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A selective inducible NOS dimerization inhibitor prevents systemic, cardiac, and pulmonary hemodynamic dysfunction in
Fumito Ichinose1, Ryuji Hataishi, Justina C Wu
1Department 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
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.
Insights
Selective inhibition of inducible nitric oxide synthase (NOS2) dimerization with BBS-2 prevents sepsis-induced cardiovascular dysfunction, including hypotension and myocardial impairment in mice.
Area of Science:
- Cardiovascular Physiology
- Sepsis Pathophysiology
- Pharmacology
Background:
- Increased nitric oxide (NO) production by inducible NO synthase (NOS2) contributes to cardiovascular complications in sepsis.
- NOS2 functions as an obligate homodimer, presenting a potential therapeutic target.
Purpose of the Study:
- To evaluate the efficacy of a selective NOS2 dimerization inhibitor, BBS-2, in preventing endotoxin-induced cardiovascular dysfunction in a mouse model.
- To assess the impact of BBS-2 on systemic hypotension, myocardial dysfunction, and impaired hypoxic pulmonary vasoconstriction (HPV).
Main Methods:
- Mice were challenged with Escherichia coli endotoxin and subsequently treated with BBS-2 or vehicle.
- Hemodynamic parameters, echocardiographic measures of myocardial function, and HPV responses were assessed.
- Plasma nitrate and nitrite levels were measured to confirm NOS2 inhibition.
Main Results:
- BBS-2 treatment effectively blocked NOS2 dimerization and inhibited endotoxin-induced increases in plasma nitrate and nitrite.
- BBS-2 administration prevented systemic hypotension and attenuated myocardial dysfunction in endotoxemic mice.
- BBS-2 treatment also preserved HPV function, which was impaired by endotoxin.
Conclusions:
- Selective inhibition of NOS2 dimerization with BBS-2 effectively mitigates key cardiovascular sequelae of sepsis in mice.
- This targeted approach, sparing other NOS isoforms, represents a promising therapeutic strategy for sepsis treatment.