The Novel P2X7 Receptor PKT100 Improves Right Ventricular Function and Survival in Pulmonary Hypertension

Background: Pulmonary hypertension (PH) is a life-threatening disease. A pro-inflammatory milieu drives maladaptive right ventricular (RV) remodelling and failure. There is an unmet need for RV-targeted pharmaco-therapies. We investigated the effect of P2X7 receptor (P2X7R) inhibition on the pulmonary vasculature and RV remodelling using the novel P2X7R antagonist, PKT100. Methods: C57BL/6 mice were administered intratracheal bleomycin or saline and treated with PKT100 (0.2 mg/kg/day) or DMSO-vehicle. RV was assessed by right heart catheterisation and echocardiography, 21 days post-treatment. Cytokines in serum and bronchoalveolar lavage fluid (BALF) were analysed by ELISA and flow cytometry. Lungs and hearts were analysed histologically for pulmonary vascular and RV remodelling. Focused-PCR using genes involved in RV remodelling was performed. Results: Right ventricular systolic pressure (RVSP) was elevated in bleomycin-treated mice (30.2±1.1, n=7) compared to controls (23.5±1.0, n=10, p=0.008). PKT100 treatment did not alter RVSP (32.4±1.8, n=9), but substantially improved survival (93% vs. 57% DMSO). There were no differences between DMSO and PKT100 bleomycin mice in pulmonary inflammation or remodelling. However RV hypertrophy was reduced in PKT100 mice. Bleomycin decreased echocardiographic surrogates of RV systolic performance (FAC, s'), which were significantly improved with PKT100. Four genes involved in RV remodelling were differentially expressed between DMSO and PKT100-treated groups. Conclusions: The novel P2X7R inhibitor, PKT100, attenuates RV hypertrophy and improves RV contractile function and survival in a mouse model of PH. PKT100 may improve ventricular response to increased afterload, and merits further investigation into the potential role of P2X7R antagonists as direct RV-focused therapies in PH.