title: Norepinephrine induces alveolar epithelial apoptosis mediated by alpha-, beta-, and angiotensin receptor activation.
abstract: 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: H E
authors.initials: HE
authors.lastname: Dincer
authors.forename: N
authors.initials: N
authors.lastname: Gangopadhyay
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.forename: B D
authors.initials: BD
authors.lastname: Uhal
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D011945:Receptors, Angiotensin / Q000502:physiology*
chemical_list: D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D004338:Drug Combinations; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D011945:Receptors, Angiotensin; D010656:Phenylephrine; D007545:Isoproterenol; D009638:Norepinephrine