Abstract
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by a progressive increase in pulmonary artery pressure due to an increase in vessel tone and occlusion of vessels. The endogenous vasodilator prostacyclin and its analogs are used as therapeutic agents for PAH. However, their pharmacological effects on occlusive vascular remodeling have not been elucidated yet. Selexipag is a recently approved, orally available and selective prostacyclin receptor agonist with a non-prostanoid structure. In this study, we investigated the pharmacological effects of selexipag on the pathology of chronic severe PAH in Sprague-Dawley and Fischer rat models in which PAH was induced by a combination of injection with the vascular endothelial growth factor receptor antagonist Sugen 5416 and exposure to hypoxia (SuHx). Oral administration of selexipag for three weeks significantly improved right ventricular systolic pressure and right ventricular (RV) hypertrophy in Sprague-Dawley SuHx rats. Selexipag attenuated the proportion of lung vessels with occlusive lesions and the medial wall thickness of lung arteries, corresponding to decreased numbers of Ki-67-positive cells and a reduced expression of collagen type 1 in remodeled vessels. Administration of selexipag to Fischer rats with SuHx-induced PAH reduced RV hypertrophy and mortality caused by RV failure. These effects were probably based on the potent prostacyclin receptor agonistic effect of selexipag on pulmonary vessels. Selexipag has been approved and is used in the clinical treatment of PAH worldwide. It is thought that these beneficial effects of prostacyclin receptor agonists on multiple aspects of PAH pathology contribute to the clinical outcomes in patients with PAH.
Highlights
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by a progressive increase in pulmonary artery pressure, which causes right ventricular (RV) hypertrophy leading to right heart failure [1]
We have previously reported that the administration of 3 mg/kg selexipag causes a slightly increased heart rate but has no effect on systemic blood pressure in rats not infused with U46619 [27]; we chose a dose of 3 mg/kg to investigate the effect of selexipag on right ventricular systolic pressure (RVSP)
We demonstrate the pharmacological effect of selexipag on the pathological features of PAH in the SD Sugen and exposure to hypoxia (SuHx) rat model and on mortality by RV failure in the Fischer SuHx rat model
Summary
Pulmonary arterial hypertension (PAH) is a lethal disease characterized by a progressive increase in pulmonary artery pressure, which causes right ventricular (RV) hypertrophy leading to right heart failure [1]. In spite of the great success of prostacyclin receptor agonists as therapeutic agents for PAH, their pharmacological effects on the pathology of PAH, such as complex occlusive vascular remodeling and mortality risk associated with RV failure, have not yet been elucidated. The SD SuHx model develops severe RV hypertrophy, systolic and diastolic RV dysfunction, and increased glucose uptake in the RV [12] These progressive RV failure phenotypes closely resemble those of patients with PAH. The efficacy of the prostacyclin receptor agonists iloprost and treprostinil have been assessed in the SD SuHx model They improve the hemodynamics but do not show ameliorative effects on pulmonary vascular remodeling [15,16]. We hypothesize that selexipag can cause potent vasodilation even in the severe PAH of the SuHx model and improve the pathological features of PAH, so in the present study we investigated the pharmacological effects of selexipag on the pathological features of PAH in the SD SuHx rat model and mortality by RV failure in the Fischer SuHx rat model
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