mild pulmonary hypertension, which disappeared in both cases within 8 weeks without any specific therapy. Though the cause of the ventricular hypertrophy remains unclear, we believe that it is the consequence of remodeling of pulmonary vasculature secondary to acute perinatal distress, resulting in persistent pulmonary hypertension and producing pressure overload on the right ventricle, and hence right ventricular hypertrophy. The finding of early and transient right ventricular hypertrophy, with normal left-sided structures and normal ventricular function, has thus far failed to gain attention in the paediatric cardiologic literature.

scholarly journals Exogenous Ghrelin Attenuates the Progression of Chronic Hypoxia-Induced Pulmonary Hypertension in Conscious Rats

Endocrinology ◽  
2007 ◽  
Vol 149 (1) ◽  
pp. 237-244 ◽  
Author(s):  
Daryl O. Schwenke ◽  
Takeshi Tokudome ◽  
Mikiyasu Shirai ◽  
Hiroshi Hosoda ◽  
Takeshi Horio ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Endothelial Nitric Oxide Synthase ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Arterial ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Chronic exposure to hypoxia, a common adverse consequence of most pulmonary disorders, can lead to a sustained increase in pulmonary arterial pressure (PAP), right ventricular hypertrophy, and is, therefore, closely associated with heart failure and increased mortality. Ghrelin, originally identified as an endogenous GH secretagogue, has recently been shown to possess potent vasodilator properties, likely involving modulation of the vascular endothelium and its associated vasoactive peptides. In this study we hypothesized that ghrelin would impede the pathogenesis of pulmonary arterial hypertension during chronic hypoxia (CH). PAP was continuously measured using radiotelemetry, in conscious male Sprague Dawley rats, in normoxia and during 2-wk CH (10% O2). During this hypoxic period, rats received a daily sc injection of either saline or ghrelin (150 μg/kg). Subsequently, heart and lung samples were collected for morphological, histological, and molecular analyses. CH significantly elevated PAP in saline-treated rats, increased wall thickness of peripheral pulmonary arteries, and, consequently, induced right ventricular hypertrophy. In these rats, CH also led to the overexpression of endothelial nitric oxide synthase mRNA and protein, as well as endothelin-1 mRNA within the lung. Exogenous ghrelin administration attenuated the CH-induced overexpression of endothelial nitric oxide synthase mRNA and protein, as well as endothelin-1 mRNA. Consequently, ghrelin significantly attenuated the development of pulmonary arterial hypertension, pulmonary vascular remodeling, and right ventricular hypertrophy. These results demonstrate the therapeutic benefits of ghrelin for impeding the pathogenesis of pulmonary hypertension and right ventricular hypertrophy, particularly in subjects prone to CH (e.g. pulmonary disorders).

Abstract 058: Novel Agonist of Adenosine Receptor Ameliorates Ventricular and Vascular Dysfunction in Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Gisele Zapata-Sudo ◽  
Allan K Alencar ◽  
Sharlene L Pereira ◽  
Emanelle Ferraz ◽  
José H Nascimento ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Wall Thickness ◽  
Adenosine Receptor ◽  
Ventricular Hypertrophy ◽  
Systolic Pressure ◽  
Right Ventricular Hypertrophy ◽  
A2a Adenosine Receptors ◽  
Pulmonary Arterial

Aims: Pulmonary arterial hypertension (PAH) consists of increased pulmonary vascular resistance and remodeling and right ventricular hypertrophy. This work investigated the effects of a new N -acylhydrazone derivative, (E)-N’-(3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide (LASSBio-1386), in rats with monocrotaline (MCT)-induced PAH. 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 i.p. injection of MCT (60 mg/kg) for PAH induction. Experimental groups were: control, MCT + vehicle (DMSO), MCT + LASSBio-1386 (50 mg/kg p.o.). The animals were treated with vehicle or LASSBio-1386 for 14 days after the onset of disease (n = 6). Right ventricular systolic pressure (RVSP) and relation between RV weight to body weight (RV/BW) were analyzed. Transthoracic echocardiography was performed to determine pulmonary acceleration time (PAT), pulmonary artery diameter and RV wall thickness. Pulmonary vascular morphometry was analyzed using images of terminal arterioles and wall thickness was measured. The parameters evaluated are shown in table 1. In addition, LASSBio-1386-induced vasorelaxation was mediated partially by the activation of A2A adenosine receptors, with an IC50 of 6.2 ± 1.2 µM. Docking analysis in the A 2A crystal structure was performed using the program GOLD 5.1 and showed the interaction of the compound with A 2A receptor. Conclusions: LASSBio-1386 effectively reversed right ventricular hypertrophy and pulmonary vascular remodeling in rats with MCT-induced PAH through activation of adenosine receptor.

p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice

2011 ◽  
Vol 300 (5) ◽  
pp. L753-L761 ◽  
Author(s):  
Shiro Mizuno ◽  
Herman J. Bogaard ◽  
Donatas Kraskauskas ◽  
Aysar Alhussaini ◽  
Jose Gomez-Arroyo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Left Ventricle ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Hypoxic Exposure ◽  
Arterial Remodeling ◽  
Pulmonary Arterial ◽  
The Right

Chronic hypoxia induces pulmonary arterial remodeling, resulting in pulmonary hypertension and right ventricular hypertrophy. Hypoxia has been implicated as a physiological stimulus for p53 induction and hypoxia-inducible factor-1α (HIF-1α). However, the subcellular interactions between hypoxic exposure and expression of p53 and HIF-1α remain unclear. To examine the role of p53 and HIF-1α expression on hypoxia-induced pulmonary arterial remodeling, wild-type (WT) and p53 knockout (p53KO) mice were exposed to either normoxia or hypoxia for 8 wk. Following chronic hypoxia, both genotypes demonstrated elevated right ventricular pressures, right ventricular hypertrophy as measured by the ratio of the right ventricle to the left ventricle plus septum weights, and vascular remodeling. However, the right ventricular systolic pressures, the ratio of the right ventricle to the left ventricle plus septum weights, and the medial wall thickness of small vessels were significantly greater in the p53KO mice than in the WT mice. The p53KO mice had lower levels of p21 and miR34a expression, and higher levels of HIF-1α, VEGF, and PDGF expression than WT mice following chronic hypoxic exposure. This was associated with a higher proliferating cell nuclear antigen expression of pulmonary artery in p53KO mice. We conclude that p53 plays a critical role in the mitigation of hypoxia-induced small pulmonary arterial remodeling. By interacting with p21 and HIF-1α, p53 may suppress hypoxic pulmonary arterial remodeling and pulmonary arterial smooth muscle cell proliferation under hypoxia.

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