| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Department of Hematology and Physiology, School of Pharmacy, University Henri Poincaré- Nancy 1, 54001 Nancy cedex, France; and 2 Laboratory of Plasma Derivatives, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892
 |
ABSTRACT |
|---|
 Top
 Abstract
 Introduction
Methods
Results
Discussion
References
|
|---|
The cardiovascular
effects of human albumin (Alb) and three human hemoglobin
(Hb) solutions, dextran-benzene-tetracarboxylate Hb,
-crosslinked Hb, and
o-raffinose-polymerized Hb were
compared in anesthetized rabbits undergoing acute isovolemic
hemodilution with Hct reduction from 41.4 ± 2.7 to 28.8 ± 1.6%. The impact of the vasoconstricting properties of Hb was examined
by measuring heart rate (HR), mean arterial pressure (MAP), abdominal
aortic, and femoral arterial blood flow, vascular resistance (VR), and aortic distension during the first 3 h after hemodilution. The impact
of the hemorheological parameters was assessed by measurements of
hemodiluted blood viscosity. In contrast to Alb, the Hb solutions elicited an immediate increase in MAP (20-38%). The effects of Alb and Hb solutions on HR, as well as on aortic and femoral arterial blood flow, were similar. VR decreased with Alb (20-28%) and
increased with all three Hb solutions (30-90%), but the MAP and
VR rising trends were different with each Hb solution. Aortic
distension decreased in Hb groups compared with the Alb group for the
first 60 min. The viscosity of hemodiluted blood was similar for all groups at high shear rates but was dependent on the viscosity of the
solutions at low shear rates. We conclude that the vasoconstriction elicited by the Hb solutions overrides the vasodilation associated with
viscosity changes due to hemodilution and would be the major factor
responsible to the cardiovascular changes.
oxygen carriers; blood flow; hemodilution; viscosity
| |
INTRODUCTION |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
PRESENTLY, HEMOGLOBIN (Hb)-based solutions are
undergoing advanced clinical trials with the aim of reducing blood
transfusion in situations of preoperative and intraoperative
hemodilution. These solutions make it possible to reduce serious
complications associated with transfusion and have the advantage,
compared with plasma exchange fluids, of possessing
O2-carrying capacity (25). However, many studies reported an increased arterial pressure after
infusion of Hb solutions, in both animals and humans, as a result of
vasoconstriction (1, 4, 6). This property has been demonstrated in
vitro in various preparations of vessels immersed in or perfused with
Hb (9, 15, 23). The most commonly accepted explanation is that free Hb
(in the ferrous form Fe2+) traps
nitric oxide (NO) released by the endothelium and thus impairs the
vasodilating action of this relaxing factor (14, 19, 23). Nakai et al.
(19) compared cellular Hb forms and free Hb derivatives in rabbit aorta
strips. Nakai et al. emphasized the contribution of Hb chemical form to
the NO-trapping action of the solutions. However, in a recent report,
Rohlfs et al. (24) concluded that the blood pressure increases observed
in rats after 50% exchange transfusion with Hb solutions could not be
the result of NO scavenging by the heme and indicated that other
physiological mechanisms were more likely to be involved. Gulati et al.
(8) also suggested a contribution by endothelin to the pressor action of diaspirin cross-linked Hb (-Hb) in hemorrhaged
rats. Stimulation of -adrenergic receptors has also been proposed as
a reason for peripheral vasoconstriction after -Hb administration
in rats (7, 26). An autoregulatory control of blood pressure in
response to changes in tissue oxygenation was also proposed by
Intaglietta et al. (13) as a contributing mechanism to vasoactivity.
Nolte et al. (20, 21) indicated that the increased blood
O2-carrying capacity in the
microcirculation after injection of -Hb could also contribute to
the pressor response of Hb as a result of alterations in vasomotion
frequency and amplitude.
Despite the large number of studies of Hb-based
O2 carriers, the incidence of the
type of modification applied to Hb on the cardiovascular function after
hemodilution is poorly documented. Therefore, we examined the effects
of three human Hb solutions: dextran-benzene-tetracarboxylate-conjugated Hb (Dex-BTC-Hb), -Hb, and o-raffinose-polymerized Hb
(PolyHb) after acute isovolemic hemodilution, compared with albumin
(Alb), a solution used in clinical practice for intravenous volume
replacement. Hemodynamic parameters and vascular resistance (VR) were
examined periodically during the first 3 h. We also measured the
variations in aortic distension, a mechanical parameter of conductance
vessels which is likely to be affected by an increase in blood
pressure. In separate experiments, measurements of blood viscosity
after hemodilution were performed to determine the possible impact of
this rheological parameter on hemodynamic changes.
| |
METHODS |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Animals and anesthesia.
