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The Mechanistic Basis for Prostacyclin Action in Pulmonary Hypertension

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The Mechanistic Basis for Prostacyclin Action in Pulmonary Hypertension View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UCL Discovery COVER FEATURE The mechanistic basis for prostacyclin action in pulmonary hypertension Pulmonary arterial hypertension (PAH) is a progressive disease dicted from vasodilator testing.3 This strongly suggests LH Clapp PhD, of the small pulmonary arteries in which patients suffer from additional benefits of PGI , probably relating to anti-pro- 2 J Patel MPharm, elevated pulmonary arterial pressure, right ventricular failure liferative, anti-thrombotic and anti-inflammatory proper- Department of Medicine, and a reduction in gas exchange. Left untreated the median ties of this agent in the pulmonary vasculature. It is assumed University College London, survival from diagnosis is ~2.8 years, though outcome is this translates into a regression of the vascular remodelling London, UK significantly worse if patients have underlying pulmonary process,5 though evidence so far is lacking in IPAH patients.6 fibrosis or scleroderma. Injury to the endothelium probably Indeed lesion formation was actually reported to be more initiates the disease process, with increased production of extensive in IPAH patients on combined prostacyclin and vasoconstrictors (endothelin and thromboxane) and growth bosantan (mixed endothelin antagonist) therapy.7 factors accompanying the loss of vasodilator and anti-platelet In this article, we will discuss the recent advances in our agents, prostacyclin and nitric oxide, which results in vascular understanding of the mechanistic basis for prostacyclin remodelling. To date prostacyclin therapy still remains the most therapy, highlighting differences in the pharmacological Figure 1. Structures of efficacious treatment for PAH, although its short half-life and action of prostacyclin agonists, the impact of PAH on prostacyclin and its analogues. cumbersome delivery (continuous infusion) meant analogues prostacyclin signalling through prostacyclin (IP) receptors Prostacyclin is a chemically with improved stability and alternative routes of delivery were and peroxisome proliferator-activated receptors (PPARs), unstable prostaglandin which is developed. Classically, prostacyclin agents are thought to and the complex effects of prostacyclin on vascular remod- readily hydrolsed in a produce haemodynamic and anti-proliferative effects through elling, which in the long term may cause these agents to fail. physiological buffer to 6-keto- prostacyclin (IP) receptors coupled to cyclic AMP generation, PGF1α. It is also subject to though other prostanoid receptors may contribute (EP2, EP4) or PROSTACYCLIN ANALOGUES metabolism by 15 hydroxyl counterbalance (EP1, EP3) these responses. Increasing evidence Prostacyclin is clinically very hard to work with and has to prostaglandin dehydrogenase and suggests peroxisome proliferator-activated receptors (PPARs) be refrigerated if not used immediately or in hotter climates, β-oxidation yielding the urinary are also cellular targets for prostacyclin agonists, regulating the i.v. delivery system requires an ice pack. The half-life is metabolite 2,3-dinor-6-keto- cell growth, inflammation and apoptosis through these approximately 3 minutes when kept in buffer at a physio- PGF1α. To increase stability, a transcription factors. Activation involves ligand binding and/or logical temperature, the vinyl-ether linkage making it sus- series of modifications in the structure of prostacyclin were membrane receptors but probably not cyclic AMP. Here we ceptible to hydrolysis to 6-keto-PGF α (Figure 1), a 1 made, giving rise to chemically discuss recent advances in our understanding of PPARs and chemically stable product but weak inhibitor of platelet stable analogues with longer how they may represent an important therapeutic target in PAH. 8 function and vascular tone. The metabolism is complex, plasma half-lives (given as but 6-keto-PGF1α can be further metabolised in the kidney terminal). Stability comes from a 8 rostacyclin (PGI2) is a 20-carbon prostanoid deriva- to the 2,3-dinor derivative. Therefore, prostacyclin is typ- hindered alcohol group at carbon tive formed within vascular endothelial and smooth ically monitored by measurement of 6-keto-PGF1α in plas- 15 as well as an ether moiety Pmuscle cells by cyclooxygenase (mainly COX-2) medi- ma or its derivative in urine, 2,3-dinor-6-keto-PGF1α. replacing the methyl group at ated oxidation of arachidonic acid.1 Back in 1976, Sir John Given this inherent instability, chemists made modifica- carbon 3 of the carboxylic acid Vane and co-workers reported that arteries (but not tions in the lower and upper side chains, giving rise to ana- side chain. platelets) contained