Exogenous nitric oxide prevents cardiovascular collapse during hemorrhagic shock


      This study investigated the systemic and microvascular hemodynamic changes related to increased nitric oxide (NO) availability following significant hemorrhage, made available by administration of NO releasing nanoparticles (NO-nps). Hemodynamic responses to hemorrhagic shock were studied in the hamster window chamber. Acute hemorrhage was induced by arterial controlled bleeding of 50% of blood volume, and the resulting hemodynamic parameters were followed over 90 min. Exogenous NO was administered in the form of NO-nps (5 mg/kg suspended in 50 μl saline) 10 min following induced hemorrhage. Control groups received equal dose of NO free nanoparticles (Control-nps) and Vehicle solution. Animals treated with NO-nps partially maintained systemic and microvascular function during hypovolemic shock compared to animals treated with Control-nps or the Vehicle (50 μl saline). The continuous NO released by the NO-nps reverted arteriolar vasoconstriction, partially recovered both functional capillary density and microvascular blood flows. Additionally, NO supplementation post hemorrhage prevented cardiac decompensation, and thereby maintained and stabilized the heart rate. Paradoxically, the peripheral vasodilation induced by the NO-nps did not decrease blood pressure, and combined with NO's effects on vascular resistance, NO-nps promoted intravascular pressure redistribution and blood flow, avoiding tissue ischemia. Therefore, by increasing NO availability with NO-nps during hypovolemic shock, it is possible that cardiac stability and microvascular perfusion can be preserved, ultimately increasing survivability and local tissue viability, and reducing hemorrhagic shock sequelae. The relevance, stability, and efficacy of exogenous NO therapy in the form of NO-nps will potentially facilitate the intended use in battlefield and trauma situations.


      To read this article in full you will need to make a payment
      Subscribe to Resuscitation
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Bellamy R.F.
        The causes of death in conventional land warfare: implications for combat casualty care research.
        Mil Med. 1984; 149: 55-62
        • Pope A.M.
        • Institute of Medicine (U.S.)
        Fluid resuscitation: state of the science for treating combat casualties and civilian injuries.
        National Academy Press, Washington, D.C.1999
        • Bacter C.R.
        • Canizaro P.C.
        • Carrico C.J.
        • Shires G.T.
        Fluid resuscitation of hemorrhagic shock.
        Postgrad Med. 1970; 48: 95-99
        • Burris D.
        • Rhee P.
        • Kaufmann C.
        • et al.
        Controlled resuscitation for uncontrolled hemorrhagic shock.
        J Trauma. 1999; 46: 216-223
        • Dubick M.A.
        • Atkins J.L.
        Small-volume fluid resuscitation for the far-forward combat environment: current concepts.
        J Trauma. 2003; 54: S43-S45
        • Kristiansson M.
        • Soop M.
        • Saraste L.
        • Sundqvist K.G.
        Cytokines in stored red blood cell concentrates: promoters of systemic inflammation and simulators of acute transfusion reactions?.
        Acta Anaesthesiol Scand. 1996; 40: 496-501
        • Ignarro L.J.
        • Byrns R.E.
        • Buga G.M.
        • Wood K.S.
        Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical.
        Circ Res. 1987; 61: 866-879
        • Salazar Vazquez B.Y.
        • Martini J.
        • Chavez Negrete A.
        • Cabrales P.
        • Tsai A.G.
        • Intaglietta M.
        Microvascular benefits of increasing plasma viscosity and maintaining blood viscosity: counterintuitive experimental findings.
        Biorheology. 2009; 46: 167-179
        • Bevers L.M.
        • Braam B.
        • Post J.A.
        • et al.
        Tetrahydrobiopterin, but not l-arginine, decreases NO synthase uncoupling in cells expressing high levels of endothelial NO synthase.
        Hypertension. 2006; 47: 87-94
        • Allen B.W.
        • Demchenko I.T.
        • Piantadosi C.A.
        Two faces of nitric oxide: implications for cellular mechanisms of oxygen toxicity.
        J Appl Physiol. 2009; 106: 662-667
        • Lancaster J.R.
        Simulation of the diffusion and reaction of endogenously produced nitric oxide.
        Proc Natl Acad Sci USA. 1994; 91: 8137-8141
        • Friedman A.J.
        • Han G.
        • Navati M.S.
        • et al.
        Sustained release nitric oxide releasing nanoparticles: characterization of a novel delivery platform based on nitrite containing hydrogel/glass composites.
        Nitric Oxide. 2008; 19: 12-20
        • Cabrales P.
        • Han G.
        • Roche C.
        • Nacharaju P.
        • Friedman A.J.
        • Friedman J.M.
        Sustained release nitric oxide from long-lived circulating nanoparticles.
        Free Radic Biol Med. 2010;
        • Colantuoni A.
        • Bertuglia S.
        • Intaglietta M.
        Quantitation of rhythmic diameter changes in arterial microcirculation.
        Am J Physiol. 1984; 246: H508-H517
        • Altman D.G.
        • Bland J.M.
        Statistics notes: how to randomise.
        BMJ. 1999; 319: 703-704
        • Winterbourn C.C.
        Reaction of superoxide with hemoglobin.