Thirty male New Zealand White rabbits (La Garenne, Villey
Saint-Etienne, France), which weighed 2.7 ± 0.3 kg, were
anesthetized with ketamine (Ketalar 50, Parke-Davis, France; 50 mg/kg
im) and pentobarbital sodium (Sanofi, France; 40 mg/kg iv, followed by infusion at 5 mg · kg
1 · h1
in the right ear marginal vein). The rabbits were placed in the dorsal
decubitus position on a heating table, and they were warmed to maintain
a constant body temperature. The trachea was intubated, and the animal
spontaneously breathed room air. At the end of the experiments,
the animals were killed by excess dose of pentobarbital sodium. The
study design was approved by the Animal Protection Bureau of the French
Ministry for Fishing, Agriculture, and Food, and the
experiments were conducted in accordance with the
Guiding Principles for Research Involving
Animals.
Surgery and instrumentation.
The left femoral artery was exposed, and a directional, pulsed, Doppler
flow probe (DBF-120A, Crystal Biotech, Holliston, MA) was placed on it.
The right femoral artery was cannulated with a heparin-filled
polyethylene catheter (0.56 mm ID) that was advanced in the abdominal
aorta for arterial pressure measurements and blood collection. After a
midline laparotomy was performed, the abdominal aorta was carefully
exposed 2 cm above the emergence of the catheter. A directional,
pulsed, Doppler flow probe (HDP-120A, Crystal Biotech) and a
single-crystal transducer designed to measure the absolute arterial
diameter, within a range of 1-12 mm and with a resolution of 0.01 mm (DMT-120-CP, Crystal Biotech), were placed on the vessel. Saline (10 ml · kg1 · h1
iv) was infused by the right ear marginal vein to maintain
fluid after the laparotomy.
Data acquisition. The femoral arterial catheter was connected to a pressure transducer (Viggo-Spectramed, Paris, France) to measure the pulsatile arterial pressure. The aortic and femoral arterial flow probes were connected to 20-MHz modules with pulse-repeated frequency of 125 kHz (PD-20, Crystal Biotech) to measure the blood flow, as reported by Haywood et al. (10). The crystal was connected to a 20-MHz echo-tracking module (WT-20, Crystal Biotech) to measure the aorta diameter in millimeters. The blood flow and echo-tracking modules were connected to a dedicated amplifier (CBI-8000, Crystal Biotech). The pressure transducer and the amplifier were connected to a personal computer for on-line data acquisition at a rate of 75 Hz (Acqknowledge + MP100 hardware and software, Biopac Systems, Goleta, CA).
Acute isovolemic hemodilution.
The rabbits were randomly allocated to experimental groups in which
hemodilution was performed with human Alb
(n = 8) or with Dex-BTC-Hb
(n = 8), -Hb
(n = 8), or PolyHb
(n = 6). After instrumentation was
completed, the animals were allowed to equilibrate during a 1-h
baseline period. Hemodilution with one of the solutions described below
was then initiated by partial-exchange transfusion to achieve a final
Hct of ~28%. Blood was withdrawn at 100 ml/h with a syringe pump
(Vial Médical SE 400, Saint-Martin-le-Vinoux, Grenoble, France)
connected to the femoral arterial catheter. The solutions were infused
at the same rate with a reciprocating syringe pump (Vial Médical
SE 400) by the right ear marginal vein. The exchange transfusion was
achieved in ~50 min, and the end of the infusion was considered as
time point t = 0.
Blood samples and hematologic parameters. Blood samples consisting of 750 µl were collected at the end of the baseline period and at various time points (t = 5, 60, 120, and 180 min), and they were replaced by an equal volume of saline. Blood samples were used for Hct determination, pH, and analysis of blood gases (ABL2, Radiometer, Copenhagen, Denmark) as well as blood and plasma total Hb concentrations (Hbtot; Co-oximeter 482, Instrumentation Laboratory, Lexington, MA). Because blood was collected by the femoral arterial catheter, measurements of arterial pressure were discontinued during the collection procedure.
Solutions.
Human Alb (5 g/dl) dissolved in Tyrode medium (in mM: 6.7 glucose, 140 Na+, 5.0 K+, 2.5 Ca2+, 1.1 Mg2+, 115.8 Cl, 0.8 phosphates, 30.0 carbonates) was supplied by Pasteur-Mérieux Sérums & Vaccins (Marcy l'Etoile, France). The Alb solution was sterile and
pyrogen free. Dex-BTC-Hb consists of 8.5 g/dl of human Hb extracted
from outdated red blood cells and conjugated to a macromolecular
allosteric effector, dextran-benzene-tetracarboxylate. Dex-BTC-Hb was
produced in collaboration with Pasteur-Mérieux Sérums & Vaccins, according to the protocol previously described, and was
suspended in Tyrode medium (pasteurized, sterile, pyrogen free) and
then frozen at 
20°C without preservatives (17,
22). -Hb (from the US Army) consists of 8.2 g/dl of
heat-treated human Hb obtained from outdated red blood cells,
stabilized by cross-linking between the two -subunits with
bis(3,5-dibromosalicyl)fumarate, suspended in Ringer lactate, and
frozen at 80°C (28). PolyHb consists of a 10 g/dl
pasteurized solution of human Hb extracted from outdated red blood
cells, cross-linked internally with raffinose, and polymerized to form
PolyHb (11, 12). PolyHb was suspended in lactated Ringer injection
[US Pharmacopoeia (in mM): 123.9-137.0 Na+, 3.6-4.4
K+, 1.2-1.5
Ca2+,
103.9-115.2
Cl, 25.7-29.0
lactate] and was frozen at 80°C without
preservatives. PolyHb was generously provided by Hemosol (Etobicoke,
Ontario, Canada).
|
In vitro viscosity measurements.
The kinematic viscosity of Alb, Dex-BTC-Hb, -Hb,
and PolyHb was determined at 37°C with an automatic capillary
viscometer (module V, Amtec, Villeneuve-Loubet, France) and expressed
in centistokes (Table 1). The principle of the instrument
is to measure automatically the flowing time of a solution in a
capillary between two points that are optically defined. The
measurement of this time is equivalent to the measurement of the
kinematic viscosity.
Ex vivo viscosity measurements.
In separate experiments, 25 male New Zealand White
rabbits weighing 2.4-2.7 kg (La Garenne) were used. While the
animals were under general anesthesia with 1% halothane (Belamont,
France) mixed in 95% O2-5%
CO2, a polyethylene tube was
inserted into the right carotid artery and tunneled subcutaneously to
emerge at the top of the back. The animals were treated with penicillin (200,000 U/kg im) and were allowed a recovery period of 1 day before
experiments. On the day of experiments, the animals received heparin
(150 U/kg iv); 5 min later, an exchange transfusion was performed to
decrease Hct to 28%. In these experiments, Alb, Dex-BTC-Hb, -Hb,
and PolyHb (n = 5, each) were used for
hemodilution. The whole blood and the blood + solution mixtures were
collected with 5% EDTA (wt/vol). The viscosity was
determined 5 min after the end of exchange transfusion, at 37°C, by
using a Couette viscometer (Low Shear 30, Contraves, Zurich,
Switzerland) for shear rates ranging from 0.5 to 128 s1 and expressed in
millipascals per second. For determination of control blood viscosity,
the Hct was adjusted to 40 and 30% (n = 5 each) by addition or subtraction of autologous plasma.
Data analysis.
Mean arterial pressure (MAP) was calculated as [1/3 (systolic
pressure diastolic pressure) + diastolic pressure]. Heart rate (HR) was calculated from the aortic blood flow signal as the
reciprocal between two consecutive systolic peaks. VR was calculated as
MAP/aortic blood flow. Aortic distension was expressed as the
difference between the aortic systolic and diastolic diameters for each
beat. MAP, HR, aortic blood flow, aortic distension, VR, and femoral
blood flow are expressed as means ± SE. Statistical comparisons
were made before hemodilution and at posthemodilution time points
(t = 5, 30, 60, 120, and 180 min) for
each group by using an analysis of variance for repeated measures.
Comparisons between groups were made for each time point by using an
analysis of variance for repeated measures with Dunn-Bonferroni
correction. A value of P < 0.05 was
considered significant.
| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Hematological results.
Hct decreased similarly in each group after exchange transfusion (from
41.4 ± 2.7 to 28.8 ± 1.6%; P < 0.05) and was stable for the 3 h of experiments (Fig.
1A).
|
-Hb > Alb (Table 1). At
5 min after exchange transfusion, marked differences were found in
blood viscosity at low shear rates; blood hemodiluted with Dex-BTC-Hb
exhibited a higher viscosity than blood hemodiluted with -Hb,
PolyHb, and Alb, respectively (Fig. 2). In
contrast, at high shear rates, the viscosity values were similar
between the groups.
|
|
Effects of hemodilution with Alb.
Hemodilution with Alb caused a progressive decrease in
MAP of 12-25% and had no effect on HR (Fig.
