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1Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore 21205; and 2Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, Maryland 21201
Submitted 24 January 2003 ; accepted in final form 11 June 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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19%) in anesthetized cats. The influence of viscosity was assessed by coinfusion of a high-viscosity solution of polyvinylpyrrolidone (PVP), which increased plasma viscosity two- to threefold. Exchange transfusion of a 5% albumin solution resulted in pial arteriolar dilation, increased CBF, and unchanged O2 transport, whereas there were no significant changes over time in a control group. Exchange transfusion of a 12% polymeric hemoglobin solution resulted in pial arteriolar constriction and unchanged CBF and O2 transport. Coinfusion of PVP with albumin produced pial arteriolar dilation that was similar to that obtained with transfusion of albumin alone. In contrast, coinfusion of PVP with hemoglobin converted the constrictor response to a dilator response that prevented a decrease in CBF. Pial arteriolar dilation to hypercapnia was unimpaired in groups transfused with albumin or hemoglobin alone but was attenuated in the largest vessels in albumin and hemoglobin groups coinfused with PVP. Unexpectedly, hypocapnic vasoconstriction was blunted in all groups after transfusion of albumin or hemoglobin alone or with PVP. We conclude that 1) the increase in arteriolar diameter after albumin transfusion represents a compensatory response that prevents decreased O2 transport at reduced O2-carrying capacity, 2) the decrease in diameter associated with near-normal O2-carrying capacity after cell-free polymeric hemoglobin transfusion represents a compensatory mechanism that prevents increased O2 transport at reduced blood viscosity, 3) pial arterioles are capable of dilating to an increase in plasma viscosity when hemoglobin is present in the plasma, 4) decreasing hematocrit does not impair pial arteriolar dilation to hypercapnia unless plasma viscosity is increased, and 5) pial arteriolar constriction to hypocapnia is impaired at reduced hematocrit independently of O2-carrying capacity.
anemia; blood substitute; carbon dioxide; cat; cerebral blood flow; pial artery
When hematocrit was reduced by an exchange transfusion of a cell-free, tetrameric hemoglobin (Hb) solution, pial arterioles were observed to constrict, whereas dilation was observed after exchange transfusion with albumin (Alb) solutions (1). This difference in the vascular response to decreased hematocrit may be attributed to increased oxygenation by cell-free Hb. However, transfusion of tetrameric Hb solutions produces renal and splanchnic vasoconstriction and arterial hypertension (29), which also may induce autoregulatory pial arteriolar constriction.
It is now appreciated that transfusion of polymers of cross-linked Hb are less likely to increase arterial blood pressure than tetramers of cross-linked Hb (22, 23), probably because of less extravasation and consequent scavenging of nitric oxide (NO) adjacent to arteriolar smooth muscle in peripheral organs. We (14) have previously described a polymerization process producing amide covalent bonds between Hb tetramers that does not require the residual presence of exogenous cross-linking agents such as glutaraldehyde or O-raffinose (14). This polymer, designated zero-link bovine Hb polymer (ZL-HbBv), has a large molecular size (20 MDa), does not extravasate into renal lymph, and does not produce arterial hypertension. The first objective of the present study was to determine whether differences in the pial arteriolar diameter response to exchange transfusion between Alb and cell-free Hb solutions are sustained over a 2-h period after transfusion of a Hb polymer that does not increase arterial blood pressure.
Patients with increased plasma viscosity secondary to elevated immunoglobulin proteins are reported to have lower CBF than anemic patients at matched hematocrit (9). Experimentally, however, increases in CBF during moderate anemia were not attenuated when plasma viscosity was increased by infusion of a viscous solution of polyvinylpyrrolidone (PVP; 1.1 MDa) unless hematocrit was reduced to <19% (21). A similar attenuation of CBF has been observed with high-molecular-weight dextran at a hematocrit of 16% (25). These results imply active vasodilation to maintain O2 transport when perturbations in plasma viscosity are imposed on the microcirculation at moderate reductions of hematocrit, but inadequate dilation at more severe reductions of hematocrit. The second objective of the present study was to test the hypothesis that cotransfusion of PVP with either Alb or polymeric Hb solutions results in increases in pial arteriolar diameter compared with the corresponding responses with either Alb or Hb transfusion alone. It was also determined whether the increase in diameter was sufficient for maintaining CBF and O2 transport.
