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Article
July 1996

Effects of Nitric Oxide Donor SIN-1 on Oxygen Availability and Regional Blood Flow During Endotoxic Shock

Author Affiliations

From the Department of Intensive Care, Erasme University Hospital, Free University of Brussels, Belgium (Drs Zhang, Rogiers, Friedman, Preiser, Spapen, and Vincent); and Department of Surgery (Immunology Laboratory), Rijksuniversiteit Limburg (Dr Buurman), the Netherlands.

Arch Surg. 1996;131(7):767-774. doi:10.1001/archsurg.1996.01430190089022
Abstract

Background:  An excessive release of nitric oxide (NO) has been incriminated in the circulatory disturbances of septic shock.

Objective:  To study the effects of an NO donor, 3-morpholinosydnonimine (SIN-1), on oxygen availability and regional blood flow during endotoxic shock to see if a beneficial effect of NO synthase inhibitors in septic shock could be conclusively demonstrated.

Materials and Methods:  In 14 anesthetized and mechanically ventilated dogs, global invasive hemodynamic monitoring was completed and ultrasonic flow probes were placed around the superior mesenteric, left renal, and left femoral arteries for simultaneous measurements of regional blood flow. All dogs received Escherichia coli endotoxin, 2 mg/kg. A control group (n=7) was administered saline at 20 mL/kg per hour, and a SIN-1 group (n=7) was given a combination of saline with SIN-1 at successive doses of 1, 2, and 4 μg/kg per minute.

Results:  Neither systemic nor pulmonary arterial pressures were influenced by SIN-1. Cardiac index, stroke index, and left ventricular stroke work index did increase at low to moderate doses of SIN-1 but tended to decrease at the highest dose. Systemic and pulmonary vascular resistances decreased. Fractional blood flow increased in the mesenteric bed at all doses used, was not influenced in the renal bed, but decreased in the femoral bed at the highest dose. Oxygen-derived variables were similar in the 2 groups. Blood lactate and plasma concentrations of tumor necrosis factor were not significantly influenced. At the end of the SIN-1 infusion, the administration of 5 mg/kg of methylene blue increased arterial pressure, pulmonary arterial pressure, and systemic and pulmonary vascular resistances but decreased cardiac index and regional blood flow.

Conclusions:  The administration of low to moderate doses of the NO donor SIN-1 can significantly increase cardiac index and superior mesenteric blood flow without deleterious effects on arterial pressure in this model of endotoxic shock. These findings support the hypothesis that NO is essential to maintain organ blood flow even during endotoxic shock.Arch Surg. 1996;131:767-774