3). Aortic blood flow decreased by 26% at
t = 180 min, and femoral arterial
blood flow increased by 33% after 120 min (Fig.
4). VR decreased (20%) after 30 min (Fig.
5). Aortic distension significantly
increased by 20% in the first 30 min after exchange transfusion (Fig.
5).
|
|
|
Effects of hemodilution with Dex-BTC-Hb. Dex-BTC-Hb induced an increase in MAP (37% maximum) in the 3 h after exchange transfusion; MAP values were significantly higher than in the Alb group (Fig. 3). A 12% decrease in HR was observed 5 min after exchange transfusion, and HR was not different from baseline value after this time (Fig. 3). Aortic blood flow increased by 35% 5 min after hemodilution, thereafter the values were not different from those of the other groups (Fig. 4). Femoral arterial blood flow decreased between 30 and 120 min (25-40%) after exchange transfusion (Fig. 4). VR progressively increased (40-60%) after 30 min and was higher than in the Alb group (Fig. 5). Aortic distension decreased by 25% in the first 60 min after hemodilution and was lower than in the Alb group all through the experiments (Fig. 5).
Effects of hemodilution with -Hb.
MAP increased by 35% for the 3 h after hemodilution
with -Hb compared with baseline value (Fig. 3) and was higher
than in the Alb group. HR and femoral arterial blood flow remained
unchanged after exchange transfusion (Fig. 3 and 4). A significant
decrease (35%) in aortic blood flow was observed at
t = 180 min (Fig. 4). VR progressively
increased (by 30-90%) after exchange transfusion and was higher
than in the Alb group all through the experiments (Fig. 5). Aortic
distension slightly decreased compared with baseline (Fig. 5).
Effects of hemodilution with PolyHb. MAP increased after hemodilution with PolyHb compared with the Alb-exchanged group, and the values were significantly different from baseline value until 180 min (Fig. 3). HR was not altered after exchange transfusion (Fig. 3). Aortic blood flow was reduced after 120 min, and femoral arterial blood flow decreased by 30% between 60 and 120 min after hemodilution (Fig. 4). VR progressively increased (25-38%) after 30 min and was higher than in the Alb group all through the experiments (Fig. 5). Aortic distension was slightly reduced compared with baseline (Fig. 5).
Comparative effects of the three Hb-based solutions.
The increase in MAP was immediate in Dex-BTC-Hb and
PolyHb groups, and MAP decreased with time, whereas it was stable in
the -Hb group (Fig. 3). Aortic blood flow was significantly
higher in Dex-BTC-Hb group compared with -Hb and PolyHb at
t = 5 min, but the flow was not
different after this time (Fig. 4). No statistical differences in HR,
femoral arterial blood flow, and aortic distension were found between
the three Hb groups at the various time points (Figs. 3-5).
Although no significant differences were found in VR, the increments
were different in the groups (Fig. 5). There was a progressively rising
trend in the Dex-BTC-Hb and -Hb groups at each time point,
whereas VR increased until 60 min and was stable thereafter in the
PolyHb group.
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
We examined the cardiovascular effects of three human
Hb solutions that were undergoing preclinical or clinical evaluation: Dex-BTC-Hb (preclinical evaluation), and -Hb and
PolyHb (clinical evaluation). The
possible influence of the type of chemical modification applied to Hb
was assessed in an exchange-transfusion protocol that led to a
reduction in Hct from 41 to 28%. The model we chose did not aim at
being a clinical model but was intended to permit a comparative study
of cardiovascular parameters after hemodilution. An important point to
consider was to have a reduction in Hct that was similar among the
experimental groups to allow valid comparisons of blood flow
measurements. Blood flow is indeed directly proportional to blood
viscosity, and, therefore, to Hct (2) as indicated by Poiseuille-Hagen
equation
|
is blood flow, 
P is the pressure
difference, 
is blood viscosity, and
r and
L are vessel radius and length, respectively.
The contribution of O2-transport parameters and acid-base status to hemodynamics was comparable in the experimental groups, because no changes in arterial blood gases and pH were observed after hemodilution (Table 2). Blood Hbtot content was above 10 g/dl (Fig. 1), the commonly accepted threshold at which oxygenation is correctly maintained. Moreover, the low endotoxin levels of the infused solutions make it possible to assume that the animals did not react to this parameter. Thus we can assume the cardiovascular changes observed with Hb solutions are related to their vasoactive and/or hemorheological effects.
