Modafinil improves monocrotaline-induced pulmonary hypertension rat model

Abstract

Background: Pulmonary arterial hypertension (PAH) progressively leads to increases in pulmonary vasoconstriction. Modafinil plays a role in vasorelaxation and blocking KCa3.1 channel with a result of elevating intracellular cyclic adenosine monophosphate (cAMP) levels. The purpose of this study is to evaluate the effects on modafinil in monocrotaline (MCT)-induced PAH rat. Methods: The rats were separated into three groups: the control group, the monocrotaline (M) group (MCT 60 mg/kg), and the modafinil (MD) group (MCT 60 mg/kg + modafinil). results: Reduced right ventricular pressure (RVP) was observed in the MD group. Right ventricular hypertrophy was improved in the MD group. Reduced number of intra-acinar pulmonary arteries and medial wall thickness were noted in the MD group. After the administration of modafinil, protein expressions of endothelin-1 (ET-1), endothelin receptor A (ERA) and KCa3.1 channel were significantly reduced. Modafinil suppressed pulmonary artery smooth muscle cell (PASMC) proliferation via cAMP and KCa3.1 channel. Additionally, we confirmed protein expressions such as Bcl-2-associated X, vascular endothelial growth factor, tumor necrosis factor-α, and interleukin-6 were reduced in the MD group. conclusion: Modafinil improved PAH by vasorelaxation and a decrease in medial thickening via ET-1, ERA, and KCa3.1 down regulation. This is a meaningful study of a modafinil in PAH model.

Effect of Ambrisentan Therapy on the Expression of Endothelin Receptor, Endothelial Nitric Oxide Synthase and NADPH Oxidase 4 in Monocrotaline-induced Pulmonary Arterial Hypertension Rat Model

“…In the present and previous studies, ET-1 and ERA protein expression levels were increased at weeks 2 and 4 after MCT injection, suggesting their importance in the progression of cardiopulmonary pathology in MCT-induced PAH rat model 14). In the 2016 study by Lee et al15), plasma ET-1 levels were found to be significantly increased in the MCT model 16). The protein expression level of eNOS decreased from 1 week after the MCT injection, whereas the NOX4 protein level was increased at week 4 in lung tissues of the MCT treated rat model.…”

Change of voltage-gated potassium channel 1.7 expressions in monocrotaline-induced pulmonary arterial hypertension rat model

“…Primary cultures of PASMCs were isolated from 10-week-old rats as previously described [ 15 ]. Briefly, a segment of the main pulmonary artery was excised and placed in Dulbecco’s modified Eagle medium containing 10% fetal bovine serum, 1% penicillin and streptomycin.…”

The ET-1-mediated carbonylation and degradation of ANXA1 induce inflammatory phenotype and proliferation of pulmonary artery smooth muscle cells in HPS

“…However, elevated ET-1 levels can activate vascular smooth muscle cells, inducing proliferation, hypertrophy, and synthesis of extracellular matrix, which lead to a diverse range of cardiovascular diseases including atherosclerosis, cardiac hypertrophy and pulmonary hypertension[8, 9]. The detrimental effects exerted by ET-1 on the vasculature include excessive accumulation of reactive oxygen species[10], promotion of vascular smooth muscle cells proliferation[11], and chronic vascular inflammation[12]. …”