BQ123, an ETA receptor antagonist, inhibits endothelin-1-mediated proliferation of human pulmonary artery smooth muscle cells.
Endothelin (ET-1) has been shown to be co-mitogenic for vascular smooth muscle cells (SMC) from human systemic arteries. A more modest growth-promoting effect has also been described in SMC from the bovine and porcine pulmonary circulation. Whether ET-1 has mitogenic properties in the human pulmonary circulation, and which ET receptor subtype mediates this response, is unknown. We first examined the effects of ET-1, ET-3, and the selective ETB agonist, Sarafotoxin 6c, on human pulmonary artery SMC growth. Cells were harvested from normal lung transplant donors. Growth was assessed by change in cell number 3 days after stimulation of quiescent cells. ET-1 in the presence of 0.3% serum produced a dose-dependent increase (82 +/- 1.5%) in cell number (threshold, 10(-11) M; maximal, 10(-7) M). ET-3 also stimulated growth (36 +/- 3.8%) but was less potent than ET-1 (threshold, 10(-9) M; maximal, 10(-7) M). The ETB selective agonist Sarafotoxin 6c had no proliferative effect. The effects of BQ123, a selective ETA receptor antagonist, on ET-1-induced growth were then assessed. BQ123 inhibited (threshold, 1.5 x 10(-7) M; maximal, 1.5 x 10(-5) M) ET-1-induced growth but had no effect on proliferation stimulated by the non-ET receptor-mediated growth factors, platelet-derived growth factor BB and 5-hydroxytryptamine. These results suggest that ET-1 is a potent co-mitogen for human proximal pulmonary artery SMC and that this effect is transduced by selective activation of the ETA receptor.
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver 80262.
M A
MA
Zamora
E C
EC
Dempsey
S J
SJ
Walchak
T J
TJ
Stelzner
D000704:Analysis of Variance; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011651:Pulmonary Artery
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)