Abstract

Name: Lucie Clapp, Professor of Vascular Physiology, Deputy Director, Institute of Cardiovascular Science, Head of Preclinical & Fundamental Science,
University College London (UCL), London WC1E 6JF, UK

Back in the late 1970s, John Vane and co-workers workers reported, that arteries contained an enzyme (prostacyclin synthase) which transformed prostaglandin intermediates to an unstable substance (prostacyclin) that inhibited platelet aggregation in a cyclic AMP-dependent manner. Shortly thereafter, this agent (epoprostenol) was given to patients with pulmonary arterial hypertension, a progressive vascular remodelling disease, where patients ultimately die from heart failure. Although a potent dilator in both the systemic and pulmonary circulation, it is now widely documented, that clinical improvement exceeds that predicted from vasodilator testing alone. This strongly suggests that other properties of prostacyclin, and that of its stable mimetics, contribute to their therapeutic benefit. Indeed, early clinical use of these agents was in the treatment of peripheral vascular disease such as critical limb ischemia associated with atherosclerosis and Buerger’s disease, an inflammatory vascular disease affecting small and medium sized arteries and veins. 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 acts a partial agonist in cyclic AMP assays. Prostanoid receptor expression profiles in normal and diseased arteries demonstrates loss of the IP receptor and upregulation of EP2 and EP3 receptors in pulmonary hypertension, affecting the action of prostacyclins mimetics in different ways. Emerging evidence suggests EP2 receptors are important 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.


Presenting author details
Full name: Professor Lucie Clapp
Contact number: +44 (0) 7743093375
UCL profile: https://iris.ucl.ac.uk/iris/browse/profile?upi≤LCLAP60
LinkedIn account: https://uk.linkedin.com/in/lucie-clapp-6903922a
Conference: ELRIG/BPS -Translating Ideas into Therapies
Session name: Clinical Insights & Experimental Medicine (Thursday pm, 1st July 2021)
Category: (Keynote Speaker, 16.00-16.50)