Endothelial Dysfunction Providing the Basis for the Treatment of Pulmonary Hypertension: The Endothelium

3 Jun
2014

This review will consider prostacyclin (PGI2), nitric oxide (NO), and endothelin-1 (ET-1). It will also introduce an important interaction between platelets and the endothelium in lung disease. The aim is first, to provide an indication for treatment based on endothelial dysfunction and second, to identify methods of noninvasive measurement that might be used to assess the extent of the disease or predict those at risk.
Endothelial Dysfunction Prostacyclin
Prostacyclin: A Treatment for Pulmonary Hypertension: The discovery of PGI2 or prostaglandin X by Moncada et al in 1976 introduced the era of endothelium study. While present in levels in the circulation of <0.05 pmol/ mL, it proved to be a potent vasodilator and an inhibitor of platelet aggregation. Despite extensive study, few indications for its clinical use as a treatment emerged. In many countries, it was simply licensed for use as a heparin substitute in hemodialysis.
The double ring structure of PGI2 is subject to hydrolysis in aqueous solution causing inactivation and the formation of 6-KETO-PGFlor In the circulation, breakdown of PGI2 is achieved within 5 min. http://asthma-inhalers-online.com so Therefore, delivery of the PGI2 was considered to be limited to IV infusion and was thought to preclude long-term treatment.
There were early indications that short-term trials of IV PGI2 achieved both pulmonary and systemic vasodilatation. To achieve a continuous delivery of PGI2, we introduced on electronic syringe pump and delivery through a subcutaneous terminal into the subclavian vein. This provided a patient, with advanced PPH, a “bridge” to heart-lung transplantation. Further controlled trials showed that this treatment improved not only quality of life but also survival. A multicenter randomized controlled trial revealed the same effect and led to US Food and Drug Administration (FDA) approval for PGI2 treatment of PPH.
Further developments have included the introduction of the analogue of PGI2, iloprost, for the treatment of PPH. Subsequent oral analogues have also been the subject of clinical trials. Finally, learning from the effect of inhaled NO, the analogues of PGI2 have been inhaled as aerosols to treat patients with PPH long term.

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