ANG-II AT(1) AND AT(2) RECEPTORS BOTH INHIBIT BFGF-INDUCED PROLIFERATION OF BOVINE ADRENOCORTICAL-CELLS

Angiotensin II (ANG II) has long been known for its presser and growth -promoting effects, which are both mediated by the AT(1) receptor. By contrast, the AT(2) receptor has recently been reported to mediate inh ibition of proliferation through as yet undefined mechanisms. We repor t here that in bovine adrenal fasciculata cells ANG II by itself does not affect growth but inhibits basic fibroblast growth factor (bFGF)-i nduced DNA synthesis and blocks the cells in G(1) phase. Consistent wi th this, ANG II inhibits cyclin D-1 expression and cyclin D-1-associat ed kinase activity. The antimitogenic effect of ANG II is partly mimic ked by the AT(2)-selective agonist CGP-42112. It is also blocked partl y and in an additive fashion by the AT(1)- and AT(2)-selective antagon ists losartan and PD-123319, indicating the contribution of both recep tor subtypes to this response. AT(1)-dependent antiproliferation is se lectively blocked by the cyclooxygenase inhibitor indomethacin and res tored by prostaglandin E-2, whereas AT(2)-receptor-mediated inhibition of growth is suppressed by the tyrosine phosphatase inhibitors orthov anadate and bpV(pic). Both pathways are, however, pertussis toxin sens itive. We hypothesize that, in fasciculata cells, the AT(1) receptor i nhibits bFGF-induced proliferation by stimulating prostaglandin synthe sis, whereas the AT(2) receptor mediates its effect through a pathway that requires protein tyrosine phosphatase activation.