References
1.
Moncada S, Palmer RMJ, Higgs EA.  Nitric oxide: physiology, pathophysiology, and pharmacology . Pharmacol Rev . 1991;43:109-142.
2.
Laszlo F, Whittle BJ, Moncada S.  Time-dependent enhancement or inhibition of endotoxin-induced vascular injury in rat intestine by nitric oxide synthesis inhibitors . Br J Pharmacol . 1994;111:1309-1315.Article
3.
Szabo C, Mitchell JA, Thiemermann C, Vane JR.  Nitric oxide-mediated hyporeactivity to noradrenaline precedes the induction of nitric oxide synthase in endotoxin shock . Br J Pharmacol . 1993;108:786-792.Article
4.
De Kimpe SJ, Hunter ML, Bryant CE, Thiemermann C, Vane JR.  Delayed circulatory failure due to the induction of nitric oxide synthase by lipoteichoic acid from Staphylococcus aureus in anaesthetized rats . Br J Pharmacol . 1995; 114:1317-1323.Article
5.
Cobb JP, Natanson C, Hoffman WD, et al.  Nω-amono-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin . J Exp Med . 1992;176:1175-1182.Article
6.
Wright CE, Rees DD, Moncada S.  Protective and pathological roles of nitric oxide in endotoxin shock . Cardiovasc Res . 1992;26:48-57.Article
7.
Minnard EA, Shou J, Naama H, Cech A, Gallagher H, Daly JM.  Inhibition of nitric oxide synthase is detrimental during endotoxemia . Arch Surg . 1994;129: 142-148.Article
8.
Pastor CM, Billiar TR.  Nitric oxide causes hyporeactivity to phenylephrine in isolated perfused livers from endotoxin-treated rats . Am J Physiol . 1995:268: G177-G182.
9.
Zhang H, Spapen H, Nguyen DN, Benlabed M, Buurman WA, Vincent JL.  Protective effects of N-acetyl-L-cysteine in endotoxemia . Am J Physiol . 1994;266: H1746-H1754.
10.
Greenberg S, Xie J, Wang Y, et al.  Tumor necrosis factor-alpha inhibits endothelium-dependent relaxation . J Appl Physiol . 1993;74:2394-2403.
11.
Moilanen E, Vuorinen P, Kankaanranta H, Metsa-Ketela T, Vapaatalo H.  Inhibition by nitric oxide-donors of human polymorphonuclear leucocyte functions . Br J Pharmacol . 1993;109:852-858.Article
12.
Bordet JC, Lagard M.  Modulation of prostacyclin/thromboxane formation by molsidomine during platelet-endothelial cell interactions . Biochem Pharmacol . 1988;37:3911-3914.Article
13.
Zhang H, Rogiers P, Preiser J-C, et al.  Effects of methylene blue on oxygen availability and regional blood flow during endotoxic shock . Crit Care Med . 1995;23:1711-1721.Article
14.
Keaney Jr JF, Puyana J-C, Francis S, Loscalzo JF, Stamler JS, Loscalzo J.  Methylene blue reverses endotoxin-induced hypotension . Circ Res . 1994;74: 1121-1125.Article
15.
Preiser J-C, Lejeune P, Roman A, et al.  Methylene blue administration in septic shock: a clinical trial . Crit Care Med . 1995;23:259-264.Article
16.
Horn GJ, Grant SK, Wolfe G, Bach TJ, Macintyre DE, Hutchinson NI.  Lipopolysaccharide-induced hypotension and vascular hyporeactivity in the rat: tissue analysis of nitric oxide synthase mRNA and protein expression in the presence and absence of dexamethasone, NG-monomethyl-L-arginine or indomethacin . J Pharmacol Exper Ther . 1995;272:452-259.
17.
Evans T, Carpenter A, Kinderman H, Cohen J.  Evidence of increased nitric oxide production in patients with the sepsis syndrome . Circ Shock . 1993;41:77-81.
18.
Petros A, Lamb G, Leone A, Moncada S, Bennet D, Vallance P.  Effects of a nitric oxide synthase inhibitor in humans with septic shock . Cardiovasc Res . 1994;28:34-39.Article
19.
Wang P, Zheng F, Chaudry IH.  Nitric oxide: to block or enhance its production during sepsis? Arch Surg . 1994;129:1137-1143.Article
20.
Kurose I, Wolf R, Grisham MB.  Modulation of ischemia/reperfusion-induced microvascular dysfunction by nitric oxide . Circ Res . 1994;74:376-382.Article
21.
Mulder MF, Van Lambalgen AA, Huisman E, Visser JJ, Van Den Bos GC, Thijs LG.  Protective role of NO in the regional hemodynamic changes during acute endotoxemia in rats . Am J Physiol . 1994;266:H1558-H1564.
