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1 Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA, USA; Department of Cardiovascular Research Center in the Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
2 Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA, USA
3 Department of Cardiac Ultrasound Laboratory in the Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
4 Berlex Biosciences, Richmond, CA, USA
5 Department of Cardiovascular Research Center in the Cardiology Division of the Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: ichinose{at}etherdome.mgh.harvard.edu.
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 followed by 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, 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 NOx 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 methylester, 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.
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