        CRC handbook of methods for oxygen radical research. CRC Press, Boca Raton, FL1985
        • Intaglietta M.
        • Silverman N.R.
        • Tompkins W.R.
        Capillary flow velocity measurements in vivo and in situ by television methods.
        Microvasc Res. 1975; 10: 165-179
        • Lipowsky H.H.
        • Zweifach B.W.
        Application of the “two-slit” photometric technique to the measurement of microvascular volumetric flow rates.
        Microvasc Res. 1978; 15: 93-101
        • Intaglietta M.
        • Tompkins W.R.
        Microvascular measurements by video image shearing and splitting.
        Microvasc Res. 1973; 5: 309-312
        • Schadt J.C.
        • Ludbrook J.
        Hemodynamic and neurohumoral responses to acute hypovolemia in conscious mammals.
        Am J Physiol. 1991; 260: H305-318
        • Rossaint R.
        • Falke K.J.
        • Lopez F.
        • Slama K.
        • Pison U.
        • Zapol W.M.
        Inhaled nitric oxide for the adult respiratory distress syndrome.
        N Engl J Med. 1993; 328: 399-405
        • Moncada S.
        • Erusalimsky J.D.
        Does nitric oxide modulate mitochondrial energy generation and apoptosis?.
        Nat Rev Mol Cell Biol. 2002; 3: 214-220
        • Lopez A.
        • Lorente J.A.
        • Steingrub J.
        • et al.
        Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock.
        Crit Care Med. 2004; 32: 21-30
        • Md S.
        • Moochhala S.M.
        • Siew-Yang K.L.
        The role of inducible nitric oxide synthase inhibitor on the arteriolar hyporesponsiveness in hemorrhagic-shocked rats.
        Life Sci. 2003; 73: 1825-1834
        • Thiemermann C.
        • Szabo C.
        • Mitchell J.A.
        • Vane J.R.
        Vascular hyporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide.
        Proc Natl Acad Sci USA. 1993; 90: 267-271
        • Banta S.
        • Yokoyama T.
        • Berthiaume F.
        • Yarmush M.L.
        Effects of dehydroepiandrosterone administration on rat hepatic metabolism following thermal injury.
        J Surg Res. 2005; 127: 93-105
        • Shimizu T.
        • Tani T.
        • Endo Y.
        • Hanasawa K.
        • Tsuchiya M.
        • Kodama M.
        Elevation of plasma peptidoglycan and peripheral blood neutrophil activation during hemorrhagic shock: plasma peptidoglycan reflects bacterial translocation and may affect neutrophil activation.
        Crit Care Med. 2002; 30: 77-82
        • Menezes J.M.
        • Hierholzer C.
        • Watkins S.C.
        • Billiar T.R.
        • Peitzman A.B.
        • Harbrecht B.G.
        The modulation of hepatic injury and heat shock expression by inhibition of inducible nitric oxide synthase after hemorrhagic shock.
        Shock. 2002; 17: 13-18
        • Fatehi-Hassanabad Z.
        • Fatehi M.
        Characterisation of some pharmacological effects of the venom from Vipera lebetina.
        Toxicon. 2004; 43: 385-391
        • Han X.
        • Kobzik L.
        • Zhao Y.Y.
        • et al.
        Nitric oxide regulation of atrioventricular node excitability.
        Can J Cardiol. 1997; 13: 1191-1201
        • Herring N.
        • Rigg L.
        • Terrar D.A.
        • Paterson D.J.
        NO-cGMP pathway increases the hyperpolarisation-activated current I(f), and heart rate during adrenergic stimulation.
        Cardiovasc Res. 2001; 52: 446-453
        • Massion P.B.
        • Balligand J.L.
        Modulation of cardiac contraction, relaxation and rate by the endothelial nitric oxide synthase (eNOS): lessons from genetically modified mice.
        J Physiol. 2003; 546: 63-75
        • Khadour F.H.
        • O’Brien D.W.
        • Fu Y.
        • Armstrong P.W.
        • Schulz R.
        Endothelial nitric oxide synthase increases in left atria of dogs with pacing-induced heart failure.
        Am J Physiol. 1998; 275: H1971-H1978
        • Mayer B.
        • Pfeiffer S.
        • Schrammel A.
        • Koesling D.
        • Schmidt K.
        • Brunner F.
        A new pathway of nitric oxide/cyclic GMP signaling involving S-nitrosoglutathione.
        J Biol Chem. 1998; 273: 3264-3270
        • De Backer D.
        • Creteur J.
        • Dubois M.J.
        • Sakr Y.
        • Vincent J.L.
        Microvascular alterations in patients with acute severe heart failure and cardiogenic shock.
        Am Heart J. 2004; 147: 91-99
        • Spronk P.E.
        • Ince C.
        • Gardien M.J.
        • Mathura K.R.
        • Oudemans-van Straaten H.M.
        • Zandstra D.F.
        Nitroglycerin in septic shock after intravascular volume resuscitation.
        Lancet. 2002; 360: 1395-1396
        • Cabrales P.
        • Tsai A.G.
        • Intaglietta M.
        Exogenous nitric oxide induces protection during hemorrhagic shock.
        Resuscitation. 2009; 80: 707-712