A selective inducible NOS dimerization inhibitor prevents systemic, cardiac, and pulmonary hemodynamic dysfunction in endotoxemic mice

• Published in: American journal of physiology. Heart and circulatory physiology 2003-12, Vol.285 (6), p.H2524-H2530
• Main Authors: Ichinose, Fumito, Hataishi, Ryuji, Wu, Justina C, Kawai, Noriko, Rodrigues, Ana Clara Tude, Mallari, Cornell, Post, Joe M, Parkinson, John F, Picard, Michael H, Bloch, Kenneth D, Zapol, Warren M
• Format: Article
• Language: English
• Subjects: Animals; Aorta - physiology; Dimerization; Endotoxemia - drug therapy; Endotoxemia - mortality; Endotoxemia - physiopathology; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Enzymologic - drug effects; Heart Diseases - drug therapy; Heart Diseases - mortality; Heart Diseases - prevention & control; Hypotension - drug therapy; Hypotension - mortality; Hypotension - prevention & control; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nitric Oxide Synthase - chemistry; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitrites - blood; Pulmonary Circulation - physiology; Vasoconstriction - physiology; Vasodilation - physiology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00530.2003

1 Department of Anesthesia and Critical Care, 2 Cardiovascular Research Center, and 3 Cardiac Ultrasound Laboratory, Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114-2620; and 4 Berlex Biosciences, Richmond, California 94804-0099 Submitted 6 June 2003 ; accepted in final form 4 August 2003 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 N G -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. nitric oxide synthase; inflammation; inhibitors Address for reprint requests and other correspondence: F. Ichinose, Dept. of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114 (E-mail: ichinose{at}etherdome.mgh.harvard.edu ).