The influence of hematocrit on CO2 reactivity has not been well studied. Increases in CBF during hypercapnia remain when red blood cells are nearly completely replaced by cell-free Hb at a hematocrit of 2% (13, 30). However, plasma viscosity can modulate the CBF response to hypercapnia (25). Increases in arterial diameter after PVP infusion could limit vasodilatory reserve to physiological stimuli such as hypercapnia. Moreover, decreases in arteriolar diameter after Hb transfusion could limit the vasoconstrictor capacity to physiological stimuli such as hypocapnia. The third objective was to test the hypothesis that the vasoconstrictor response to hypocapnia and the vasodilatory response to hypercapnia remained intact after transfusion of either Alb or Hb solutions with or without concurrent PVP infusion despite changes in baseline diameter and blood O2-carrying capacity.
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METHODS |
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20 MDa as previously described (14). The solution was subjected to diafiltration at 300 kDa to separate large-molecular weight polymerized Hb from the remaining tetramers and small polymers. The purified large polymers were transferred into lactated Ringer solution by dialysis, detoxificated with Detoxigel (Pierce), irradiated to avoid any endotoxin contamination, and stored at –70°C. The PO2 at 50% oxyhemoglobin saturation (P50) was near 4 mmHg at 37°C with essentially no cooperativity or Bohr effect. The Hb concentration in the final solution was between 11 and 12 g/dl with a colloid osmotic pressure of 10 mmHg (cat plasma 15 mmHg).
Surgical procedures. All experiments were approved by the institutional animal care and use committee. Mixed-breed male cats weighing 2.4–3.1 kg were anesthetized with halothane (2–3%) for oral intubation and insertion of arterial and venous catheters. After insertion of the first venous catheter, intravenous anesthetics were continuously infused (8 mg·kg–1·h–1 pentobarbital and 70 µg·kg–1·h–1 fentanyl). The lungs were mechanically ventilated with 30% O2 to maintain the arterial PO2 (PaO2) between 150 and 200 mmHg. The arterial PCO2 (PaCO2) was kept between 32 and 34 mmHg with the aid of end-tidal CO2 monitoring. Muscle paralysis was achieved by a single dose of pancuronium bromide (0.1 mg/kg) to facilitate electrocauterization.
Two catheters were placed into femoral veins and advanced into the inferior vena cava for infusion of drugs and transfusion of fluids during the blood exchange. One femoral arterial catheter was used for the continuous monitoring of arterial blood pressure, and a second arterial catheter was used for withdrawal of blood during exchange transfusion and microsphere blood flow measurements. After a left thoracotomy, a catheter was inserted into the left atrium for the injection of radiolabeled microspheres. After these surgical procedures, halothane was discontinued, and anesthesia was maintained with pentobarbital and fentanyl. The cat was turned prone, and its head was positioned in a stereotaxic frame 3 cm above the heart. After a 1-cm cylinder of bone was removed over the right parietal cortex, a plastic ring was placed around the hole and filled with artificial cerebrospinal fluid (1). In this chamber the dura was cut, and the pial vessels were exposed. A thermistor was integrated in this chamber. Chamber temperature was maintained at 38 ± 0.5°C with a heating lamp while body temperature was maintained with a warmed water blanket. The chamber was sealed with a glass coverslip. Diameter of pial arterioles was measured with a microscope fitted with a video camera. The percent changes in diameter were analyzed separately for arterioles with baseline diameters <50, 50–100, and >100 µm. When multiple arterioles of each size category were present, the percent responses were averaged so that a single value was used for each cat in the statistical analysis.
Arterial blood pressure was continuously monitored. Arterial pH, PaCO2, and PaO2 were measured with a self-calibrating electrode system (model 246, Chiron Diagnostics). Total Hb and CaO2 were measured with a hemoximeter adjusted for cat blood (model OSM 3, Radiometer). Values for plasma Hb were reported as an equivalent concentration of Hb tetramers. The algorithm used for cat blood by the hemoximeter was found to underestimate the ZL-HbBv concentration by 15% compared with samples measured spectrophotometrically with an extinction coefficient of 0.837 cm2/mg at 540 nm after treatment of the samples with carbon monoxide and sodium dithionite. Accordingly, corrections of whole blood Hb values were made based on the fraction of Hb in the plasma compartment. Because less than one-third of total Hb in the blood sample was ZL-HbBv, the corrected values were within 5% of the values measured with the hemoximeter. Plasma viscosity was measured gravimetrically with an Ostwald viscometer. Regional CBF was measured with radiolabeled microspheres (15.5 ± 0.5 µm diameter, New England Nuclear) by the reference withdrawal method (5). Six radioactive isotopes (57Co, 114mIn, 113Sn, 103Ru, 95Nb, and 46Sc) were injected in random sequence into each animal. Approximately 1.5 x 106 microspheres were injected into the left atrium over a 20-s period, followed by a 5-ml saline flush. Reference blood samples were withdrawn from the aorta at 1.94 ml/min beginning 30 s before the injection and continuing for 90 s after the saline flush. Tissue and blood samples were analyzed in an autogamma scintillation spectrometer (Minaxi model 5530, Packard Instruments). Blood flow was calculated as the product of the withdrawal rate (1.94 ml/ min) times the counts in the tissue (corrected for the isotope overlap) divided by the counts in the arterial reference sample. Cerebrovascular resistance was calculated as mean arterial blood pressure divided by CBF. Cerebral O2 transport was calculated as the product of CBF and CaO2.
Experimental protocol. After 45 min from the end of the surgical preparation, baseline value measurements of arterial blood gas values, arterial pressure, blood flow, and pial arteriolar diameter were made. The cats were assigned to one of the following five groups: 1) control group, in which no exchange transfusion was performed (n = 10); 2) exchange transfusion with 5% human Alb solution (Alb group; n = 10); 3) exchange transfusion with the Hb solution (Hb group n = 9); 4) exchange transfusion with 5% human Alb solution and 20% PVP solution (1.1 MDa) in a dose of 1.1 mg/kg to induce an increase in plasma viscosity (Alb+PVP group; n = 8); and 5) exchange transfusion with the Hb solution and 20% PVP (1.1 mg/kg) (Hb+PVP group; n = 6). Transfusion of the PVP solution was alternated intermittently with transfusion of the Alb or Hb solution. The exchange transfusion was done at a rate of 1.9 ml/min until the hematocrit was reduced to 18% (30 min). Additional amounts of either Alb or ZL-HbBv solutions were infused in the respective groups during the experiment to replace blood volume during sampling and to keep hematocrit constant.
Sets of measurements were obtained 1 and 2 h after the end of the transfusion. Hypocapnia (PaCO2 20 mmHg) was then induced by increasing the ventilatory rate. Measurements were taken at 10 min of hyperventilation and 20 min after the return to normocapnia. Hypercapnia (PaCO2 70 mmHg) was then produced by adding CO2 to the inspired gas, and measurements were repeated at 10 min of hypercapnia.
Statistical evaluation. Values among the five groups at each time point were compared by one-way ANOVA and the Newman-Keuls multiple range test at P < 0.05. Comparisons of CBF and O2 transport at 1 and 2 h after transfusion were made with baseline values within groups by paired t-tests with the Bonferroni correction. Data are presented as means ± SE.
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RESULTS |
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Coinfusion of PVP increased plasma viscosity two- to threefold compared with the corresponding values in the Alb and Hb groups (Table 2). Mean arterial blood pressure was not significantly changed at 1 or 2 h after transfusion in any group (Fig. 1). Arterial pressure in the transfused groups did not differ significantly from values in the control group at any time point during the experiment.
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Hemodilution with Alb caused an increase of mean CBF that maintained cerebral O2 transport (Fig. 2). Coinfusion of PVP with Alb also resulted in an increase in CBF from baseline, but CBF was not significantly different from CBF in the control group. Although CBF in the Alb + PVP group was less than CBF in the Alb group, neither the percent increase in CBF nor the change in O2 transport was significantly different. With exchange transfusion of Hb, neither CBF nor O2 transport was significantly changed. When PVP was coinfused with Hb, CBF was similar to that with Hb alone, but O2 transport declined as a result of the decrease in CaO2. Values at 2 h were similar to those at 1 h after transfusion in all groups.
