Role of prostacyclin in pulmonary hypertension

Abstract

Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it's discovery in the 1970s concerted efforts have been made to make the best therapeutic utility of prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of prostacyclin but that target the receptors that prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to prostacyclin and its use in pulmonary arterial hypertension.

Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system

“…Prostacyclin can also exert longer term genomic effects by directing gene transcription. Prostacyclin acts primarily on two receptors; the cell surface GPCR IP receptor and the cytosolic nuclear receptor PPARβ (Mitchell et al, ). Additionally, in some situations, prostacyclin can act on other prostanoid receptors to produce common and/or contradictory effects.…”

In silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone receptor antagonist properties

“…The PPAR␤/␦ agonist GW501516 completed proof-of-concept clinical trials successfully for dyslipidaemia [7] and hypercholesteraemia [8], although further clinical trials were halted due to toxicology issues [9]. Since this point, much interest has gathered as to the use of PPAR␤/␦ agonists in various disease settings, as the nuclear receptor has multiple regulatory roles in cell function and differentiation from controlling smooth muscle tone to remodelling of the pulmonary circulation [9][10][11].…”

Metal-organic framework (MOF) nanomedicine preparations of sildenafil designed for the future treatment of pulmonary arterial hypertension

“…Whilst these drugs show efficacy in PAH, they have limited pharmacokinetics and affect the systemic circulation, which ultimately limits the dose of drug that can be used. As such, we [1][2][3] and others [4][5][6] have suggested that PAH is a disease that would benefit from the application of controlled drug release, with the possibility of introducing targeted drug delivery strategies, using a nanomedicine approach. Whilst this idea is relatively novel, a limited number of studies are emerging describing nanomedicine formulations suitable for application in PAH.…”