Polymerized hemoglobin restores cardiovascular and kidney function in endotoxin-induced shock in the rat.

Heneka, Michael T.; Löschmann, P.-A.; Oßwald, Hartmut

doi:10.1172/jci119132

Cited by 48 publications

(23 citation statements)

References 37 publications

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“…NO scavengers have the theoretical advantage of neutralizing only the portion of presynthesized NO to which the agent is exposed, without directly interfering with NOS function (18,62). Several NO scavengers have been identified, but not all are taken up by cells, and some, particularly free hemoglobin, exhibit unacceptable toxicity (63).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

Broderick¹,

Veena²,

Zhuang

et al. 2005

Journal of Biological Chemistry

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Nitric oxide (NO) is an important signaling molecule, and a number of NO synthesis inhibitors and scavengers have been developed to allow study of NO functions and to reduce excess NO levels in disease states. We showed previously that cobinamide, a cobalamin (vitamin B 12 ) precursor, binds NO with high affinity, and we now evaluated the potential of cobinamide as a NO scavenger in biologic systems. We found that cobinamide reversed NO-stimulated fluid secretion in Drosophila Malpighian tubules, both when applied in the form of a NO donor and when produced intracellularly by nitricoxide synthase. Moreover, feeding flies cobinamide markedly attenuated subsequent NO-induced increases in tubular fluid secretion. Cobinamide was taken up efficiently by cultured rodent cells and prevented NOinduced phosphorylation of the vasodilator-stimulated phosphoprotein VASP both when NO was provided to the cells and when NO was generated intracellularly. Cobinamide appeared to act via scavenging NO because it reduced nitrite and nitrate concentrations in both the fly and mammalian cell systems, and it did not interfere with cGMP-induced phosphorylation of VASP. In rodent and human cells, cobinamide exhibited toxicity at concentrations >50 M with toxicity completely prevented by providing equimolar amounts of cobalamin. Combining cobalamin with cobinamide had no effect on the ability of cobinamide to scavenge NO. Cobinamide did not inhibit the in vitro activity of either of the two mammalian cobalamin-dependent enzymes, methionine synthase or methylmalonyl-coenzyme A mutase; however, it did inhibit the in vivo activities of the enzymes in the absence, but not presence, of cobalamin, suggesting that cobinamide toxicity was secondary to interference with cobalamin metabolism. As part of these studies, we developed a facile method for producing and purifying cobinamide. We conclude that cobinamide is an effective intra-and extracellular NO scavenger whose modest toxicity can be eliminated by cobalamin.

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Section: Discussionmentioning

confidence: 99%

Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

Broderick¹,

Veena²,

Zhuang

et al. 2005

Journal of Biological Chemistry

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“…The use of Hb-containing agents such as HBOC-201 are thought to cause vasoconstriction by scavenging of NO in the vascular lumen (10). This reduction in local NO concentration leads to vascular constriction (9,13).…”

Section: Discussionmentioning

confidence: 99%

A novel hemoglobin-based blood substitute protects against myocardial reperfusion injury

Caswell¹,

Strange²,

Rimmer³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. A novel hemoglobin-based blood substitute protects against myocardial reperfusion injury. Am J Physiol Heart Circ Physiol 288: H1794 -H1801, 2005 doi:10.1152/ajpheart.00905.2004 Cambridge, MA) is a glutaraldehyde-polymerized bovine hemoglobin (Hb) solution that is stroma free, has lower viscosity than blood, and promotes O 2 unloading. We investigated the effects of HBOC-201 in a canine model of myocardial ischemia-reperfusion injury. Dogs were anesthetized and subjected to 90 min of regional myocardial ischemia and 270 min of reperfusion. HBOC-201 or 0.9% saline vehicle equivalent to 10% total blood volume was infused 30 min before myocardial ischemia. Hemodynamic data and peripheral blood samples were taken at baseline, 1 h of myocardial ischemia, and 1, 2, and 4 h of reperfusion. At 270 min of reperfusion, the area at risk (AAR) per left ventricle and the area of infarction (Inf) per AAR were determined. The myocardial AARs in the two study groups were similar. In addition, myocardial blood flow (as measured by radioactive microspheres) in the ischemic zone was similar between the vehicle and HBOC-201 groups. HBOC-201-infused dogs demonstrated a significant (P Ͻ 0.01) 56% reduction in Inf/AAR. Analysis of blood samples taken at 4 h of reperfusion showed a significant (P Ͻ 0.05) reduction in creatine kinase MB isoform for the HBOC-201 group. Histological analysis of the myocardium demonstrated significant (P Ͻ 0.01) reductions in neutrophil infiltration in the HBOC-201 group. These data indicate that treatment with HBOC-201 before myocardial ischemia-reperfusion reduces the extent of myocardial inflammation and ischemia-reperfusion injury in the canine myocardium.

