Desensitization of angiotensin II: effect on [Ca2+](i), inositol triphosphate, and prolactin in pituitary cells

Activation of pituitary angiotensin (ANG II) type 1 receptors (AT(1)) mobil izes intracellular Ca2+, resulting in increased prolactin secretion. We fir st assessed desensitization of AT(1) receptors by testing ANG II-induced in tracellular Ca2+ concentration ([Ca2+](i)) response in rat anterior pituita ry cells. A period as short as 1 min with 10(-7) M ANG II was effective in producing desensitization (remaining response was 66.8 +/- 2.1% of nondesen sitized cells). Desensitization was a concentration-related event (EC50 : 1 .1 nM). Although partial recovery was obtained 15 min after removal of ANG II, full response could not be achieved even after 4 h (77.6 +/- 2.4%). Exp eriments with 5 x 10(-7) M ionomycin indicated that intracellular Ca2+ stor es of desensitized cells had already recovered when desensitization was sti ll significant. The thyrotropin-releasing hormone (TRH)-induced intracellul ar Ca2+ peak was attenuated in the ANG II-pretreated group. ANG II pretreat ment also desensitized ANG II- and TRH-induced inositol phosphate generatio n (72.8 +/- 3.5 and 69.6 +/- 6.1%, respectively, for inositol triphosphate) and prolactin secretion (53.4 +/- 2.3 and 65.1 +/- 7.2%), effects independ ent of PKC activation. We conclude that, in pituitary cells, inositol triph osphate formation, [Ca2+](i) mobilization, and prolactin release in respons e to ANG II undergo rapid, long-lasting, homologous and heterologous desens itization.