title: A selective inducible NOS dimerization inhibitor prevents systemic, cardiac, and pulmonary hemodynamic dysfunction in endotoxemic mice.
abstract: Increased nitric oxide (NO) production by inducible NO synthase (NOS2), an obligate homodimer, is implicated in the cardiovascular sequelae of sepsis. We tested the ability of a highly selective NOS2 dimerization inhibitor (BBS-2) to prevent endotoxin-induced systemic hypotension, myocardial dysfunction, and impaired hypoxic pulmonary vasoconstriction (HPV) in mice. Mice were challenged with Escherichia coli endotoxin before treatment with BBS-2 or vehicle. Systemic blood pressure was measured before and 4 and 7 h after endotoxin challenge, and echocardiographic parameters of myocardial function were measured before and 7 h after endotoxin challenge. The pulmonary vasoconstrictor response to left mainstem bronchus occlusion, which is a measure of HPV, was studied 22 h after endotoxin challenge. BBS-2 treatment alone did not alter baseline hemodynamics. BBS-2 treatment blocked NOS2 dimerization and completely inhibited the endotoxin-induced increase of plasma nitrate and nitrite levels. Treatment with BBS-2 after endotoxin administration prevented systemic hypotension and attenuated myocardial dysfunction. BBS-2 also prevented endotoxin-induced impairment of HPV. In contrast, treatment with NG-nitro-l-arginine methyl ester, which is an inhibitor of all three NOS isoforms, prevented the systemic hypotension but further aggravated the myocardial dysfunction associated with endotoxin challenge. Treatment with BBS-2 prevented endotoxin from causing key features of cardiovascular dysfunction in endotoxemic mice. Selective inhibition of NOS2 dimerization with BBS-2, while sparing the activities of other NOS isoforms, may prove to be a useful treatment strategy in sepsis.
authors.affiliation: Department of Anesthesia and Critical Care and Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114-2620, USA. ichinose@etherdome.mgh.harvard.edu
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hataishi
authors.forename: Justina C
authors.initials: JC
authors.lastname: Wu
authors.forename: Noriko
authors.initials: N
authors.lastname: Kawai
authors.forename: Ana Clara Tude
authors.initials: AC
authors.lastname: Rodrigues
authors.forename: Cornell
authors.initials: C
authors.lastname: Mallari
authors.forename: Joe M
authors.initials: JM
authors.lastname: Post
authors.forename: John F
authors.initials: JF
authors.lastname: Parkinson
authors.forename: Michael H
authors.initials: MH
authors.lastname: Picard
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.forename: Warren M
authors.initials: WM
authors.lastname: Zapol
mesh_terms: D000818:Animals; D001011:Aorta / Q000502:physiology; D019281:Dimerization; D019446:Endotoxemia / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006331:Heart Diseases / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control; D007022:Hypotension / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019001:Nitric Oxide Synthase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D011652:Pulmonary Circulation / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D009573:Nitrites; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse