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Diaspirin cross-linked hemoglobin (DCLHb) is a promising hemoglobin-based, oxygen-carrying resuscitative solution. DCLHb (400 mg/kg, iv) produces significant cardiovascular effects, along with an increase in plasma endothelin-1 (ET-1) level, when administered to conscious or anesthetized rats. Present studies were performed to determine whether the cardiovascular effects of DCLHb are due to an increase in the conversion of proendothelin-1 (1-38) (proET-1) to ET-1 by endothelin-converting enzyme (ECE). The regional circulatory and systemic hemodynamic effects of proET-1 (20 micrograms/kg, iv) and DCLHb (400 mg/kg, iv) were determined by using a radioactive microsphere technique in control rats and rats pretreated with phosphoramidon (ECE inhibitor). Administration of proET-1 produced an immediate increase in mean arterial pressure (MAP)(52%) and total peripheral resistance (TPR) (55%); stroke volume (SV) and cardiac output were not affected in the initial phase but were decreased subsequently. Heart rate (HR) was not affected after administration of proET-1. A significant increase in blood flow to the heart (39%), brain (46%), kidneys (74%), portal system (40%), and gastrointestinal tract (GIT) (42%) was also observed after administration of proET-1. Vascular resistance was found to be significantly increased in the mesentery and pancreas (168%) and in the musculoskeletal system (147%) and decreased in the kidneys (-11%) after administration of proET-1. Phosphoramidon (4 mg/kg, iv) pretreatment attenuated the increase in MAP and TPR induced by proET-1. Phosphoramidon pretreatment significantly attenuated the proET-1-induced increase in blood flow to the heart, brain, kidneys, portal system, and GIT. The increase in vascular resistance induced by proET-1 in the mesentery and pancreas and in the musculoskeletal system was also attenuated by phosphoramidon. DCLHb increased MAP (63%) and TPR (54%) without affecting HR. DCLHb increased blood flow to the heart (95%), GIT (45%), portal system (43%), and skin (79%) and increased vascular resistance in the musculoskeletal system (58%). In phosphoramidon-treated rats, DCLHb increased MAP (99%), HR (25%), cardiac output (37%), and TPR (60%). DCLHb increased blood flow to the heart (104%), brain (66%), kidneys (49%), GIT (59%), portal system (63%), and skin (100%) when administered to phosphoramidon-treated rats. Phosphoramidon did not attenuate any of the DCLHb-induced cardiovascular effects. It is concluded that proET-1 increases blood flow to various organs and that phosphoramidon, an ECE inhibitor, could block the proET-1-induced increases in regional blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of endothelin-converting enzyme in the systemic hemodynamics and regional circulatory effects of proendothelin-1 (1-38) and diaspirin cross-linked hemoglobin in rats. 749 May 15

Diaspirin cross-linked hemoglobin (DCLHb) (Baxter Healthcare Corporation) is a promising resuscitative fluid. The effect of DCLHb (400 mg/kg, i.v.), on regional circulation and systemic hemodynamics was studied in male Sprague-Dawley rats using a radioactive microsphere technique. Systemic hemodynamics, distribution of cardiac output, regional blood flow and vascular resistance were determined before (baseline) and 15, 30 and 60 min after the administration of DCLHb. Infusion of an equal volume of saline did not produce any significant change in systemic hemodynamics or regional circulation. DCLHb produced an increase (79%) in the mean blood pressure which lasted for more than 60 min. Heart rate, cardiac output and stroke volume were not significantly affected, while total peripheral resistance was increased after the administration of DCLHb. DCLHb produced significant increases in blood flow to the heart, gastrointestinal tract (GIT), portal system and skin. The blood flow to the kidney, brain and musculoskeletal system was not significantly affected by DCLHb. The vascular resistance was not altered in the heart, brain, GIT, portal system, kidney or skin, but there was a marked increase in the vascular resistance in the musculoskeletal system. There was a significant increase in the percentage of cardiac output to visceral organs like heart, GIT and portal system, while a marked decrease in the percent cardiac output to musculoskeletal system was observed with DCLHb. It is concluded that the blood flow to most of the organs is either increased or is not affected by DCLHb.
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PMID:Regional circulatory and systemic hemodynamic effects of diaspirin cross-linked hemoglobin in the rat. 799 79

Diaspirin crosslinked hemoglobin (DCLHb) (400 mg/kg, i.v.) produces an increase in blood pressure and blood flow to the heart, spleen, stomach, small intestine, skin, mesentery and pancreas when administered to rats. The present study was conducted to determine (1) whether prazosin, an alpha 1-adrenergic antagonist, can block the pressor effect of DCLHb and (2) the effect of prazosin pretreatment on regional circulatory changes induced by DCLHb in rats. DCLHb (400 mg/kg, i.v.) produced an increase in blood pressure (64%), cardiac output (20%) and total peripheral resistance (65%) when administered to control rats. Infusion of DCLHb in prazosin (1 mg/kg, i.v.) treated rats did not show any significant pressor effect, but reversed the hypotensive effect of prazosin. Cardiac output and stroke volume were significantly increased and total peripheral resistance decreased in prazosin treated rats as compared to control (untreated) rats. DCLHb significantly increased blood flow to the heart, gastrointestinal tract, portal system (spleen), and skin of control rats. Blood flow to the brain, kidneys, and musculo-skeletal system was not altered following the infusion of DCLHb in controls rats. Infusion of DCLHb in prazosin treated rats produced a significant increase in blood flow to the brain, heart, kidneys, gastrointestinal tract, portal system, skin and musculoskeletal system. In summary, prazosin pretreatment blocked the pressor effect of DCLHb, however, blood flow to the heart, brain, gastrointestinal tract, portal system, kidneys, skin and musculoskeletal system was increased by DCLHb. It is concluded that blood flow to most of the organs is increased by DCLHb but the pressor effect of DCLHb is blocked by prazosin pretreatment.
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PMID:Prazosin blocks the pressor but not the regional circulatory effects of diaspirin crosslinked hemoglobin. 801 55

Diaspirin cross-linked hemoglobin (DCLHb) (400 mg/kg, i.v.) produced a pressor effect that was equal to that produced by norepinephrine (NE) (25 micrograms/kg/min i.v. infusion). Total peripheral resistance was increased by DCLHb and more significantly by NE. Heart rate was not affected by DCLHb but was significantly increased by NE. The cardiac output and stroke volume were insignificantly increased by DCLHb but were significantly decreased by NE. DCLHb and NE produced a significant increase in blood flow to the heart. The vascular resistance in the heart was not affected by DCLHb but was decreased by NE. DCLHb did not affect the renal and brain circulation, but NE in kidneys decreased the blood flow and increased the vascular resistance, whereas in the brain it increased the blood flow and decreased the vascular resistance. DCLHb increased the blood flow to the stomach and small intestine. The vascular resistance was not affected by DCLHb in the gastrointestinal tract. NE did not affect the blood circulation in the gastrointestinal tract. Blood flow to the spleen was increased by DCLHb, and there was no change in the vascular resistance. NE insignificantly decreased the blood flow to the spleen and significantly increased the vascular resistance. The blood circulation to the mesentery and pancreas was not affected by DCLHb, whereas NE increased the blood flow without affecting the vascular resistance. DCLHb produced a significant increase in the blood flow to the skin without affecting the vascular resistance, whereas NE did not affect the blood flow but increased the vascular resistance. DCLHb did not affect the blood flow to the musculo-skeletal system but increased the vascular resistance, whereas NE decreased the blood flow and increased the vascular resistance. In summary, although the pressor effect of DCLHb and NE at the doses studied is equal, DCLHb did not decrease the blood flow to any organ, whereas NE produced significant decreases in blood flow to several organs. It is concluded that the blood flow to most of the organs is either increased or not affected by DCLHb.
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PMID:Effect of diaspirin cross-linked hemoglobin and norepinephrine on systemic hemodynamics and regional circulation in rats. 830 Dec 7

Diaspirin cross-linked hemoglobin (DCLHb), a hemoglobin-based blood substitute, has been found to improve systemic hemodynamics, cutaneous oxygen tension, and normalization of blood lactate levels and acid-base equilibrium after hemorrhage in animals. The present study was conducted to determine the dose-dependent effect of a 10% solution of DCLHb (20, 50, and 100% of shed blood volume; SBV) on regional blood circulation in hemorrhaged rats. Hemorrhage was induced in urethane-anesthetized rats by bleeding them at a rate of approximately .5 to 1 mL/min until a mean arterial pressure of 35-40 mmHg was achieved. This was maintained for up to 90 min to reach a base deficit of more than -12 mmol/L. Hemorrhage significantly decreased oxygen consumption, mean arterial pressure, cardiac output, stroke volume, and regional blood circulation, but increased total peripheral resistance. The vehicle Ringer's lactate (RL at 20% of SBV, intravenously) did not produce any improvements in oxygen consumption, base deficit, systemic hemodynamics, and regional blood circulation. DCLHb increased oxygen consumption, decreased base deficit, and produced significant improvements in systemic hemodynamics and regional blood flow in a dose-dependent manner. The increase in blood flow was highly significant until 60 min, but was less marked at 120 min, after resuscitation with DCLHb. Resuscitation with RL (300% of SBV) significantly improved systemic and regional blood circulation. However, the improvement was greater after resuscitation with DCLHb (50 or 100% of SBV) as compared with RL at 300% SBV. DCLHb in the dose of 50% of SBV produced maximal resuscitative effects, which were comparable to a DCLHb dose of 100% of SBV. The effect of DCLHb at 50% of SBV on renal cortical blood perfusion, concentration of moving red blood cells (CMBC), and blood velocity was also studied using laser Doppler flowmetry. Hemorrhage produced a decrease in renal cortical blood perfusion (85.3%), which was due to a decrease in the CMBC (61.0%) and their velocity (64.2%). Resuscitation with the RL did not produce any improvement in renal cortical perfusion. However, resuscitation with DCLHb significantly increased renal cortical perfusion (364.7%) due to an increase in both CMBC (123.4%) and their velocity (109.9%). It is concluded that DCLHb in a dose of 50% of SBV produces maximal improvement in regional blood circulation of hemorrhaged rats.
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PMID:Dose-dependent effect of diaspirin cross-linked hemoglobin on regional blood circulation of severely hemorrhaged rats. 946 76

Diaspirin Cross-linked Hemoglobin (DCLHb), a hemoglobin-based oxygen carrier, improves regional blood circulation and systemic hemodynamics in normal and hemorrhaged rats. The action of DCLHb is partly mediated by its scavenging effect on nitric oxide. This study was undertaken to determine the effect of DCLHb on nitric oxide mechanism in hemorrhagic conditions. We studied the modulation of cardiovascular effects of DCLHb by a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) in hemorrhaged rats. The base deficit, survival time, oxygen consumption, and blood circulation to the brain, heart, gastrointestinal tract, and kidneys were determined in 1) DCLHb (100 mg/kg, intravenously (i.v.), 2) L-NAME (2 mg/kg, i.v.), 3) L-NAME (2 mg/kg, i.v.) + DCLHb (100 mg/kg, i.v.), and 4) L-arginine (100 mg/kg/h, i.v.) + DCLHb (100 mg/kg, i.v.) treated rats. Hemorrhage was induced in urethane-anesthetized male rats by bleeding them at a rate of approximately .5 to 1 mL/min, until a mean arterial pressure of 35-40 mmHg was achieved. This blood pressure was maintained for 30 min. Sham-operated nonhemorrhaged rats survived for >300 min, whereas hemorrhaged rats survived for only 85+/-31 min. Hemorrhage significantly increased base deficit and decreased oxygen consumption. A significant decrease in heart rate, mean arterial pressure, cardiac output, stroke volume, and in blood flow to the gastrointestinal tract and kidneys was observed after hemorrhage. Resuscitation with DCLHb produced a significant increase in survival time, oxygen consumption, heart rate, mean arterial pressure, cardiac output, total peripheral resistance, and blood flow to the brain, heart, and kidneys. In contrast, resuscitation with L-NAME did not improve base deficit, survival time, oxygen consumption, systemic hemodynamics, or regional blood flow. L-arginine pretreatment did not affect DCLHb-induced resuscitation of hemorrhaged rats. Furthermore, L-NAME (pretreated or co-administered) attenuated the resuscitative effect of DCLHb. These data suggest that nitric oxide mechanism may not be the only mechanism involved in the resuscitative effect of DCLHb.
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PMID:Modulation of resuscitative effect of diaspirin cross-linked hemoglobin by L-NAME in rats. 952 31

Diaspirin crosslinked hemoglobin (DCLHb; Baxter Healthcare Corp, Deerfield, IL) is hemoglobin-based oxygen carrier which, in our laboratory, improved hemodynamic parameters in a rat burn shock model. Our objective was to compare the effects on hemodynamic parameters and metabolic acidosis of resuscitation with different doses of fresh blood (FB) vs DCLHb. Male Wistar rats (200 to 250 g), surgically prepared for an acute study, were randomly assigned to one of five treatment groups. (n = 8): I. SHAM (not burned, not resuscitated), II. DCLHb 2 ml/kg/% Total Body Surface Area (TBSA) burn and 2 ml/kg/% TBSA burn of Lactated Ringers (LR), III. DCLHb 1 ml/kg/% TBSA burn and 1 ml/kg/% TBSA burn of LR IV. FB 2 ml/kg/% TBSA burn and 2 ml/kg/% TBSA burn of LR V. FB 1 ml/kg/% TBSA burn and 1 ml/kg/% TBSA burn of LR After placement of indwelling catheters, the following baseline hemodynamic values were obtained mean arterial pressure (MAP), cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR) and base excess (BE). The animals were immediately intravenously resuscitated after receiving a 30% scald burn and were followed for 6 hours. Resuscitation was based on the Parkland formula. Blood was obtained from donor male Wistar rats. The animals were euthanized at 6 hours. MAP remained within normal range in all groups. The SVR, CO, SV and BE were normalized earlier in the LR-DCLHb groups when compared to the LR-FB groups (p < 0.05). Early resuscitation with DCLHb is superior to FB in improving hemodynamics in this model. There appears to be a direct relationship between dose and effect with the use of DCLHb. DCLHb could be useful in decreasing resuscitation fluid requirements in acute burns without compromising general tissue perfusion.
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PMID:Comparison of resuscitation with diaspirin crosslinked hemoglobin (DCLHb) vs fresh blood in a rat burn shock model. 1009 35