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Cerebrovascular resistance (CVR) decreased after exchange transfusion with Alb or Alb + PVP, and the percent change was significantly different from the time control group (Fig. 3). Hemodilution with Alb or with Alb + PVP produced a similar degree of pial arteriolar dilation. Transfusion of Hb generated pial arteriolar constriction at 1 h in all size vessels without a significant change in CVR. By 2 h, the constrictor response was attenuated. However, coinfusion of PVP with Hb reversed the early vasoconstrictive effect and resulted in sustained pial vasodilation of all size arterioles. The percent change in diameter in the Hb + PVP group differed significantly from that in the Hb group and, in the case of the smallest and largest arterioles, from the Alb + PVP group. In contrast, the percent change in CVR was not different from values in the control or Hb group.
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Effect of hemodilution on the CO2 response of pial arterioles. The level of PaCO2 achieved during hypocapnia and hypercapnia was similar among groups (Table 1). Hypocapnia caused a CBF reduction in the control and Alb groups but no significant change in the other groups (Fig. 4A). The percent decreases in CBF in the Alb + PVP, Hb, and Hb + PVP groups were significantly smaller than that in the control group. With induction of hypercapnia, the percent increase in CBF was attenuated in the Alb + PVP, Hb, and Hb + PVP groups compared with both the control and Alb groups (Fig. 4B).
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The percent increase in CVR during hypocapnia was significantly attenuated in the Alb group, and no significant change in CVR occurred in the Alb + PVP, Hb, and Hb + PVP groups (Fig. 5). Compared with the vasoconstrictor response of pial arterioles in the control group, the hypocapnia-induced vasoconstrictor response was impaired in all of the other groups (Fig. 5). The addition of PVP to Alb or Hb did not restore the hypocapnic response.
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The percent decrease in CVR during hypercapnia was attenuated in the Hb + PVP group compared with the control group. The hypercapnic dilation of pial arterioles was intact in all size vessels in the Alb and Hb groups. In large vessels, however, the addition of PVP to Alb or Hb significantly attenuated the vasodilator response to hypercapnia compared with the control group. Large vessel dilation in the Hb + PVP group also was less than that in the Hb group. In small arterioles, the group effect on hypercapnic dilation was less consistent (P = 0.1).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Hemodilution results in a decrease in CVR that can be accompanied by either decreases (6, 16, 17), no change (10), or increases (1) in arterial diameter. Active changes in arteriolar diameter have been referred to as viscosity autoregulation, analogous to pressure-induced autoregulation (18). In the case of viscosity autoregulation, changes in vascular diameter will be affected by changes in endothelial wall shear stress and by oxygenation. Changes in oxygenation, in turn, will be influenced by the balance of decreased blood viscosity promoting blood flow versus the decrease in O2-carrying capacity. Thus the variable changes in arteriolar diameter reported in the literature during hemodilution may be influenced by the balance of several factors including baseline values of hematocrit, viscosity, O2-carrying capacity, vascular diameter, and oxidative metabolism, as well as the degree of hemodilution and its associated effects on these parameters. In the present model using anesthetized cats in which arterial hematocrit is reduced from 32% to 18–19%, we observed dilation of pial arterioles both in the current study as well as in a previous report (1). This vasodilation was associated with an increase in CBF that was sufficient to maintain cerebral O2 transport. Maintenance of cerebral O2 transport during anemia has been described in several studies (2, 6, 11), although some investigators have reported a moderate decrease in bulk oxygen transport (4, 24). Therefore, we have postulated that active changes in vascular diameter during anemia represent an oxygen-dependent regulatory process.
Our data with cell-free Hb are consistent with this oxygen-dependent hypothesis. Exchange transfusion with cell-free Hb or Alb to a hematocrit of 18% in the cat decreases whole blood viscosity equivalently by 25% (27), yet changes in arteriolar diameter are directionally different (1). The decrease in arteriolar diameter observed in the present study with a large-MW polymer of ZL-HbBV is similar in magnitude to that previously reported with the lower MW cross-linked tetrameric Hb at similar plasma concentrations of heme (1). Because exchange transfusion of the ZL-HbBv polymer did not increase arterial blood pressure, the decrease in arteriolar diameter is not primarily due to an increase in transmural pressure. Furthermore, the constriction is unlikely to be solely due to scavenging of NO by cell-free Hb because 1) NO synthase inhibition causes a decrease in cerebral O2 transport (15), whereas we observed no change in cerebral O2 transport after Hb transfusion; and 2) endothelial-dependent dilation of pial arterioles to acetylcholine and ADP is not attenuated by the presence of cell-free Hb in the plasma (1). Therefore, the maintenance of cerebral O2 transport at equivalent levels after Alb transfusion and ZL-HbBv transfusion argues that changes in arteriolar diameter compensate for imposed changes in viscosity in a manner that maintains bulk O2 transport to the microcirculation. This concept is also consistent with our previous observations showing that decreasing PaO2 after exchange transfusion with Alb or cross-linked Hb tetramers results in indistinguishable levels of CBF at equivalent levels of CaO2 and consequently results in constant O2 transport (28).
