A selective inducible NOS dimerization inhibitor prevents systemic, cardiac, and pulmonary hemodynamic dysfunction in endotoxemic mice.
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.
Ichinose
Fumito
F
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
Hataishi
Ryuji
R
Wu
Justina C
JC
Kawai
Noriko
N
Rodrigues
Ana Clara Tude
AC
Mallari
Cornell
C
Post
Joe M
JM
Parkinson
John F
JF
Picard
Michael H
MH
Bloch
Kenneth D
KD
Zapol
Warren M
WM
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
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