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.
Zamora
M A
MA
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver 80262.
Dempsey
E C
EC
Walchak
S J
SJ
Stelzner
T J
TJ
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)