Diverse pharmacology of prostacyclin mimetics: Implications for pulmonary hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a progressive vascular remodelling disease where patients ultimately die from heart failure. Increased production of vasoconstrictors (endothelin-1 and thromboxane A2) accompanied by loss of prostacyclin, nitric oxide (NO), bone morphogenetic protein receptor type 2 (BMPR2) and TASK-1 combine to cause endothelial apoptosis, smooth muscle hyperactivity and thickening of the blood vessel wall. Prostacyclin remains the most efficacious treatment for PAH, and several prostacyclin analogues are approved for use via different administration routes. They act as vasodilators but potently inhibit platelet aggregation, cell proliferation and inflammation. The pharmacology of each prostacyclin (IP) receptor agonist is distinct, with other targets contributing to their therapeutic and side-effect profile, including prostanoid EP1, EP3, EP2 and DP1 receptors, alongside peroxisome proliferator-activated receptors (PPARs), to which prostacyclin and some analogues directly bind. To improve selectivity, selexipag, a non-prostanoid was developed, whose only significant biological target is the IP receptor, but is a partial agonist in cyclic AMP assays and has no anti-aggregatory properties in vivo. Prostanoid receptor expression profiles in the normal and diseased lung demonstrate loss of the IP receptor and upregulation of EP2 and EP3 receptors in PAH, affecting the action of prostacyclin mimetics in different ways. We discuss how prostacyclins might rescue BMPR2 and TASK-1 dysfunction and the importance of EP2 receptors as negative modulators of vascular tone, proliferation and fibrosis. Alongside DP1 and EP4 receptors, they have specific roles in veins and airways. Whether drugs selective for the IP receptor confer a superior or reduced therapeutic benefit remains an important clinical question as do the role of platelets in PAH.