Constriction was observed in all size pial arterioles 1 h after transfusion of ZL-HbBv. This pattern is somewhat different from that obtained during arterial hypertension, where the percent constriction is greater in larger arteries (12). This constrictor response was blunted by 2 h after transfusion. This attenuation was not attributable to changes in arterial blood gas values or by a decrease in plasma Hb concentration. Thus there appears to be some adaptation over time to the postulated O2-dependent constrictor response. Nevertheless, the change in diameter after ZL-HbBv transfusion remained significantly different from that seen 2 h after Alb transfusion.
Transfusion of PVP to increase plasma viscosity has been tested in conscious rats at different levels of hematocrit (21). Results indicated that cerebral O2 transport could be maintained when PVP was infused over a hematocrit range of 19–30% but that O2 transport declined when PVP was transfused at a hematocrit of 15%. These results imply that increasing plasma viscosity causes additional cerebral vasodilation to help maintain O2 transport during moderate anemia but that vasodilatory reserve becomes limited during severe anemia, when tissue hypoxia is presumed to become more prominent (2). Thus we anticipated that the increase in pial arteriolar diameter in the Alb + PVP group would be greater than in the Alb group to compensate for the twofold increase in plasma viscosity. However, the dilation was similar in magnitude in all size arterioles in the Alb and Alb + PVP groups. One explanation for a similar percent increase in CBF in the Alb and Alb + PVP groups despite a difference in plasma viscosity is that small intraparenchymal arterioles dilated to a greater extent in the Alb + PVP group. Another issue is the impact of increasing plasma viscosity on whole blood viscosity. We did not measure whole blood viscosity in this experiment. It is possible that the increase in plasma viscosity to 2.4 cP in the Alb + PVP group did not have a large enough effect on whole blood viscosity to cause additional pial arteriolar dilation. The lack of additional dilation was not due to an inability of the blood vessels to further dilate, because additional dilation was observed during hypercapnia, albeit at a reduced magnitude. Increasing plasma viscosity with high-molecular weight dextran in anesthetized rats reduced CBF at a hematocrit of 15% (25). Furthermore, doubling plasma viscosity with dextran infusion, which decreased hematocrit from 43 to 34%, failed to increase CBF in anesthetized dogs (3), thereby implying that cerebral O2 transport decreased. A similar finding was observed in humans with proteinemia (9). Therefore, the lack of additional vasodilation in the Alb + PVP group in the present study is probably not specific for the use of PVP to increase plasma viscosity.
In contrast to the lack of additional vasodilation with coinfusion of PVP and Alb, coinfusion of PVP with the ZL-HbBv polymer resulted in marked dilation of pial arterioles. This vasodilation prevented a decrease in CBF in the face of a twofold increase in plasma viscosity. This result is consistent with the argument that the decrease in vascular diameter seen with ZL-HbBv transfusion alone was a consequence of decreased blood viscosity because the response can be converted to a vasodilatory response when plasma viscosity is increased. Thus the presence of a cell-free Hb polymer, per se, does not interfere with viscosity autoregulation. These results are in agreement with those of Waschke et al. (31), who reported no decrement in CBF when PVP was coinfused with tetrameric Hb at a hematocrit of only 2–3%. Interestingly, increasing plasma viscosity with high-MW dextran reduced CBF under conditions of hypoxic hypoxia but not during normoxia (25). One explanation for these observations is that tissue hypoxia interferes with viscosity autoregulation. Our finding of vasodilation with coinfusion of PVP and ZL-HbBv, which exceeded the vasodilation with coinfusion of PVP and Alb, implies that viscosity autoregulation depends on enhanced oxygenation provided by cell-free Hb.