Comparative effects of Alb and Hb solutions. Human Alb was used as a control solution because it has a viscosity similar to that of plasma and most Hb solutions presently undergoing clinical tests. The cardiovascular responses to hemodilution with non-O2-carrying and Hb solutions have been extensively characterized. Unlike the case with Hb solutions, hemodilution with volume-replacement solutions devoid of O2-carrying capacity increases cardiac output by a compensatory mechanism that aims at maintenance of O2 delivery at prehemodilution values (27). In clinical practice, such as cardiopulmonary bypass, hemodilution is conducted to reach a final Hct of <30% (3, 5, 27). In our protocol, we did not measure absolute cardiac output, but it was estimated by aortic blood flow. We did not find major differences in aortic blood flow between the Alb and Hb groups, although Hct was reduced to ~28%, nor did we find any major difference in HR.
Blood viscosity reduction has been proposed as the major factor responsible for the increase in cardiac output with non-O2-carrying solutions rather than decreased O2 delivery (27). In a recent study, Dietz et al. (6) compared the effects of Alb and-Hb in a partial-exchange transfusion model in which blood
viscosity changes were similar with both solutions. They concluded that the vasoconstricting properties of the Hb solution had a greater effect
on vasculature than blood viscosity. Our viscosity
measurements are consistent with these findings: at high shear rates,
reflecting the rheological behavior of blood in the conductance
vessels, such as the abdominal aorta, the viscosity of hemodiluted
blood was similar for Alb and Hb, despite differences in the proper viscosity of the solutions (Fig. 2, Table 1). In contrast, at low shear
rate values (0.5-5
s1), reflecting the
hemorheological behavior in the small vessels, the viscosity of
hemodiluted blood is highly dependent on the viscosity of the solutions
(Fig. 2). The beneficial effect of the low viscosity of Hb solutions in
the microcirculation is of great interest, because these solutions
could thus improve oxygenation more efficiently than whole blood in
ischemic tissues (3, 20, 21). But the improvement of oxygenation due to
viscosity reduction could also induce vasoactive responses by
autoregulation mechanisms, as proposed by Intaglietta et al. (13).
We observed major differences between Alb and Hb groups in MAP, VR, and
aortic distension; these differences are related to the vasoactive
properties of the solutions. MAP and VR decreased after exchange
transfusion with Alb, whereas Hb solutions increased both MAP and VR.
The VR, calculated in our experiments as the ratio of MAP to aortic
blood flow, describes the vascular bed distal to the
location of the flowmeter (i.e., the abdominal aorta). The rise in VR
after Hb infusion in the three groups confirms the vasoconstricting
effect of these solutions, which led to increased pressure (1,
6-8, 14, 20, 27). In contrast, the decrease in VR and MAP in the
Alb-hemodiluted group indicates that hemodilution with a solution
without vasoconstrictor properties (Alb) evokes vasodilation, as
previously reported (6). Aortic distension was expressed as the
difference between systolic and diastolic aorta diameter as measured
with an echo-tracking device. In our experimental model, aortic
distension was reduced in the three groups of animals hemodiluted with
Hb compared with Alb-hemodiluted animals for the first 60 min after
exchange transfusion (Fig. 5). In contrast, the transient increase in
aortic distension after hemodilution with Alb may be due to decreased
blood pressure. Although we did not measure the absolute distensibility
{the property of conductance vessels which contribute to
propagate the pressure pulse and to buffer stroke volume
[expressed as diameter/(diameter × pressure)]
(16)}, we can assume that the changes in aortic distension after
Hb infusion are caused by increased wall stress elicited by increased
blood pressure.
As discussed above, the impact of the viscosity of Alb and Hb solutions
was similar at the macrohemodynamic level; thus the alterations in MAP,
VR, and aortic distension can basically be attributed to the Hb-induced
vasoconstriction. Many mechanisms have been proposed to explain the
vasoconstrictor action of Hb: 1)
inhibition of the NO-dependent vascular smooth muscle relaxation by
NO-scavenging action of free Hb (4, 9, 14, 15, 23), 2) sensitization of -adrenergic
receptors (7, 26), 3) involvement of
endothelin (8), and 4) increase in
microcirculation vascular tone as a response to increased blood
O2-carrying capacity (13, 20, 21).
Comparison of Dex-BTC-Hb, -Hb, and
PolyHb effects.
The three solutions were prepared from human Hb that
was extracted from outdated banked red blood cells according to
specific protocols previously described (11, 12, 22, 28). The three Hb
solutions are isosmolar to plasma, but each solution has specific physicochemical properties, the contribution of which to the
hemodynamic effects cannot be absolutely defined (Table 1). There is a
clear difference in oncotic pressure between Dex-BTC-Hb and -Hb
vs. PolyHb that would differentially affect the plasma volume expansion ability of the solutions (18). This could explain at least in part the
large increase in aortic blood flow after administration of Dex-BTC-Hb,
as a result of an increase in preload. However, the colloid oncotic
pressure measured in vitro is only an approximation of the oncotic
behavior of the macromolecules in vivo, and the exact quantitative
effect is unknown.
