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

Norepinephrine (NE) induces apoptosis in cardiac myocytes, and autocrine production of angiotensin (ANG) II is required for apoptosis of alveolar epithelial 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 Cell Physiol 185: 253--259, 2000). On this basis, we hypothesized that NE might induce apoptosis of AECs in a manner inhibitable by ANG system antagonists. Purified NE induced apoptosis in the human A549 AEC-derived cell line or in primary cultures of rat AECs, with EC(50) values of 200 and 20 nM, respectively. Neither the alpha-agonist phenylephrine nor the beta-agonist isoproterenol 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-converting enzyme inhibitor lisinopril or the ANG II receptor antagonist saralasin, each at concentrations capable of blocking Fas- or tumor necrosis factor-alpha-induced apoptosis. These data suggest that NE induces apoptosis of human and rat AECs through a mechanism involving the combination of alpha- and beta-adrenoceptor activation followed by autocrine generation of ANG II.