Neuronal Nitric Oxide Synthase is Involved in Vascular Hyporeactivity and Multiple Organ Dysfunction Associated with Hemorrhagic Shock.

Abstract

Severe hemorrhage can lead to global ischemia and hemorrhagic shock (HS), resulting in multiple organ failure (MOF) and death. Restoration of blood flow and re-oxygenation is associated with an exacerbation of tissue injury and inflammatory response. The neuronal nitric oxide synthase (nNOS) has been implicated in vascular collapse and systemic inflammation of septic shock; however, the role of nNOS in HS is poorly understood. The aim of this study was to evaluate the role of nNOS in the MOF associated with HS.Rats were subjected to HS under anesthesia. Mean arterial pressure was reduced to 30  mmHg for 90  min, followed by resuscitation with shed blood. Rats were randomly treated with two chemically distinct nNOS inhibitors [ARL 17477 (1 mg/kg) and 7-nitroindazol (5 mg/kg)] or vehicle upon resuscitation. Four hours later, parameters of organ injury and dysfunction were assessed.HS was associated with MOF development. Inhibition of nNOS activity at resuscitation protected rats against the MOF and vascular dysfunction. In addition, treatment of HS rats with nNOS inhibitors attenuated neutrophil infiltration into target organs and decreased the activation of NF-κB, iNOS expression, NO production, and nitrosylation of proteins. Furthermore, nNOS inhibition also reduced the levels of pro-inflammatory cytokines TNF-α and IL-6 in HS rats.In conclusion, two distinct inhibitors of nNOS activity reduced the MOF, vascular dysfunction, and the systemic inflammation associated with HS. Thus, nNOS inhibitors may be useful as an adjunct therapy before fluids and blood administration in HS patients to avoid the MOF associated with reperfusion injury during resuscitation.

• Authors: Regina Sordi, Fausto Chiazza, Massimo Collino, Jamil Assreuy, Christoph Thiemermann
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 45 Issue 5 Pg. 525-33 (May 2016) ISSN: 1540-0514 [Electronic] United States
• PMID: 26863124 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ARL 17477
• Amidines
• Indazoles
• Interleukin-6
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Nitric Oxide Synthase Type I
• 7-nitroindazole

Topics

• Amidines (pharmacology)
• Animals
• Indazoles (pharmacology)
• Interleukin-6 (metabolism)
• Male
• Multiple Organ Failure (enzymology, etiology, metabolism)
• NF-kappa B (metabolism)
• Neutrophil Infiltration (drug effects)
• Nitric Oxide Synthase Type I (antagonists & inhibitors, metabolism)
• Rats
• Rats, Wistar
• Shock, Hemorrhagic (complications, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)