22.
Hussain SNA, Roussos C.  Distribution of respiratory muscle and organ blood flow during endotoxic shock in dogs . J Appl Physiol . 1985;59:1802-1808.
23.
Van Lambalgen AA, Bronsveld W, Van Den Bos GC, Thijs LG, Kester ADM.  Skeletal muscle perfusion and metabolism during canine endotoxin shock . Cardiovasc Res . 1985;19:278-287.Article
24.
Zhang H, Spapen H, Manikis P, et al.  Tirilazad mesylate (U-74006F) inhibits effects of endotoxin in dogs . Am J Physiol . 1995;268:H1847-H1855.
25.
Schulz R, Nava E, Moncada S.  Induction and potential biological relevance of a Ca2+-independent nitric oxide synthase in the myocardium . Br J Pharmacol 1992;105:575-580.Article
26.
Siegfried MR, Erhardt J, Rider T, Ma X-L, Lefer AM.  Cardioprotection and attenuation of endothelial dysfunction by organic nitric oxide donors in myocardial ischemia-reperfusion . J Pharmacol Exp Ther . 1992;260:668-675.
27.
Schlüter KD, Weber M, Schraven E, Piper HM.  NO donor SIN-1 protects against reoxygenation-induced cardiomyocyte injury by a dual action . Am J Physiol . 1994;267:H1461-H1466.
28.
Lander HM, Sehajpal PK, Novogrodsky A.  Nitric oxide signaling: a possible role for G proteins . J Immunology . 1993;151:7182-7187.
29.
Robertson FM, Offner PJ, Ciceri DP, Becker WK, Pruitt Jr BA.  Detrimental hemodynamic effects of nitric oxide synthase inhibition in septic shock . Arch Surg . 1994;129:149-156.Article
30.
Zapol WM, Jones R.  Vascular components of ARDS: clinical pulmonary hemodynamics and morphology . Am Rev Respir Dis . 1987;136:471-464.Article
31.
Boughton-Smith NK, Hucheson IR, Deakin AM.  Protective effect of S-nitroso-N-acetyl-penicillamine in endotoxin-induced acute intestinal damage in the rat . Eur J Pharmacol . 1994;191:485-488.Article
32.
Nishida J, McCuskey RS, McDonnell D, Fox ES.  Protective role of NO in hepatic microcirculatory dysfunction during endotoxemia . Am J Physiol . 1994; 267:G1135-G1141.
33.
Gauthier TW, Davenpeck KL, Lefer AM.  Nitric oxide attenuates leukocyte-endothelial interaction via P-selectin in splanchnic ischemia-reperfusion . Am J Physiol . 1994;267:G562-G568.
34.
Arndt H, Russell JB, Kurose I.  Mediators of leukocyte adhesion in rat mesenteric venules elicited by inhibition of nitric oxide synthesis . Gastroenterology . 1993;105:675-680.
35.
Kanwar S, Wallace JL, Befus D.  Nitric oxide synthesis inhibition increases epithelial permeability via mast cells . Am J Physiol . 1994;266:G222-G229.
36.
Payne D, Kubes P.  Nitric oxide donors reduce the rise in reperfusion-induced intestinal mucosal permeability . Am J Physiol . 1993;265:G189-G195.
37.
Harbrecht BG, Billar TR, Stasler J, et al.  Nitric oxide synthesis serves to reduce hepatic damage during acute murine endotoxemia . Crit Care Med . 1992; 20:1568-1574.Article
38.
Spain DA, Wilson MA, Bar-Natan MF, Garrison RN.  Nitric oxide synthase inhibition aggravates intestinal microvascular vasoconstriction and hypoperfusion of bacteremia . J Trauma . 1994;36:720-725.Article
39.
Caplan MS, Hedlund E, Hill N.  The role of endogenous nitric oxide and platelet-activating factor in hypoxia-induced intestinal injury in rats . Gastroenterology . 1994;106:346-352.
40.
Parker JL, Adams HR.  Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia . Circ Res . 1993;72:539-551.Article
41.
Mariotto S, Cuzzolin L, Adami A, Del Soldato P, Suzuki H, Benoni G.  Inhibition by sodium nitroprusside of the expression of inducible nitric oxide synthase in rat neutrophils . Br J Pharmacol . 1995;114;1105-1106.Article
42.
Hogg N, Darley-Usmar VM, Wilson MT.  Production of hydroxyl radicals from the simultaneous generation of superoxide and nitric oxide . Biochem J . 1992; 281:419-424.
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