Shock/Sepsis/Trauma/Critical Care| Volume 171, ISSUE 1, e97-e106, November 2011

Download started.


Magnesium Sulfate Mitigates Lung Injury Induced by Bilateral Lower Limb Ischemia-Reperfusion in Rats

Published:April 13, 2011DOI:


      Lower limb ischemia-reperfusion (I/R) elicits oxidative stress and causes inflammation in lung tissues that may lead to lung injury. Magnesium sulfate (MgSO4) possesses potent anti-oxidation and anti-inflammation capacity. We sought to elucidate whether MgSO4 could mitigate I/R-induced lung injury. As MgSO4 is an L-type calcium channel inhibitor, the role of the L-type calcium channels was elucidated.

      Materials and Methods

      Adult male rats were allocated to receive I/R, I/R plus MgSO4 (10, 50, or 100 mg/kg), or I/R plus MgSO4 (100 mg/kg) plus the L-type calcium channels activator BAY-K8644 (20 μg/kg) (n = 12 in each group). Control groups were run simultaneously. I/R was induced by applying rubber band tourniquets high around each thigh for 3 h followed by reperfusion for 3 h. After euthanization, degrees of lung injury, oxidative stress, and inflammation were determined.


      Arterial blood gas and histologic assays, including histopathology, leukocyte infiltration (polymorphonuclear leukocytes/alveoli ratio and myeloperoxidase activity), and lung water content, confirmed that I/R caused significant lung injury. Significant increases in inflammatory molecules (chemokine, cytokine, and prostaglandin E2 concentrations) and lipid peroxidation (malondialdehyde concentration) confirmed that I/R caused significant inflammation and oxidative stress in rat lungs. MgSO4, at the dosages of 50 and 100 mg/kg but not 10 mg/kg, attenuated the oxidative stress, inflammation, and lung injury induced by I/R. Moreover, BAY-K8644 reversed the protective effects of MgSO4.


