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Am. J. Respir. Cell Mol. Biol., Volume 26, Number 2, February, 2002 194-201

Differential Effects of Stable Prostacyclin Analogs on Smooth Muscle Proliferation and Cyclic AMP Generation in Human Pulmonary Artery

Lucie H. Clapp, Paul Finney, Sally Turcato, Sandy Tran, Lewis J. Rubin, and Andrew Tinker

Centre for Clinical Pharmacology, Department of Medicine, University College London, London, United Kingdom; and Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Diego, California

Primary pulmonary hypertension is characterized by increased pulmonary vascular resistance and smooth muscle proliferation. Stable analogs are increasingly being used to treat this disease, although no data exists comparing their effects on proliferation. We therefore investigated the antiproliferative activity of several prostacyclin (PGI2) analogs on human pulmonary arterial smooth muscle cells, including UT-15 and iloprost, analogs that have recently completed successful clinical trials. Serum-induced proliferation, as assessed by [3H]thymidine incorporation (30 h) or cell number (48 h), was significantly inhibited with a 10-fold difference in potency, ranking in effectiveness UT-15 > iloprost > cicaprost > beraprost. Effects were reversed by the adenylyl cyclase inhibitor, 2,5'dideoxyadenosine (DDA) but not SQ22536. Intracellular cyclic AMP (cAMP) was elevated by all analogs and inhibited by DDA, although SQ22536 was a highly variable inhibitor, suggesting that different pathways might mediate cAMP generation. UT-15 produced a significantly larger and more sustained increase in cAMP compared with other analogs, with iloprost being the weakest elevator. Thus, PGI2 analogs potently inhibit proliferation of human pulmonary artery, probably via a cAMP-dependent pathway, although cAMP elevation in itself is not a good predictor of antiproliferative potency.

Abbreviations: cyclic AMP, cAMP; 2'5'dideoxyadenosine, DDA; fetal bovine serum, FBS; human pulmonary artery smooth muscle cells, HPASMC; 3-isobutyl-1-methylxanthine, IBMX; primary pulmonary hypertension, PPH; platelet-derived growth factor, PDGF; prostacyclin, PGI2; prostacyclin receptor, IP receptor; smooth muscle cell growth medium, SmGM; trichloroacetic acid, TCA.




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