an enzyme (PGI2 synthase) which trans- formed prostaglandin intermediates (endoperoxides) to an COOH unstable substance (PGI2) that inhibited platelet aggregation O 1 (reviewed in Gryglewski ). This prostanoid was subse- 2,3-Dinor 6 Keto PGF 1 α (urine) quently found to be a potent dilator of both the systemic and pulmonary circulation and an inhibitor of smooth muscle 15 hydroxyl prostaglandin dehydrogenase OH OH Treprostinil (t1/2= 180-270 min) 1 α cell proliferation. In the early 1980s, Rubin and colleagues 6- Keto PGF 1 (plasma) COOH were the first to give prostacyclin to adult patients with idio- O COOH pathic pulmonary arterial hypertension (IPAH), showing it CH could acutely reduce mean pulmonary arterial pressure and 3 2 pulmonary vascular resistance and increase cardiac output. OH OH Cicaprost (t1/2= 60 min) Subsequently, a number of randomised controlled trials STABILITY H-OH O of intravenous prostacyclin (epoprostenol) have described COOH improvements in pulmonary haemodynamics, exercise tol- O CH erance and clinical symptoms.3 Alongside epoprostenol, 3 OH OH HO other therapies have been developed, including endothelial OH Beraprost (t1/2= 40-60 min) antagonists and phosphodiesterase (PDE) type five PGI2 (t1/2= 2 min) COOH inhibitors.4 These improve clinical symptoms in PAH, though to date only prostacyclin has been shown to have a CH significant impact on long-term survival.3,4 A key thing to 3 note is that <20% of PAH patients respond to vasodilator OH OH Iloprost (t = 20-30 min) therapy, and many have improvement exceeding that pre- 1/2 ➟ SPRING/SUMMER 2010 | INTERNATIONAL JOURNAL OF RESPIRATORY CARE 27 PROSTACYCLIN ACTION IN PULMONARY HYPERTENSION important therapeutic target for the treatment of hyperlip- Veins Arteries idaemia (fibrates) and PPARγ for type 2 diabetes (glita- Platelets zones), with increasing evidence suggesting they may also PGI <PGE PGI be novel targets in inflammatory and remodelling lung dis- PGI2<<TXA2 2 2 2 eases.16,19,20 PGI2<PGE2 Some analogues, including beraprost and iloprost, but not EP3 IP TP cicaprost, bind to and transcriptionally activate PPARs,15,21 EP though cicaprost is still capable of activating PPARγ in 1 Gq Gi AC Gs Gq HEK293 cells.22 The mechanism by which analogues acti- PLC G? vate PPARs has not been extensively investigated. However, ATP cAMP PKA with respect to PPARγ, both IP receptor and IP receptor- PIP 2+ 2 PDE 1, 2, 3, 4 Ca IP3 &DAG independent mechanisms have been reported, though this Ca2+ 5’ AMP Relaxation does not appear to necessitate cAMP elevation but could Disaggregation 22,23 Vasoconstriction involve phosphorylation of the ligand-binding domain. Antiproliferative Thrombosis Cell growth Signalling through other prostanoid receptors In trying to understand the cellular effects of prostacyclin, one has to remember that it has poor selectivity for Figure 2. Prostacyclin poorly logues not readily hydrolysable in solution (Figure 1). For prostanoid receptors, binding to and activating EP1, EP3 and discriminates between prostanoid example, the ability of treprostinil (formally UT-15) to TP receptors, albeit at higher concentrations (15–45-fold receptors. Prostacyclin binds to inhibit platelet aggregation is not compromised if incubat- for EP1 and EP3 and <100-fold for TP) compared with the the IP receptor, which is coupled ed in human plasma for 4 hours at 37°C prior to transfer to corresponding natural ligand.24–26 Activation of these via Gs protein to adenylyl cyclase platelet-enriched plasma.8 Iloprost, which shares the same receptors would tend to elevate Ca2+ and/or lower cAMP and cyclic AMP production. pentanoic side chain to prostacyclin, will, however, very through different G protein pathways,12,18 leading to vaso- Prostacyclin can also bind to and slowly degrade at room temperature and is most suscepti- constriction, thrombosis and cell proliferation (Figure 2). activate other prostanoid ble to β-oxidation, making its terminal plasma half-life less In human lung and platelets, EP3 and TP receptors are the receptors, including EP3 and TP in human pulmonary arteries, and (20–30 minutes) than either beraprost (40–60 minutes) or main prostanoid receptor to oppose signalling through IP 9–11 treprostinil (180–270 minutes). Several drug formula- receptors, the exception being pulmonary veins where EP1 platelets and EP1 and TP in pulmonary veins. These receptors tions now exist for clinical use including intravenous (ilo- and TP receptors appear to counteract prostanoid-induced 18,27 counteract IP receptor signalling prost, treprostinil), oral (beraprost, treprostinil), inhaled relaxation. Thus prostacyclin has the potential for dele- by elevating intracellular Ca2+ (iloprost and treprostinil) and subcutaneous (treprostinil). terious effects if IP receptor expression is compromised and/or lowering cyclic AMP and/or if
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