Organ-specific changes in vascular reactivity and roles of inducible nitric oxide synthase and endothelin-1 in a rabbit endotoxic shock model

BACKGROUND Hemorrhagic shock-induced changes in vascular reactivity appear organ- specific. In the present study, we examined the hypothesis that vascular reactivity induced by septic shock similarly displays organ-specific differences and is regulated by inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1). METHODS Endotoxic shock was induced in rabbits by administration of LPS (1 mg/kg), and organ specificity of vascular reactivity of superior mesenteric artery (SMA), celiac artery (CA) and left renal artery (LRA) as well as the potential involvement of iNOS and ET-1 examined. RESULTS Vascular reactivity of SMA, CA and LRA was increased at the early stages and decreased at the late stages after LPS administration. SMA showed the greatest decrease in vascular reactivity in response to norepinephrine (NE) (34.9%) and acetylcholine (Ach; 32.3%), followed by LRA (NE, 33.7%; Ach, 30.5%) and CA (NE, 16.2%), whereas the relaxation reactivity of CA in response to Ach was increased to 159%. The mRNA and protein levels of iNOS and ET-1 in SMA, CA and LRA were not affected at the early stages of endotoxic shock after LPS administration but significantly increased at the late stages. Expression levels were higher in SMA than CA and LRA and negatively correlated with the decrease in vascular reactivity. The iNOS and ET-1 inhibitors, AG (20 mg/kg) and PD-142893 (0.02 mg/kg), respectively, induced significant improvements in vascular reactivity and organ perfusion and stabilized the hemodynamic parameters in rabbits subjected to endotoxic shock. CONCLUSION Changes in vascular reactivity during endotoxic shock are organ-specific. Differential expression patterns of iNOS and ET-1 in different blood vessels contribute to the organ specificity of vascular reactivity. Level of Evidence therapeutic study, level II CORRESPONDING AUTHORS: Liangming Liu and Tao Li, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Daping, Chongqing 400042, People’s Republic of China, Tel: +86-23-68757421(o), Fax: +86-23-68757421, E-mail: liangmingliu@yahoo.com, lt200132@163.com Equal contribution to this work. Tao Li, PhD and Liang-ming Liu, MD, PhD. Address for reprints: Liangming Liu, MD, PhD, Tao Li, PhD, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, P.R.China; E-mail: liangmingliu@yahoo.com, lt200132@163.com Interest: No conflict of interest exists in the submission of this manuscript. Disclosure: This study was supported by the Innovative Research group of National Natural Science Foundation(81721001), Innovative Team of the Ministry of Education(IRT1216), State Key Laboratory Project (SKLZZ 201207), and Military Medical plan (AWS16J032). These funding agencies had no role in study design, collection/analyses of data, decision to publish, or manuscript preparation. This study was approved by the Research Council and Animal Care and Use Committee of Research Institute of surgery, Third Military Medical University. Our methods conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication, 8th edition, 2011). © 2018 Lippincott Williams & Wilkins, Inc.

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