Hemorrhagic shock and nitric oxide release from erythrocytic nitric oxide synthase: A quantitative analysis

Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, 613 Traylor Building, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Microvascular Research (Impact Factor: 2.13). 04/2009; 78(1):107-18. DOI: 10.1016/j.mvr.2009.02.009
Source: PubMed


A large loss of blood during hemorrhage can result in profound shock, a state of hypotension associated with hemodynamic abnormalities. One of the hypotheses to account for this collapse of homeostasis is that the production of nitric oxide (NO), a gas molecule that dilates blood vessels, is significantly impaired during hemorrhage, resulting in a mismatch between O(2) delivery and the metabolic activity in the tissues. NO can be released from multiple sources in the vasculature. Recent studies have shown that erythrocytes express functional endothelial nitric oxide synthase (NOS3), which potentially serves as an intraluminal NO source. NO delivery from this source is complex: erythrocytes are not only NO producers but also act as potent sinks because of the high affinity of NO for hemoglobin. To test our hypothesis that the loss of erythrocytic NOS3 during hemorrhage contributes to NO deficiency-related shock, we have constructed a multicellular computational model that simulates NO production and transport to allow us to quantify the loss of NO under different hemorrhagic conditions. Our model shows that: (1) during mild hemorrhage and subsequent hemodilution (hematocrit >30%), NO from this intraluminal source is only slightly decreased in the vascular smooth muscle, but the NO level is significantly reduced under severe hemorrhagic conditions (hematocrit <30%); (2) whether a significant amount of NO from this source can be delivered to vascular smooth muscle is strongly dependent on the existence of a protective mechanism for NO delivery; (3) if the expression level of NOS3 on erythrocytes is similar to that on endothelial cells, we estimate approximately 13 pM NO at the vascular smooth muscle from this source when such a protective mechanism is involved. This study provides a basis for detailed studies to characterize the impairment of NO release pathways during hemorrhage and yield important insights for the development of resuscitation methods.

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    • "It has been argued that RBC have a dual role in tissue oxygenation: in addition to their wellknown oxygen carrier function, RBC may contribute to the regulation of local blood flow with NO playing a central role in this process [35]. NO synthesized by RBC NOS activity has been hypothesized to contribute to the RBC-originated NO pool, although Chen, et al. reported that the amount of NO generated by RBC NOS may not represent a physiologically important fraction of total NO bioavailability at vascular wall [36]. Experimental studies directly exploring the contribution of the enzymatic generation of NO by RBC to local vasomotor control do not yet exist. "
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    • "Computer simulations indicate that, as has been shown for other intraerythrocytic pathways, whether a significant amount of NO from this source can be delivered to vascular smooth muscle is strongly dependent on the existence of a protected mechanism for NO delivery. If the expression level of NOS3 in erythrocytes is similar to that in endothelial cells, a combined NOS biochemical pathway analysis model [16] [17] and NO transport model [13] would predict a level of ∼13 pM NO in the vascular smooth muscle from this source, given the existence of such a protected NO transport mechanism [15] "
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