Despite the increase in arteriolar diameter after coinfusion of PVP and ZL-HbBv, cerebral O2 transport decreased. One limitation of this experiment is that coinfusion of PVP resulted in a lower Hb concentration in the plasma at equivalent hematocrit. To achieve a plasma Hb concentration comparable with the group transfused with ZL-HbBv alone would have required mixing PVP with a concentration of ZL-HbBv two- to threefold greater than the 12% solution transfused in the ZL-HbBv group. This was not feasible. Hence, we elected to keep the reduction in hematocrit and the amount of PVP infused comparable with the Alb + PVP group and let the plasma Hb concentration be less than in the ZL-HbBv group. Consequently, CaO2 with PVP plus ZL-HbBv was less than with ZL-HbBv alone. Thus we cannot exclude that part of the vasodilation response was attributable to a decrease in CaO2. However, it should be borne in mind that delivery of O2 to the tissue by cell-free Hb is related not only to the O2 unloaded solely from the cell-free Hb but also potentially by facilitated unloading of O2 from red blood cell-based Hb. One component of the resistance to O2 delivery into the tissue is attributed to the low solubility of O2 in the plasma between red blood cells and the endothelial wall. In vitro, cell-free Hb delivers O2 more effectively than an equivalent amount of red blood cell Hb (19, 20). The presence of the Hb polymer in the plasma increases the effective O2 solubility and may facilitate the transport of O2 from the red blood cell to the vascular wall. This mechanism may contribute to the postulated increased tissue oxygenation despite the high O2 affinity of this Hb polymer (P50 4 mmHg).
Cerebrovascular reactivity to hypercapnia has not been well studied under anemic conditions. The present results indicate that pial arterial diameter dilation during hypercapnia was not impaired after hemodilution with the Alb solution or by the presence of the cell-free Hb polymer. However, the percent increase in CBF was attenuated by the Hb polymer. This result suggests that vasodilation in intraparenchymal vessels was reduced in the presence of the polymer possibly as a result of increased tone secondary to enhanced perivascular PO2 by the plasma-based O2 carrier. With both Alb + PVP transfusion and Hb + PVP transfusion, the CBF and large pial arterial responses to hypercapnia were attenuated. The CBF response to hypercapnia has also been reported to be attenuated by transfusion of high-molecular weight dextran (25) and by coinfusion of PVP with cross-linked tetrameric Hb (13). The increase in normocapnic baseline diameter in both PVP groups may account for the limited hypercapnic vasodilation. However, normocapnic baseline diameter in the Alb + PVP group was similar to that in the Alb group, yet the vasodilatory response to hypercapnia was greater in the Alb group. Thus there may be an effect of plasma viscosity on hypercapnic dilation independent of baseline diameter.
In the case of hypocapnia, both the increase in CVR and the decrease in diameter of all size pial arterioles were markedly reduced in all four transfused groups. This unexpected result indicates that the loss of hypocapnic vasoconstriction may be related to the low hematocrit, per se, rather than to an effect of viscosity, oxygenation, or baseline diameter. In particular, the lack of hypocapnic constriction with ZL-HbBv transfusion is probably not attributable to changes in baseline diameter or wall shear stress because increasing these parameters with coinfusion of PVP did not restore hypocapnic constriction. In the case of transfusion of Alb alone, hypocapnia still produced a decrease in CBF despite the loss of pial arteriolar constriction. These results imply that hypocapnic vasoconstriction was not completely lost in intraparenchymal arterioles.
In summary, increasing arterial O2-carrying capacity at a reduced hematocrit with the ZL-HbBv polymer resulted in vasoconstriction that counteracted the reduced blood viscosity such that there was little net change in overall CVR. In contrast, increasing plasma viscosity prevented this vasoconstrictor response. These results support the concept that active changes in cerebrovascular diameter to imposed changes in blood viscosity represent an O2-dependent process that attempts to maintain cerebral O2 transport.
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DISCLOSURES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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2-adrenergic, and nitric oxide-dependent interactions on canine cerebral blood flow. Am J Physiol Heart Circ Physiol 266: H476–H482, 1994.
-crosslinked hemoglobin transfusion and nitric oxide synthase inhibition. Crit Care Med 24: 558–565, 1996.[Web of Science][Medline]
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