Norepinephrine induces alveolar epithelial apoptosis mediated by alpha-, beta-, and angiotensin receptor activation

Norepinephrine (NE) induces apoptosis in cardiac myocytes, and autocrine pr oduction of angiotensin (ANG) II is required for apoptosis of alveolar epit helial cells (AECs) (Wang R, Zagariya A, Ang E, Ibarra-Sunga O, and Uhal BD . Am J Physiol Lung Cell Mol Physiol 277: L1245-L1250, 1999; Wang R, Alam G , Zagariya A, Gidea C, Pinillos H, Lalude O, Choudhary G, and Uhal BD. J Ce ll Physiol 185: 253-259, 2000). On this basis, we hypothesized that NE migh t induce apoptosis of AECs in a manner inhibitable by ANG system antagonist s. Purified NE induced apoptosis in the human A549 ARC-derived cell line or in primary cultures of rat AECs, with EC50 values of 200 and 20 nM, respec tively. Neither the alpha -agonist phenylephrine nor the beta -agonist isop roterenol could mimic NE when tested alone but when applied together could induce apoptosis with potency equal to NE. Apoptosis and net cell loss (47- 59% in 40 h) in response to NE was completely abrogated by the ANG-converti ng enzyme inhibitor lisinopril or the ANG II receptor antagonist saralasin, each at concentrations capable of blocking Fas- or tumor necrosis factor-a lpha -induced apoptosis. These data suggest that NE induces apoptosis of hu man and rat AECs through a mechanism involving the combination of alpha- an d beta -adrenoceptor activation followed by autocrine generation of ANG II.