title: Lack of inducible NO synthase reduces oxidative stress and enhances cardiac response to isoproterenol in mice with deoxycorticosterone acetate-salt hypertension.
abstract: Although NO derived from endothelial NO synthase (eNOS) is thought to be cardioprotective, the role of inducible NO synthase (iNOS) remains controversial. Using mice lacking iNOS (iNOS-/-), we studied (1) whether development of hypertension, cardiac hypertrophy, and dysfunction after deoxycorticosterone acetate (DOCA)-salt would be less severe compared with wild-type controls (WT; C57BL/6J), and (2) whether the cardioprotection attributable to lack of iNOS is mediated by reduced oxidative stress. Mice were uninephrectomized and received either DOCA-salt (30 mg/mouse SC and 1% NaCl+0.2% KCl in drinking water) or vehicle (tap water) for 12 weeks. Systolic blood pressure (SBP) was measured weekly. Left ventricular (LV) ejection fraction (EF) by echocardiography and cardiac response to isoproterenol (50 ng/mouse IV) were studied at the end of the experiment. Expression of eNOS and iNOS as well as the oxidative stress markers 4-hydroxy-2-nonenal (4-HNE, a marker of lipid peroxidation) and nitrotyrosine (a marker for peroxynitrite) were determined by Western blot and immunohistochemical staining, respectively. DOCA-salt increased SBP and LV weight similarly in both strains and decreased EF in WT but not in iNOS-/-. Cardiac contractile and relaxation responses to isoproterenol were greater, 4-HNE and nitrotyrosine levels were lower, and eNOS expression tended to be higher in iNOS-/-. We conclude that lack of iNOS leads to better preservation of cardiac function, which may be mediated by reduced oxidative stress and increased eNOS; however, it does not seem to play a significant role in preventing DOCA-salt-induced hypertension and hypertrophy.
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Health System, Wayne State University, Detroit, MI 48202-2689, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
authors.forename: Jiang
authors.initials: J
authors.lastname: Xu
authors.forename: Nour-Eddine
authors.initials: NE
authors.lastname: Rhaleb
authors.forename: Fangfei
authors.initials: F
authors.lastname: Wang
authors.forename: Chunxia
authors.initials: C
authors.lastname: Lin
authors.forename: James J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pagano
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003900:Desoxycorticosterone; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress; D012965:Sodium Chloride; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000447:Aldehydes; D002316:Cardiotonic Agents; C002744:3-nitrotyrosine; D003900:Desoxycorticosterone; D014443:Tyrosine; D012965:Sodium Chloride; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C027576:4-hydroxy-2-nonenal; D007545:Isoproterenol