      MgSO4 mitigates lung injury induced by bilateral lower limb I/R in rats. The mechanisms may involve inhibiting the L-type calcium channels.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Surgical Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Yeager R.A.
        • Moneta G.L.
        • Taylor Jr., L.M.
        • et al.
        Surgical management of severe acute lower extremity ischemia.
        J Vasc Surg. 1992; 15: 385
        • Hossny A.
        Blunt popliteal artery injury with complete lower limb ischemia: Is routine use of temporary intraluminal arterial shunt justified?.
        J Vasc Surg. 2004; 40: 61
        • Campbell W.B.
        • Collin J.
        • Morris P.J.
        The mortality of abdominal aortic aneurysm.
        Ann R Coll Surg Engl. 1986; 68: 275
        • Yassin M.M.
        • Harkin D.W.
        • Barros D’Sa A.A.
        • et al.
        Lower limb ischemia-reperfusion injury triggers a systemic inflammatory response and multiple organ dysfunction.
        World J Surg. 2002; 26: 115
        • Bar J.
        • Ben Haroush A.
        • Feldberg D.
        • et al.
        The pharmacologic approach to the prevention of preeclampsia: From antiplatelet, antithrombosis and antioxidant therapy to anticonvulsants.
        Curr Med Chem Cardiovasc Hematol Agents. 2005; 3: 181
        • Lin C.Y.
        • Tsai P.S.
        • Hung Y.C.
        • et al.
        L-type calcium channels are involved in mediating the anti-inflammatory effects of magnesium sulphate.
        Br J Anaesth. 2010; 104: 44
        • Rochelson B.
        • Dowling O.
        • Schwartz N.
        • et al.
        Magnesium sulfate suppresses inflammatory responses by human umbilical vein endothelial cells (HuVECs) through the NFkappaB pathway.
        J Reprod Immunol. 2007; 73: 101
        • Ariza A.C.
        • Bobadilla N.
        • Fernandez C.
        • et al.
        Effects of magnesium sulfate on lipid peroxidation and blood pressure regulators in preeclampsia.
        Clin Biochem. 2005; 38: 128
        • Maulik D.
        • Qayyum I.
        • Powell S.R.
        • et al.
        Post-hypoxic magnesium decreases nuclear oxidative damage in the fetal guinea pig brain.
        Brain Res. 2001; 890: 130
        • Peker S.
        • Abacioglu U.
        • Sun I.
        • et al.
        Prophylactic effects of magnesium and vitamin E in rat spinal cord radiation damage: Evaluation based on lipid peroxidation levels.
        Life Sci. 2004; 75: 1523
        • Sonna L.A.
        • Hirshman C.A.
        • Croxton T.L.
        Role of calcium channel blockade in relaxation of tracheal smooth muscle by extracellular Mg2+.
        Am J Physiol. 1996; 271: L251
        • Pryde P.G.
        • Mittendorf R.
        Contemporary usage of obstetric magnesium sulfate: Indication, contraindication, and relevance of dose.
        Obstet Gynecol. 2009; 114: 669
        • Yang C.H.
        • Tsai P.S.
        • Wang T.Y.
        • et al.
        Dexmedetomidine-ketamine combination mitigates acute lung injury in haemorrhagic shock rats.
        Resuscitation. 2009; l80: 1204
        • Yan Z.
        • Stapleton P.P.
        • Freeman T.A.
        • et al.
        Enhanced expression of cyclooxygenase-2 and prostaglandin E2 in response to endotoxin after trauma is dependent on MAPK and NF-kappaB mechanisms.
        Cell Immunol. 2004; 232: 116
        • Huang Y.H.
        • Tsai P.S.
        • Kai Y.F.
        • et al.
        Lidocaine inhibition of inducible nitric oxide synthase and cationic amino Acid transporter-2 transcription in activated murine macrophages may involve voltage-sensitive Na+ channel.
        Anesth Analg. 2006; 102: 1739
        • Futaki N.
        • Takahashi S.
        • Kitagawa T.
        • et al.
        Selective inhibition of cyclooxygenase-2 by NS-398 in endotoxin shock rats in vivo.
        Inflamm Res. 1997; l46: 496
        • Chang K.Y.
        • Tsai P.S.
        • Huang T.Y.
        • et al.
        HO-1 mediates the effects of HBO pretreatment against sepsis.
        J Surg Res. 2006; 136: 143
        • Wang l.F.
        • Patel M.
        • Razavi H.M.
        • et al.
        Role of inducible nitric oxide synthase in pulmonary microvascular protein leak in murine sepsis.
        Am J Respir Crit Care Med. 2002; 165: 1634
        • Becker L.B.
        New concepts in reactive oxygen species and cardiovascular reperfusion physiology.
        Cardiovasc Res. 2004; 61: 461
        • Kaminski K.A.
        • Bonda T.A.
        • Korecki J.
        • et al.
        Oxidative stress and neutrophil activation–the two keystones of ischemia/reperfusion injury.
        Int J Cardiol. 2002; 86: 41
        • Blackwell T.S.
        • Christman J.W.
        The role of nuclear factor-kappa B in cytokine gene regulation.
        Am J Respir Cell Mol Biol. 1997; 17: 3
        • Asehnoune K.
        • Strassheim D.
        • Mitra S.
        • et al.
        Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B.
        J Immunol. 2004; 172: 2522
        • Powers K.A.
        • Szaszi K.
        • Khadaroo R.G.
        • et al.
        Oxidative stress generated by hemorrhagic shock recruits Toll-like receptor 4 to the plasma membrane in macrophages.
        J Exp Med. 2006; 203: 1951
        • Wang H.
        • Li Z.Y.
        • Wu H.S.
        • et al.
        Endogenous danger signals trigger hepatic ischemia/reperfusion injury through toll-like receptor 4/nuclear factor-kappa B pathway.
        Chin Med.J (Engl). 2007; 120: 509
        • Azenabor A.A.
        • Chaudhry A.U.
        Effective macrophage redox defense against Chlamydia pneumoniae depends on L-type Ca2+ channel activation.
        Med Microbiol Immunol. 2003; 192: 99
        • Werling L.L.
        • Hoehner P.J.
        • Hurt K.J.
        • et al.
        Increased activation of L-type voltage-dependent calcium channels is associated with glycine enhancement of N-methyl-D-aspartate-stimulated dopamine release in global cerebral ischemia/reperfusion.
        J Neurochem. 1994; 63: 215
        • Zhou X.
        • Yang W.
        • Li J.
        Ca2+- and protein kinase C-dependent signaling pathway for nuclear factor-kappaB activation, inducible nitric-oxide synthase expression, and tumor necrosis factor-alpha production in lipopolysaccharide-stimulated rat peritoneal macrophages.
        J Biol Chem. 2006; 281: 31337
        • Di Lisa F.
        • Bernardi P.
        Mitochondrial function as a determinant of recovery or death in cell response to injury.
        Mol Cell Biochem. 1998; 184: 379
        • Chattopadhyay P.
        • Chaudhury P.
        • Wahi A.K.
        Ca2+ concentrations are key determinants of ischemia-reperfusion-induced apoptosis: Significance for the molecular mechanism of Bcl-2 action.
        Appl Biochem Biotechnol. 2010; 160: 968
        • Wickersham N.E.
        • Johnson J.J.
        • Meyrick B.O.
        • et al.
        Lung ischemia-reperfusion injury in awake sheep: Protection with verapamil.
        J Appl Physiol. 1991; 71: 1554
        • Katayama Y.
        • Fukuchi T.
        • McKee A.
        • et al.
        Effect of nicardipine, a Ca2+ channel blocker, on pyruvate dehydrogenase activity and energy metabolites during cerebral ischemia and reperfusion in gerbil brain.
        Brain Res. 1998; 781: 212
        • Rowe B.H.
        • Camargo Jr., C.A.
        The role of magnesium sulfate in the acute and chronic management of asthma.
        Curr Opin Pulm Med. 2008; 14: 70
        • Gloviczki P.
        Surgical repair of thoracoabdominal aneurysms: Patient selection, techniques and results.
        Cardiovasc Surg. 2002; 10: 434
        • Esen F.
        • Erdem T.
        • Aktan D.
        • et al.
        Effect of magnesium sulfate administration on blood-brain barrier in a rat model of intraperitoneal sepsis: A randomized controlled experimental study.
        Crit Care. 2005; 9: R18

      Linked Article

      • A Healthy Dose of Heavy Metal: Magnesium and Acute Lung Injury
        Journal of Surgical ResearchVol. 178Issue 2
        • Preview
          Acute lung injury (ALI) and its more serious manifestation, acute respiratory distress syndrome (ARDS), are all too common occurrences in intensive care units around the world that create a large debt to society both in the short term [1] and the long term [2]. These clinical syndromes claim thousands of lives each year and have been the object of many high profile studies in the past two decades. Unfortunately, despite extensive research efforts, we still have relatively little we can do to treat this condition.
        • Full-Text
        • PDF