TY - JOUR
T1 - Hemorrhagic shock and nitric oxide release from erythrocytic nitric oxide synthase
T2 - A quantitative analysis
AU - Chen, Kejing
AU - Pittman, Roland N.
AU - Popel, Aleksander S.
N1 - Funding Information:
This research was supported by NIH grants R01 HL079087 and R01 HL018292. We thank Dr. Nikolaos Tsoukias for the contribution to the design of Fig. 1 .
PY - 2009/6
Y1 - 2009/6
N2 - 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 O2 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 ∼ 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.
AB - 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 O2 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 ∼ 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.
KW - Computational model
KW - Endothelial nitric oxide synthase
KW - Erythrocyte
KW - Hemorrhage
KW - Nitric oxide
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U2 - 10.1016/j.mvr.2009.02.009
DO - 10.1016/j.mvr.2009.02.009
M3 - Article
C2 - 19285090
AN - SCOPUS:67349147930
SN - 0026-2862
VL - 78
SP - 107
EP - 118
JO - Microvascular Research
JF - Microvascular Research
IS - 1
ER -