-Hb,
(administered dose, 3.1 g) and was higher for PolyHb (administered dose, 3.7 g). The concentration of plasma Hb was dose dependent, because it was higher in PolyHb group vs. Dex-BTC-Hb and -Hb (Fig. 1C). The plasma retention
times, estimated from the data shown in Fig.
1C, indicated that -Hb had a
shorter half-life (~4 h) than Dex-BTC-Hb (~6 h) and PolyHb (~7 h)
in this experimental model. Despite these differences, we could have
expected that the impact of the dose administered on the blood pressure
was similar, because only a small dose of free Hb is necessary to achieve maximal pressor effect immediately (plateau effect). The three
Hb solutions induced a significant increase in MAP, with specific
increments for each of the solutions (Fig. 3). Dex-BTC-Hb and -Hb
induced a significant rise in MAP compared with preexchange values for
3 h, whereas the increase with PolyHb was no longer significant after 2 h. There was also a progressive rising trend in the VR in
Dex-BTC-Hb and -Hb groups, whereas VR increased until 60 min and
was stable thereafter in the PolyHb group (Fig. 5). In contrast,
statistical comparisons indicated that Dex-BTC-Hb, -Hb, and
PolyHb had similar acute effects on HR, aortic blood flow, femoral
blood flow, and aortic distension (Figs. 3-5).
As discussed previously, despite large differences in viscosity between
Dex-BTC-Hb vs. -Hb and PolyHb (Table 1), the rheological properties of the Hb solutions had limited impact on the hemodynamic changes (Fig. 2). The differences in the pressor action elicited by the
solutions could instead be attributed to the specific permeability characteristics of the modified Hbs. The NO-scavenging action and the
role it plays in inhibiting vasodilator mechanisms are indeed thought
to be related to the leakage of Hb across the endothelial barrier into
the space directly surrounding the smooth muscle cells (1, 19). The
polymerization of Hb, aiming to increase its molecular size, would
hence result in an impaired penetration into the vascular wall (1, 19)
and could explain the limited vasoconstricting action of PolyHb
compared with -Hb and Dex-BTC-Hb. The structural modification of
the heme pocket induced by the chemical modifications applied to Hb,
and thereby the changes in affinity of the heme moiety for NO, is
another factor likely to be involved in the different cardiovascular
effects of the solutions. The accessibility to the 
93 cysteine
residue of the globin, known to react with NO and thus to contribute to
its transport by Hb (14), may also be different from one solution to
another, thus resulting in different vasoactive effects. The
interaction of Hb with other regulatory elements involved at the
vascular wall level (endothelin, -adrenergic receptors) could also
be specific to the type of modification applied to Hb and requires further investigation.
In summary, Dex-BTC-Hb, -Hb, and PolyHb have
specific vasoactive effects, but in regard to the multiple parameters
possibly involved, the proper action of the chemical modification is
difficult to establish in vivo. The contribution of viscosity to the
macrohemodynamic changes induced seems, however, to be blunted by the
vasoconstricting properties of Hb solutions.
| |
ACKNOWLEDGEMENTS |
|---|
We are grateful to Hemosol, Inc., for supplying o-raffinose polymerized hemoglobin. Calculations were performed with software developed by Michel Dubuit (Centre Interuniversitaire de Ressources Informatiques de Lorraine, Vandoeuvre-lès-Nancy, France).
| |
FOOTNOTES |
|---|
This research was supported in part by the Association Recherche et Transfusion, Paris, France.
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. §1734 solely to indicate this fact.
Address for reprint requests: A. Caron, Laboratoire d'Hématologie et de Physiologie, Faculté de Pharmacie, 5 rue Albert Lebrun, 54001 Nancy cedex, France (E-mail: caron{at}pharma.u-nancy.fr).
Received 8 April 1998; accepted in final form 5 October 1998.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
1.
Abassi, Z.,
S. Kotob,
F. Pieruzzi,
M. Abouassali,
H. R. Keiser,
J. C. Fratantoni,
and
A. I. Alayash.
Effects of polymerization on the hypertensive action of diaspirin cross-linked hemoglobin in rats.
J. Lab. Clin. Med.
129:
603-610,
1997[Medline].
2.
Birchard, G. F.
Optimal hematocrit: theory, regulation and implications.
Am. Zool.
37:
65-72,
1997.
