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Effects of Early Neuronal and Delayed Inducible Nitric Oxide Synthase Blockade on Cardiovascular, Renal, and Hepatic Function in Ovine Sepsis

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Effects of Early Neuronal and Delayed Inducible Nitric Oxide Synthase Blockade on Cardiovascular, Renal, and Hepatic Function in Ovine Sepsis CRITICAL CARE MEDICINE Anesthesiology 2010; 113:1376–84 Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins Effects of Early Neuronal and Delayed Inducible Nitric Oxide Synthase Blockade on Cardiovascular, Renal, and Hepatic Function in Ovine Sepsis Matthias Lange, M.D.,* Atsumori Hamahata, M.D.,† Daniel L. Traber, Ph.D.,‡ Yoshimitsu Nakano, M.D.,§ Aimalohi Esechie, Ph.D.,§ Collette Jonkam, M.D.,§ Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/113/6/1376/252582/0000542-201012000-00025.pdf by guest on 28 September 2021 Elbert B. Whorton, M.S., Ph.D.,࿣ Sanna von Borzyskowski,# Lillian D. Traber, R.N.,** Perenlei Enkhbaatar, M.D., Ph.D.†† ABSTRACT to 12 h and an inducible nitric oxide synthase inhibitor from Background: Recent evidence suggests that nitric oxide 12 to 24 h postinjury (n ϭ 6). produced via the neuronal nitric oxide synthase is in- Results: The injury induced arterial hypotension, vascular volved mainly in the early response to sepsis, whereas leakage, myocardial depression, and signs of renal and he- nitric oxide derived from the inducible nitric oxide syn- patic dysfunctions. The treatment significantly attenuated, thase is responsible during the later phase. We hypothe- but did not fully prevent, the decreases in mean arterial pres- sized that early neuronal and delayed inducible nitric ox- sure and left ventricular stroke work index. Although the ide synthase blockade attenuates multiple organ elevation of creatinine levels was partially prevented, the de- dysfunctions during sepsis. creases in urine output and creatinine clearance were not Methods: Sheep were randomly allocated to sham-injured, affected. The injury-related increases in bilirubin levels, in- nontreated animals (n ϭ 6); injured (48 breaths of cotton ternational normalized ratio, and lipid peroxidation in liver smoke and instillation of Pseudomonas aeruginosa into the tissue were significantly attenuated. Although plasma nitrite/ lungs), nontreated animals (n ϭ 7); and injured animals nitrate levels were significantly increased versus baseline from treated with a neuronal nitric oxide synthase inhibitor from 1 12–24 h in controls, plasma nitrite/nitrate levels were not increased in treated animals. Conclusions: The combination treatment shows potential * Research Fellow, Department of Anesthesiology, The Univer- sity of Texas Medical Branch and Shriners Hospitals for Children, benefit on sepsis-related arterial hypotension and surro- Galveston, Texas, and Department of Anesthesiology and Intensive gate parameters of organ dysfunctions in sheep. It may be Care, University of Muenster, Muenster, Germany; † Research Fel- crucial to identify the time course of expression and acti- low, Department of Anesthesiology, The University of Texas Med- ical Branch and Shriners Hospitals for Children, and Department of vation of different nitric oxide synthase isoforms in future Plastic and Reconstructive Surgery, Tokyo WomenЈs Medical Uni- investigations. versity, Tokyo, Japan; ‡ Professor, § Research Fellow, Department of Anesthesiology, # Laboratory Assistant, ** Research Nurse, †† As- sociate Professor, The University of Texas Medical Branch and What We Already Know about This Topic Shriners Hospitals for Children; ࿣ Statistical Consultant and Associate Professor, Division of Biostatistics and Epidemiology, The Univer- ❖ Excessive production of nitric oxide by nitric oxide synthase sity of Texas Medical Branch and Shriners Hospitals for Children. (NOS) may play a critical role in the pathogenesis of vasodila- Received from the Department of Anesthesiology, The University tory shock. Nitric oxide production may come primarily from of Texas Medical Branch and Shriners Hospitals for Children, neuronal NOS (nNOS) in the early response to bacterial chal- Galveston, Texas. Submitted for publication April 15, 2010. Ac- lenge and from inducible NOS (iNOS) in the later phase. cepted for publication August 17, 2010. This is a U.S. Government work. No claim is made to original government works. This study What This Article Tells Us That Is New was supported by grant 0565028Y from the American Heart Asso- ❖ ciation, Dallas, Texas; grants SBI 8450, SBI 8954, and SBI 8630 from In an ovine sepsis model, early nNOS blockade and subse- the Shriners of North America, Tampa, Florida; and by grants quent iNOS blockade show potential benefit with regard to GM066312 and GM060688 from the National Institutes of Health, systemic arterial hypotension and surrogate parameters of Bethesda, Maryland. organ dysfunction. Address correspondence to Dr. Lange: Investigational Intensive Care Unit, Department of Anesthesiology, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77550. EVERE sepsis and septic shock are leading causes of [email protected]. Information on purchasing reprints may be found at morbidity and mortality among critically ill patients.1 Of www.anethesiology.org or on the masthead page at the beginning of S this issue. ANESTHESIOLOGY’s articles are made freely accessible to all the many aspects in the pathophysiology of sepsis, develop- readers, for personal use, 6 months from the cover date of the issue. ment of progressive cardiovascular failure caused by excessive 1376 Anesthesiology, V 113 • No 6 • December 2010 Selective NOS Inhibition in Ovine Sepsis vasodilation and vascular hyporesponsiveness to cat- Texas) suspended in 30 ml of 0.9% NaCl solution was in- echolamines represents a major clinical problem.2 The he- stilled into the right middle and lower lobes and left lower modynamic changes during sepsis are further characterized lobe of the lung (10 ml each). The animals assigned to the by a maldistribution of systemic and microvascular blood sham-injured group were subjected to an identical proce- flow, resulting in an impairment of organ blood flow and dure, but 48 breaths of room air instead of smoke were ap- multiple organ dysfunctions.3 plied, and 30 ml of saline instead of bacterial suspension were Excessive production of nitric oxide by nitric oxide syn- instilled. Anesthesia was then discontinued, and the sheep thase (NOS) is believed to play a critical role in the patho- were allowed to awaken. genesis of vasodilatory shock.2 Previous investigations dem- onstrated that excessive nitric oxide may further exert Experimental Protocol cytotoxic effects by reacting with superoxide radicals from The sepsis experiments were performed pairwise to correct Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/113/6/1376/252582/0000542-201012000-00025.pdf by guest on 28 September 2021 activated neutrophils, thereby yielding reactive oxygen spe- for possible variations in the bacterial suspension. After in- cies and possibly contributing to multiple organ damage.4,5 jury, the animals were randomized by flipping a coin. The In this regard, pharmacological inhibition of NOS in differ- following three groups were studied: (1) sham-injured, non- ent sepsis models revealed beneficial effects of this approach treated animals (sham, n ϭ 6), (2) injured, nontreated ani- on various outcome variables.6–8 However, the clinical rele- mals (control, n ϭ 7), 3) injured animals treated with the vance of these findings remains questionable, especially since specific neuronal NOS inhibitor 7-nitroindazole (7-NI; 1 Ϫ Ϫ a phase III trial demonstrated an increase in mortality among mg ⅐ kg 1 ⅐ h 1; Sigma–Aldrich, St. Louis, MO)6 from 1 to patients with septic shock who were treated with a nonselec- 12 h postinjury and with the specific inducible NOS inhib- Ϫ Ϫ tive NOS inhibitor.9 Notably, recent evidence suggests that itor BBS-2 (100 ␮g ⅐ kg 1 ⅐ h 1; Berlex, Richmond, CA)7 nitric oxide production via the neuronal NOS is mainly in- from 12 to 24 h postinjury (treatment, n ϭ 6). The animals volved in the early response to bacterial challenge, whereas of the sham and control groups received only the vehicle. The nitric oxide derived from the inducible NOS is responsible investigators were blinded to the group assignment. The se- during the later phase of the disease process.6–8 Thus, selec- lectivity of BBS-2 for the inducible NOS is 620- and 1,500- tive inhibition of different NOS isoforms at different time fold higher versus neuronal and endothelial NOS, respec- points may be superior to nonselective NOS blockade. In tively.13 The chosen dosage of 7-NI has been established in this regard, a previous study reported potential benefit of this previous studies using the same and a similar animal mo- approach on pulmonary morbidity following acute lung in- del.6,14,15 It has previously been demonstrated that infusion Ϫ Ϫ jury and sepsis.10 of 7-NI in sheep at a dose of 1 mg ⅐ kg 1 ⅐ h 1 effectively In the present study, we tested the hypothesis that early suppresses plasma nitrate/nitrite levels6,14,15 and establishes 15 inhibition of neuronal NOS and subsequent inhibition of plasma concentrations of 7-NI far below the IC50 reported inducible NOS attenuates cardiovascular, hepatic, and renal for endothelial and inducible NOS.16 All sheep were me- dysfunctions in an established ovine model of sepsis. chanically ventilated (Servo Ventilator 900C; Siemens, El- ema, Sweden) with a tidal volume of 12–15 ml/kg and a Materials and Methods positive-end expiratory pressure of 5 cm H2O during the entire study period of 24 h. The fraction of inspired oxygen This study was approved by the Institutional Animal Care was set at 1.0 for the first 3 h postinjury and was then ad- and Use Committee of the
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