The selective PGI2 receptor agonist selexipag ameliorates Sugen 5416/hypoxia-induced pulmonary arterial hypertension in rats

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.

Assessment of Inhaled Treprostinil Palmitil, Inhaled and Intravenous Treprostinil, and Oral Selexipag in a Sugen/Hypoxia Rat Model of Pulmonary Arterial Hypertension

“…For IV TRE, we used a dose infusion rate of 810 ng/kg/min that was based upon data from a previous study in Su/Hx-challenged rats (Chaudhary et al, 2018) and demonstrated acute pulmonary vasodilation in our experiments. Furthermore, based upon previously published data in Su/Hx challenged rats, an oral dosing frequency of 30 mg/kg selexipag administered BID was selected (Honda et al, 2020) with pulmonary vasodilation at this dose observed up to 4 h in our acute Hx challenged rats.…”

“…The dose selection for the compounds tested was based upon a combination of published data (Chaudhary et al, 2018;Honda et al 2020) and efficacy studies in healthy rats measuring the inhibition of pulmonary vasoconstriction induced by challenge with an inhaled hypoxic mixture (Corboz et al, 2021c).…”

Exploring the failing right ventricle in pulmonary hypertension by cardiac magnetic resonance: An in vivo study utilizing Macitentan

“…This current study followed an established Su/Hx protocol. 25 After the disease had been established (baseline), the rats were then treated with drugs or vehicles for further 3 weeks. Our Su/Hx rat model replicated the lower RVEF observed in a modified Su/Hx mouse protocol carried 22 as well as within clinic in PAH patients.…”

Antiproliferative effect of selexipag active metabolite MRE‐269 on pulmonary arterial smooth muscle cells from patients with chronic thromboembolic pulmonary hypertension

“…Selexipag reduces right ventricular systolic pressure and attenuates pulmonary vascular remodeling in concert with reducing proliferative vascular smooth muscle cells in monocrotaline or Sugen 5416/hypoxia‐induced PH in rats. 18 , 19 , 20 Selexipag is rapidly absorbed after oral administration and hydrolyzed to its active metabolite MRE‐269 ({4‐[(5,6‐diphenylpyrazin‐2‐yl)(isopropyl)amino]butoxy}acetic acid; also known as ACT‐333679). MRE‐269 has more potent activity and a longer half‐life than selexipag; therefore, it is considered to be the major contributor to the pharmacological activity of the drug.…”