Defective Intracellular Calcium Handling in Monocrotaline-Induced Right Ventricular Hypertrophy: Protective Effect of Long-Term Endothelin-A Receptor Blockade with 2-Benzo[1,3]dioxol-5-yl-3-benzyl-4-(4-methoxy-phenyl-)- 4-oxobut-2-enoate-sodium (PD 155080)

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.

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Nox2 Upregulation and p38α MAPK Activation in Right Ventricular Hypertrophy of Rats Exposed to Long-Term Chronic Intermittent Hypobaric Hypoxia

International Journal of Molecular Sciences ◽

10.3390/ijms21228576 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8576

Author(s):

Eduardo Pena ◽

Patricia Siques ◽

Julio Brito ◽

Silvia M. Arribas ◽

Rainer Böger ◽

...

Keyword(s):

Lipid Peroxidation ◽

Nadph Oxidase ◽

Right Ventricular ◽

Hypobaric Hypoxia ◽

Ventricular Hypertrophy ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Right Ventricular Hypertrophy ◽

Mapk Activation ◽

Intermittent Hypobaric Hypoxia

One of the consequences of high altitude (hypobaric hypoxia) exposure is the development of right ventricular hypertrophy (RVH). One particular type of exposure is long-term chronic intermittent hypobaric hypoxia (CIH); the molecular alterations in RVH in this particular condition are less known. Studies show an important role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex-induced oxidative stress and protein kinase activation in different models of cardiac hypertrophy. The aim was to determine the oxidative level, NADPH oxidase expression and MAPK activation in rats with RVH induced by CIH. Male Wistar rats were randomly subjected to CIH (2 days hypoxia/2 days normoxia; n = 10) and normoxia (NX; n = 10) for 30 days. Hypoxia was simulated with a hypobaric chamber. Measurements in the RV included the following: hypertrophy, Nox2, Nox4, p22phox, LOX-1 and HIF-1α expression, lipid peroxidation and H2O2 concentration, and p38α and Akt activation. All CIH rats developed RVH and showed an upregulation of LOX-1, Nox2 and p22phox and an increase in lipid peroxidation, HIF-1α stabilization and p38α activation. Rats with long-term CIH-induced RVH clearly showed Nox2, p22phox and LOX-1 upregulation and increased lipid peroxidation, HIF-1α stabilization and p38α activation. Therefore, these molecules may be considered new targets in CIH-induced RVH.

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E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.2.l225 ◽

1999 ◽

Vol 277 (2) ◽

pp. L225-L232 ◽

Cited By ~ 6

Author(s):

Norihisa Hanasato ◽

Masahiko Oka ◽

Masashi Muramatsu ◽

Mayu Nishino ◽

Hideyuki Adachi ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Cardiac Output ◽

Arterial Pressure ◽

Right Ventricular ◽

Ventricular Hypertrophy ◽

Chronic Hypoxia ◽

Systemic Arterial Pressure ◽

Right Ventricular Hypertrophy ◽

Pulmonary Arterial

The purpose of this study was to determine whether E-4010, a newly synthesized potent and selective orally active phosphodiesterase (PDE) 5 inhibitor, would prevent the development of chronic hypoxia-induced pulmonary hypertension in rats. In conscious, pulmonary hypertensive rats, a single oral administration of E-4010 (1.0 mg/kg) caused an acute, long-lasting reduction in mean pulmonary arterial pressure (PAP), with no significant effects on systemic arterial pressure, cardiac output, and heart rate. In rats that received food containing 0.01 or 0.1% E-4010 during the 3-wk exposure to hypoxia, mean PAP was significantly decreased (mean PAP 24.0 ± 0.9, 16.2 ± 0.8, and 12.8 ± 0.5 mmHg in rats treated with 0, 0.01, and 0.1% E-4010-containing food, respectively), whereas mean systemic arterial pressure was unchanged and cardiac output was slightly increased compared with chronically hypoxic control rats. Right ventricular hypertrophy, medial wall thickness in pulmonary arteries corresponding to the respiratory and terminal bronchioles, and the degree of muscularization of more distal arteries were less severe in E-4010-treated rats. Long-term treatment with E-4010 caused an increase in cGMP levels in lung tissue and plasma but not in aortic tissue and no significant change in cAMP levels in either lung, aorta, or plasma. These results suggest that long-term oral treatment with E-4010 reduced the increase in PAP, right ventricular hypertrophy, and pulmonary arterial remodeling induced by exposure to chronic hypoxia, probably through increasing cGMP levels in the pulmonary vascular smooth muscle.

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Contractile reserve but not tension is reduced in monocrotaline-induced right ventricular hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00536.2002 ◽

2004 ◽

Vol 286 (3) ◽

pp. H979-H984 ◽

Cited By ~ 10

Author(s):

J. Pieter Versluis ◽

Johannes W. Heslinga ◽

Pieter Sipkema ◽

Nico Westerhof

Keyword(s):

Right Ventricular ◽

Ventricular Hypertrophy ◽

Vehicle Control ◽

Right Ventricular Hypertrophy ◽

Calcium Handling ◽

Contractile Reserve ◽

Maximal Tension ◽

Recirculation Fraction ◽

Rat Papillary Muscle

The objective of this study was to evaluate the role of right ventricular hypertrophy on developed tension (Fdev) and contractile reserve of rat papillary muscle by using a model of monocrotaline (Mct)-induced pulmonary hypertension. Calcium handling and the influence of bicarbonate ([Formula: see text]) were also addressed with the use of two different buffers ([Formula: see text] and HEPES). Wistar rats were injected with either Mct (40 mg/kg sc) or vehicle control (Con). Isometrically contracting right ventricular papillary muscles were studied at 80% of the length of maximal developed force. Contractile reserve (1 – Fdev/Fmax) was calculated from Fdev and maximal tension (Fmax). Calcium recirculation was determined with postextrasystolic potentiation. Both groups of muscles were superfused with either [Formula: see text] (Con-B and Mct-B, both n = 6) or HEPES (Con-H and Mct-H, both n = 6) buffer. With hypertrophy, contractions were slower but Fdev was not changed. However, Fmax was decreased ( P < 0.05). With [Formula: see text], Fmax decreased from 23.8 ± 6.5 mN·mm–2 in Con-B, to 13.7 ± 3.3 mN·mm–2 in Mct-B. With HEPES, it decreased from 16.3 ± 3.5 mN·mm–2 ( n = 6, Con-H) to 8.3 ± 1.6 mN·mm–2 (Mct-H). Contractile reserve during hypertrophy was therefore also decreased ( P < 0.05). With [Formula: see text], it decreased from 0.73 ± 0.03 (Con-B) to 0.55 ± 0.04 (Mct-B). With HEPES, it decreased ( P < 0.001) from 0.64 ± 0.07 (Con-H) to 0.19 ± 0.06 (Mct-H). The recirculation fraction decreased ( P < 0.05) from 0.59 ± 0.04 in Con-B to 0.44 ± 0.04 in Mct-B. We conclude that contractile reserve and recirculation fraction are impaired during hypertrophy, with a stronger effect under HEPES than [Formula: see text] superfusion.

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