Lodenafil treatment in the monocrotaline model of pulmonary hypertension in rats

Polonio, Igor Bastos; Acencio, Milena Marques Pagliarelli; Pazetti, Rogério; Almeida, Francine Maria de; Silva, Bárbara Soares da; Pereira, Karina; Souza, Rogério

doi:10.1590/s1806-37132014000400010

Cited by 13 publications

(7 citation statements)

References 7 publications

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“…Monocrotaline is a pyrrolizidine alkaloid present in the stems, leaves, and seeds of the plant Crotalaria spectabilis and in all the other plants of the Crotalaria genus. MCT-induced PAH is similar to human PAH in terms of hemodynamic and histopathological severity, including upregulation of inflammatory cytokines, vascular remodeling, and proliferation of smooth muscle cells, endothelial dysfunction, and RV failure [ 30 , 31 ]. Furthermore, proinflammatory cytokines, such as IL-1, IL-6, and TNF-α, are excessively produced in animals treated with MCT [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response

et al. 2018

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Background: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance, leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. Several studies have demonstrated that betaine possesses outstanding anti-inflammatory effects. However, whether betaine exerts protective effects on PAH by inhibiting inflammatory responses in the lungs needs to be explored. To test our hypothesis, we aimed to investigate the effects of betaine on monocrotaline-induced PAH in rats and attempted to further clarify the possible mechanisms. Methods: PAH was induced by monocrotaline (50 mg/kg) and oral administration of betaine (100, 200, and 400 mg/kg/day). The mean pulmonary arterial pressure, right ventricular systolic pressure, and right ventricle hypertrophy index were used to evaluate the development of PAH. Hematoxylin and eosin staining and Masson staining were performed to measure the extents of vascular remodeling and proliferation in fibrous tissue. Monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were also detected by immunohistochemical staining. Nuclear factor-κB (NF-κB), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β) were assessed by Western blot. Results: This study showed that betaine improved the abnormalities in right ventricular systolic pressure, mean pulmonary arterial pressure, right ventricle hypertrophy index, and pulmonary arterial remodeling induced by monocrotaline compared with the PAH group. The levels of MCP-1 and ET-1 also decreased. Western blot indicated that the protein expression levels of NF-κB, TNF-α, and IL-1β significantly decreased (p < 0.01). Conclusion: Our study demonstrated that betaine attenuated PAH through its anti-inflammatory effects. Hence, the present data may offer novel targets and promising pharmacological perspectives for treating monocrotaline-induced PAH.

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Section: Discussionmentioning

confidence: 99%

Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response

et al. 2018

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“…We preliminarily determined the optimal dosage range of isorhamnetin to protect pulmonary arterial hypertension in rats through pre-experiment and reference to relevant literatures (Gao et al, 2017;Qiu, Sun, Zhang, Li, & Wang, 2016). PAH was a highly malignant disease with a very low survival rate, and PAH animal models also had extremely low survival rates (Benza et al, 2012;Polonio et al, 2014). Compared with the MCT group, isorhamnetin significantly improved survival rates, body weight loss and general conditions (including feeding, free movement, shininess of fur, shortness of breath, and bluing of lips).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of isorhamnetin on pulmonary arterial hypertension: in vivo and in vitro studies

Chang

Wang

Jing

et al. 2020

Phytotherapy Research

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Pulmonary arterial hypertension (PAH) is a malignant disease with high mortality and closely involves the bone morphogenetic protein (BMP) pathway. Mutations in BMPR2 caused proliferation of pulmonary artery smooth muscle cells (PASMCs) leading to PAH. Isorhamnetin, one of the main naturally occurring flavonoids extracted from Hippophae rhamnoides L, shows antiinflammatory and anti-proliferative properties. Nevertheless, the effects of isorhamnetin on PAH remain unclear. This study aimed to investigate whether isorhamnetin has protective effects against PAH and explore possible mechanisms. An in vivo model of PAH induced by monocrotaline (MCT) was employed, and sildenafil and isorhamnetin were orally administered for 21 consecutive days. An in vitro model induced by TNF-α was employed, and cell proliferation of HPASMCs was detected. Results indicated that isorhamnetin significantly improved hemodynamic, histopathological, and echocardiographic changes in MCT-induced PAH in rats. In vitro, isorhamnetin suppressed TNF-α-induced HPASMCs proliferation. Furthermore, isorhamnetin improved protein expression of BMPR2 and suppressed protein expression of TNF-α and IL-6 in rat lungs. Isorhamnetin improved protein expression of BMPR2 and p-smad1/5 and mRNA expression of Id1 and Id3 in HPASMCs. Isorhamnetin ameliorated MCT-induced PAH in rats and inhibited TNF-α-induced HPASMCs proliferation by a mechanism likely involving the regulation of the BMP signaling pathway.

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“…Phosphodiesterase 5 (PDE5) inhibitors approved to treat PAH are sildenafil, tadalafil and vardenafil [ 7 ], whose mechanism involves increasing the bioavailability of cyclic guanosine monophosphate (cGMP) by inhibiting its degradation [ 8 ]. Therefore, a PDE5 inhibitor developed in Brazil, lodenafil [ 9 ], has shown promising results regarding PAH treatment [ 10 ] because of its comparable efficacy to sildenafil in preclinical studies on reverting PAH [ 11 ]. Mortality consequent to PAH is high [ 12 ] because current therapy fails to reverse the structural and signaling changes in pulmonary arteries (deregulated angiogenesis, high production and release of growth factors, strong resistance to apoptosis, abnormal formation of an inflammatory environment within and surrounding vessel walls) [ 13 ] and the RV (ischemia, metabolic dysfunction, fibrosis) [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Benefit of the Association of Lodenafil with Mesenchymal Stem Cells on Hypoxia-induced Pulmonary Hypertension in Rats

Silva

Alencar

et al. 2020

Cells

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Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. This work investigated the benefit of the association of human umbilical cord mesenchymal stem cells (hMSCs) with lodenafil, a phosphodiesterase-5 inhibitor, in an animal model of PAH. Male Wistar rats were exposed to hypoxia (10% O2) for three weeks plus a weekly i.p. injection of a vascular endothelial growth factor receptor inhibitor (SU5416, 20 mg/kg, SuHx). After confirmation of PAH, animals received intravenous injection of 5.105 hMSCs or vehicle, followed by oral treatment with lodenafil carbonate (10 mg/kg/day) for 14 days. The ratio between pulmonary artery acceleration time and RV ejection time reduced from 0.42 ± 0.01 (control) to 0.24 ± 0.01 in the SuHx group, which was not altered by lodenafil alone but was recovered to 0.31 ± 0.01 when administered in association with hMSCs. RV afterload was confirmed in the SuHx group with an increased RV systolic pressure (mmHg) of 52.1 ± 8.8 normalized to 29.6 ± 2.2 after treatment with the association. Treatment with hMSCs + lodenafil reversed RV hypertrophy, fibrosis and interstitial cell infiltration in the SuHx group. Combined therapy of lodenafil and hMSCs may be a strategy for PAH treatment.

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Lodenafil treatment in the monocrotaline model of pulmonary hypertension in rats

Cited by 13 publications

References 7 publications

Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response

Betaine Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibiting Inflammatory Response

Protective effects of isorhamnetin on pulmonary arterial hypertension: in vivo and in vitro studies

Therapeutic Benefit of the Association of Lodenafil with Mesenchymal Stem Cells on Hypoxia-induced Pulmonary Hypertension in Rats

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