BQ123, AN ET(A) 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 smoot h muscle cells (SMC) from human systemic arteries. A more modest growt h-promoting effect has also been described in SMC from the bovine and porcine pulmonary circulation. Whether ET-1 has mitogenic properties i n the human pulmonary circulation, and which ET receptor subtype media tes this response, is unknown. We first examined the effects of ET-1, ET-3, and the selective ET(B) agonist, Sarafotoxin 6c, on human pulmon ary artery SMC growth. Cells were harvested from normal lung transplan t donors. Growth was assessed by change in cell number 3 days after st imulation of quiescent cells. ET-1 in the presence of 0.3% serum produ ced 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 ET(B) selective agonist Sarafotoxin 6c had no proliferative effect. The effects of BQ123, a selective ET(A) receptor antagonist, o n 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 n o effect on proliferation stimulated by the non-ET receptor-mediated g rowth factors, platelet-derived growth factor BB and 5-hydroxytryptami ne. These results suggest that ET-1 is a potent co-mitogen for human p roximal pulmonary artery SMC and that this effect is transduced by sel ective activation of the ET(A) receptor.