3.
Cole, D. J.,
J. C. Drummond,
P. M. Patel,
J. C. Nary,
and
R. L. Applegate.
Effect of oncotic pressure of diaspirin cross-linked hemoglobin (DCLHb) on brain injury after temporary focal cerebral ischemia in rats.
Anesth. Analg.
83:
342-347,
1996[Abstract].
4.
Collins, P.,
J. Burman,
H. I. Chung,
and
K. Fox.
Hemoglobin inhibits endothelium-dependent relaxation to acetylcholine in human coronary arteries in vivo.
Circulation
87:
80-85,
1993[Medline].
5.
Cooper, J. R.,
and
S. Slogoff.
Hemodilution and priming solutions for cardiopulmonary bypass.
In: Cardiopulmonary Bypass: Principles and Practice, edited by G. P. Gravlec,
R. F. Davis,
and J. R. Utley. Baltimore, MD: Williams & Wilkins, 1993, p. 124-137.
6.
Dietz, N. M.,
C. M. Martin,
A. G. Beltran-del-Rio,
and
M. J. Joyner.
The effects of cross-linked hemoglobin on regional vascular conductance in dogs.
Anesth. Analg.
85:
265-273,
1997[Abstract].
7.
Gulati, A.,
and
S. Rebello.
Role of adrenergic mechanisms in the pressor effect of diaspirin cross-linked hemoglobin.
J. Lab. Clin. Med.
124:
125-133,
1994[Medline].
8.
Gulati, A.,
A. P. Sen,
A. C. Sharma,
and
G. Singh.
Role of ET and NO in resuscitative effect of diaspirin cross-linked hemoglobin after hemorrhage in rat.
Am. J. Physiol.
273 (Heart Circ. Physiol. 42):
H827-H836,
1997
9.
Hart, J. L.,
M. A. Ledvina,
and
S. M. Muldoon.
Actions of diaspirin cross-linked hemoglobin on isolated rat and dog vessels.
J. Lab. Clin. Med.
129:
356-363,
1997[Medline].
10.
Haywood, J. R.,
R. A. Schaffer,
C. Fastenow,
G. D. Fink,
and
M. J. Brody.
Regional blood flow measurement with pulsed Doppler flowmeter in conscious rat.
Am. J. Physiol.
241 (Heart Circ. Physiol. 10):
H273-H278,
1981
11.
Hsia, J. C. Pasteurizable,
freeze-driable hemoglobin-based blood substitute. US
Pat. 4,857,636. 15 Aug. 1989.
12.
Hsia, J. C.
o-Raffinose polymerized hemoglobin as a red blood cell substitute (Abstract).
Biomater. Artif. Cells Immobilization Biotechnol.
19:
402,
1991.
13.
Intaglietta, M.,
P. C. Johnson,
and
R. M. Winslow.
Microvascular and tissue oxygen distribution.
Cardiovasc. Res.
32:
632-643,
1996[Medline].
14.
Jia, L.,
C. Bonaventura,
J. Bonaventura,
and
J. S. Stamler.
S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control.
Nature
380:
221-226,
1996[Medline].
15.
Kim, H. W.,
and
A. G. Greenburg.
Hemoglobin mediated vasoctivity in isolated vascular rings.
Artif. Cells Blood Substit. Immobil. Biotechnol.
23:
303-309,
1995[Medline].
16.
Marchais, S. J., A. P. Guerin, B. Pannier, G. Delavaud, and G. M. London. Arterial compliance and
blood pressure. Drugs 46, Suppl. 2: 82-87, 1993.
17.
Menu, P.,
B. Faivre,
P. Labrude,
P. Riffard,
M. Grandgeorge,
and
C. Vigneron.
Human hemoglobin conjugated to carboxylate dextran as a potential red blood cell substitute. II. Pharmacotoxicological evaluation.
Biomater. Artif. Cells Immobilization Biotechnol.
22:
551-558,
1994.
18.
Migita, R.,
A. Gonzales,
M. L. Gonzales,
K. D. Vandegriff,
and
R. Winslow.
Blood volume and cardiac index in rats after exchange transfusion with hemoglobin-based oxygen carriers.
J. Appl. Physiol.
82:
1995-2002,
1997
19.
Nakai, K.,
T. Ohta,
I. Sakuma,
K. Akama,
Y. Kobayashi,
S. Tokuyama,
A. Kitabatake,
Y. Nakazato,
T. A. Takahashi,
and
S. Sadayoshi.
Inhibition of endothelium-dependent relaxation by hemoglobin in rabbit aortic strips: comparison between acellular hemoglobin derivatives and cellular hemoglobins.
