@article {PatelP2355, author = {Jigisha Patel and David Abraham and Andrew Nelson and Adam Silverstein and Lucie Clapp}, title = {Comparison of current therapies against endothelin-induced growth in pulmonary smooth arterial muscle cells (PASMCs) derived from patients with pulmonary arterial hypertension}, volume = {44}, number = {Suppl 58}, elocation-id = {P2355}, year = {2014}, publisher = {European Respiratory Society}, abstract = {Pulmonary arterial hypertension (PAH) is a highly proliferative, vascular remodelling disease leading to heart failure and death. Endothelin-1 (ET-1) levels are raised and correlate with a poor outcome in PAH. Agents targeting the prostacyclin, ET-1 and cyclic GMP pathway are widely used to treat PAH but no direct comparison of multiple agents from all three pathways exists in vitro. Aim: To compare effects of prostacyclin mimetics (iloprost, treprostinil and MRE-269), tadalafil (PDE5 inhibitor), riociguat (guanylyl cyclase activator) and ET-1 receptor antagonists (ETRAs), bosentan and macitentan on cell proliferation in PASMCs derived from PAH patients (n=5). Methods: PASMCs were incubated in serum {\textpm} ET-1 (0.001-300nM). Drugs were evaluated in cells treated with 3nM ET-1 and serum. Cell proliferation was assessed using an MTS assay. Results: ET-1 modestly increased proliferation (1.5 fold at 100nM), but when combined with serum, the magnitude and potency of ET-1 was enhanced 3 and 10 fold, respectively. All drugs reduced proliferation with a rank order of the lowest (0.1nM-1000nM) dose to significantly (P\<0.05) inhibit being treprostinil\>riociguat>=MRE-269>=tadalafil=iloprost\>\>macitentan>=bosentan. ETRAs decreased (>=3 fold) while cGMP elevating agents increased (>=10 fold) the potency of treprostinil when combined. Conclusion: The efficacy of the different PAH therapies to inhibit ET-1 induced growth in PASMCs derived from PAH patients varied 10,000 fold. Prostacyclins and cGMP elevating agents, especially when combined, appear more effective antiproliferative agents than ETRAs.}, issn = {0903-1936}, URL = {https://erj.ersjournals.com/content/44/Suppl_58/P2355}, eprint = {https://erj.ersjournals.com/content}, journal = {European Respiratory Journal} }