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“…Because it is known that HBOC-201 produces an increase in MAP (18) in addition to providing greater O 2 delivery, Phe was included to investigate the confounding vasopressor actions of HBOC-201 as a possible mechanism of recovery. Likewise, HBOC-201 has been shown to reduce NO activity in vitro after septic shock (15). L-NAME, a NO synthase inhibitor, also served as another control group to examine the possible hemodynamic effects of HBOC-201 via NO inhibitory pathways (7,15).…”

Section: Experimental Designmentioning

confidence: 99%

“…Likewise, HBOC-201 has been shown to reduce NO activity in vitro after septic shock (15). L-NAME, a NO synthase inhibitor, also served as another control group to examine the possible hemodynamic effects of HBOC-201 via NO inhibitory pathways (7,15). The number of animals studied in each group is detailed below.…”

Section: Experimental Designmentioning

confidence: 99%

“…Manufactured from bovine whole blood filtration and ion-exchange high-pressure liquid chromatography and devoid of plasma, red blood cell (RBC) stroma, and endotoxins, HBOC-201 is prepared in a balanced electrolyte solution and lacks an immunological response when given to animals and humans (14,23). Hemodynamically, increases in mean arterial pressure (MAP) and systemic vascular resistance are seen after HBOC-201 administration (18), likely through nitric oxide (NO) inhibition (12,15). Oxygen delivery to tissue has been shown to be faster and three times more efficient than human Hb (20,26).…”

mentioning

confidence: 99%

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A polymerized bovine hemoglobin oxygen carrier preserves regional myocardial function and reduces infarct size after acute myocardial ischemia

George¹,

Yi²,

Schulman³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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. A polymerized bovine hemoglobin oxygen carrier preserves regional myocardial function and reduces infarct size after acute myocardial ischemia. Am J Physiol Heart Circ Physiol 291: H1126 -H1137, 2006. First published April 14, 2006 doi:10.1152/ajpheart.00076.2006.-The purpose of this study was to test if HBOC-201, a hemoglobin-based oxygen-carrying solution, can decrease infarct size (or Inf) during acute, severe myocardial ischemia and reperfusion. To test the impact of HBOC-201 on infarct size, ischemia was produced in 18 dogs by coronary stenosis to achieve 80 -95% flow reduction for 195 min along with pacing 10% above the spontaneous heart rate, followed by 180 min of reperfusion. Animals were randomized to intravenous infusion of HBOC-201 (1 g/kg) (n ϭ 6), normal saline (NS) (n ϭ 6), or phenylephrine (Phe) (n ϭ 6, as a control for the increased blood pressure seen with HBOC-201), given 15 min after the start of ischemia. Amount of infarct was quantified as the ratio between area at risk (AAR) and Inf after Evans blue and 2,3,5-triphenyltetrazolium chloride staining. Hearts were divided into five layers from base (layer A) to apex (layer E) and photographed for digital image analysis of AAR and Inf. Regional myocardial function (RMF) was also measured after 60 min of ischemia and 15 min of reperfusion. Inf/AAR was significantly reduced after HBOC-201 therapy (4.4 Ϯ 2.2%) vs. NS (26.0 Ϯ 3.6%) and Phe (25.7 Ϯ 4.1%) (both, P Ͻ 0.05). RMF after reperfusion was restored to 92% of baseline with HBOC-201 compared with 11% of baseline after NS (P Ͻ 0.05) and 49% after Phe (P ϭ not significant). HBOC-201 administration after induction of severe myocardial ischemia by acute coronary stenosis reduces infarct size and improves myocardial viability.coronary; blood; nitric oxide inhibitor OVER 600,000 people die each year in the United States from complications of ischemic heart disease, including acute myocardial infarction (AMI), congestive heart failure (CHF), and fatal arrhythmias (22), and its treatment continues to challenge the medical community. With an estimated 1.1 million new cases of AMI each year, the burden on the health care system and society is enormous (2). The need for improved myocardial protection after acute ischemia is paramount. Despite a vast array of therapies that reportedly attenuate ischemiareperfusion injury, clinical application of these therapies has been meager and disappointing (22). The trend for earlier percutaneous revascularization (PCI) has helped to improve outcomes (11). However, the problems of contractile dysfunction during acute ischemia, expansion of infarct size (or Inf), and reperfusion injury have largely remained unaddressed and are more complex than simply restoring flow. In addition, the logistical requirements for early PCI, such as trained interventional cardiologists, specialized equipment, and transport time to treatment, limit its use as an immediate treatment for patients with AMI. Thus a noninvasive cardioprotective strategy that can be applied in a prehospital ...

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Polymerized hemoglobin restores cardiovascular and kidney function in endotoxin-induced shock in the rat.

Abstract: Sepsis and its complications, hypotension, shock, and multiorgan failure continue to represent a significant cause of mortality among hospitalized patients, affecting approximately 200,000 patients per year in the US and 100,000 in Europe (

Cited by 48 publications

References 37 publications

Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

Nitric Oxide Scavenging by the Cobalamin Precursor Cobinamide

A novel hemoglobin-based blood substitute protects against myocardial reperfusion injury

A polymerized bovine hemoglobin oxygen carrier preserves regional myocardial function and reduces infarct size after acute myocardial ischemia

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