J. Cardiovasc. Pharmacol.
28:
115-123,
1996[Medline].
20.
Nolte, D.,
A. Botzlar,
S. Pickelmann,
E. Bouskela,
and
K. Messmer.
Effetcs of diaspirin-cross-linked hemoglobin (DCLHb) on the microcirculation of striated skin muscle in the hamster: a study on safety and toxicity.
J. Lab. Clin. Med.
130:
314-327,
1997[Medline].
21.
Nolte, D.,
P. Steinhauser,
S. Pickelmann,
S. Berger,
R. Härtl,
and
K. Messmer.
Effects of diaspirin-cross-linked hemoglobin (DCLHb) on local tissue oxygen tension in striated skin muscle: an efficacy study in the hamster.
J. Lab. Clin. Med.
130:
328-338,
1997[Medline].
22.
Prouchayret, F.,
G. Fasan,
M. Grandgeorge,
C. Vigneron,
P. Menu,
and
E. Dellacherie.
A potential blood substitute from carboxylic dextran and oxyhemoglobin. I. Preparation, purification and characterization.
In: Blood Substitutes and Oxygen Carriers, edited by T. M. S. Chang. New York: Dekker, 1993, p. 144-147.
23.
Rioux, F.,
G. Drapeau,
and
F. Marceau.
Recombinant human hemoglobin (rHb1.1) selectively inhibits vasorelaxation elicited by nitric oxide donors in rabbit isolated aortic rings.
J. Cardiovasc. Pharmacol.
25:
587-594,
1995[Medline].
24.
Rohlfs, R. J.,
E. Bruner,
A. Chiu,
A. Gonzales,
M. L. Gonzales,
D. Magde,
M. D. Magde, Jr.,
K. D. Vandegriff,
and
R. M. Winslow.
Arterial blood pressure responses to cell-free hemoglobin solutions and the reaction with nitric oxide.
J. Biol. Chem.
273:
12128-12134,
1998
25.
Scott, M. G.,
D. F. Kucik,
L. T. Goodnough,
and
T. G. Monk.
Blood substitutes: evolution and future applications.
Clin. Chem.
43:
1724-1731,
1997
26.
Sharma, A. C.,
and
A. Gulati.
Yohimbine modulates diaspirin crosslinked hemoglobin-induced systemic hemodynamics and regional circulatory effects.
Crit. Care Med.
23:
874-884,
1995[Medline].
27.
Spahn, D. R.,
B. J. Leone,
J. G. Reves,
and
T. Pasch.
Cardiovascular and coronary physiology of acute isovolemic hemodilution: a review of nonoxygen-carrying and oxygen-carrying solutions.
Anesth. Analg.
78:
1000-1021,
1994
28.
Winslow, R. M.,
and
K. W. Chapmann.
Pilot scale preparation of hemoglobin solutions.
In: Methods in Enzymology. Hemoglobins, Biochemical and Analytical Methods, edited by J. Everse,
K. D. Vandegriff,
and R. M. Winslow. Orlando, FL: Academic, 1994, vol. 231, part B, p. 3-16.
This article has been cited by other articles:
|
|
 |
|
  R. O. Dull, B. J. DeWitt, R. Dinavahi, L. Schwartz, C. Hubert, N. Pace, and C. Fronticelli Quantitative assessment of hemoglobin-induced endothelial barrier dysfunction J Appl Physiol, November 1, 2004; 97(5): 1930 - 1937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Rochon, A. Caron, M. Toussaint-Hacquard, A. I. Alayash, M. Gentils, P. Labrude, J. F. Stoltz, and P. Menu Hemodilution With Stoma-Free Hemoglobin at Physiologically Maintained Viscosity Delays the Onset of Vasoconstriction Hypertension, May 1, 2004; 43(5): 1110 - 1115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kavdia, R. N. Pittman, and A. S. Popel Theoretical analysis of effects of blood substitute affinity and cooperativity on organ oxygen transport J Appl Physiol, December 1, 2002; 93(6): 2122 - 2128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Jahr, F. Lurie, S. Xi, M. Golkaryeh, O. Kuznetsova, R. Kullar, and B. Driessen A Novel Approach to Measuring Circulating Blood Volume: The Use of a Hemoglobin-Based Oxygen Carrier in a Rabbit Model Anesth. Analg., March 1, 2001; 92(3): 609 - 614. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Caron, P. Menu, B. Faivre-Fiorina, P. Labrude, A. Alayash, and C. Vigneron Systemic and renal hemodynamics after moderate hemodilution with HbOCs in anesthetized rabbits Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1974 - H1983. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
