Efficacy of treprostinil in the SU5416-hypoxia model of severe pulmonary arterial hypertension: haemodynamic benefits are not associated with improvements in arterial remodelling

Abstract

Background and Purpose: Pulmonary arterial hypertension (PAH) is a life-threatening disease that leads to progressive pulmonary hypertension, right heart failure and death. Parenteral prostaglandins (PGs), including treprostinil, a prostacyclin analogue, represent the most effective medical treatment for severe PAH. We investigated the effect of treprostinil on established severe PAH and underlying mechanisms using the rat SU5416 (SU, a VEGF receptor-2 inhibitor)-chronic hypoxia (Hx) model of PAH. Experimental Approach: Male Sprague Dawley rats were injected with SU (20 mg·kg−1, s.c.) followed by 3 weeks of Hx (10% O2) to induce severe PAH. Four weeks post-SU injection, baseline right ventricular (RV) systolic pressure (RVSP) was measured, and the rats were randomized to receive vehicle or treprostinil treatment (Trep-100: 100 ng·kg−1·min−1 or Trep-810: 810 ng·kg−1·min−1). Following 3 weeks of treatment, haemodynamic and echocardiographic assessments were performed, and tissue samples were collected for protein expression and histological analysis. Key Results: At week 7, no difference in RVSP or RV hypertrophy was observed between vehicle and Trep-100; however, Trep-810 significantly reduced RVSP and RV hypertrophy. Trep-810 treatment significantly improved cardiac structure and function. Further, a short-term infusion of treprostinil in rats with established PAH at 4 weeks post-SU produced an acute, dose-dependent reduction in RVSP consistent with a vasodilator effect. However, chronic Trep-810 treatment did not alter media wall thickness, degree of vascular occlusion or total vessel count in the lungs. Conclusions and Implications: Treprostinil exerts therapeutic benefits in PAH through decreased vascular resistance and improved cardiac structure and function; however, treprostinil treatment does not have direct impact vascular remodelling.