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in rat tissues:
TmDOTP5 vs.
CoEDTA as markers of
extracellular tissue space
1 Department of Chemistry, The distribution
of TmDOTP5
extracellular space marker; intracellular sodium; tissue
distribution
THERE IS CONSIDERABLE INTEREST in monitoring and
measuring the concentration of intracellular Na in intact cells,
perfused tissue, and in vivo (12, 21, 27, 30). The most common analytical methods available for measuring Na in biological tissue include ion-selective microelectrodes, fluorescent indicator dyes, atomic absorption spectroscopy (AAS), and nuclear magnetic resonance (NMR) spectroscopy. The first method measures Na activity directly and
does not require knowledge of intracellular or extracellular volumes.
Although extracellular ions are most commonly detected by using
microelectrodes (16), intracellular measurements are possible in single
cells. The second method relies on introducing an Na-sensitive ligand
into the intracellular space (5). Again, this method does not require
knowledge of the intracellular volume and is usually limited to studies
of isolated cells. The last two analytical methods do require an
independent estimate of the volume of the intracellular space and
extracellular space (ECS).
Traditionally, the volume of the ECS is measured by using a chemical
marker that is known to be confined to that space. An ideal marker must
be noninvasive, chemically stable and not degraded by the tissue, have
high analytical sensitivity, and distribute rapidly and uniformly into
all ECS. Common ECS markers include various inert, negatively charged
transition metal complexes (6, 28) and various inert sugars such as
inulin, sucrose, and sorbital (17, 18). These markers can be
quantitated by enzymatic assay, using radiolabeled materials, or, in
the case of metal complexes, by either AAS or emission spectroscopy.
58CoEDTA Each of the above methods is, by necessity, destructive. NMR offers the
potential to monitor intracellular space and ECS completely noninvasively. Although these techniques have been demonstrated most
often in studies of isolated cells and perfused organs, NMR methods can
in principle be applied in vivo. A combination of 1H- and
59Co-NMR using the water signal as
a measure of total volume and Co(CN)3 In the present study,
thulium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene
phosphonate) (TmDOTP5 All protocols were approved by the University's Institutional Animal
Care and Research Advisory Committee. Male Sprague-Dawley rats
(260-390 g) were initially anesthetized with a 0.5-ml
intramuscular injection of ketamine (87 mg/ml) and xylazine (13 mg/ml).
A tracheotomy was performed to ensure a clear breathing passageway
throughout the experiment. The animals were not ventilated. The carotid
artery and one jugular vein were cannulated through a midline neck
incision. The line from the carotid artery was used to collect blood
samples while the line from the jugular vein was used to administer 80 mM TmDOTP5 Three different infusion studies were performed. In the first, 80 mM
TmDOTP5 In the third type of infusion experiment, 80 mM
TmDOTP5 Sample preparation and atomic absorption
methods. Urine and blood samples were diluted 1:50 (or
as needed) for Tm, Co, Na, Mg, and Ca determinations by AAS. Each
tissue sample was digested in 2 ml of an acid mixture containing 5:1:1
concentrated nitric, sulfuric, and perchloric acids, respectively. The
tissue digests were heated at 60°C overnight in a water bath. After
cooling, the digests were diluted to 10 ml, then diluted again as
needed. KCl at a final concentration of 2,000 parts/million was added to all samples to prevent overionization of Na (24). A Varian SpectrAA-5 atomic absorption spectrometer was used to analyze samples
for Tm, Na, Co, Mg, and Ca at 372.2, 330.2, 241.0, 285.2, and 239.9 nm,
respectively. Tm and Co were measured in a nitrous oxide-acetylene
flame, whereas Na, Mg, and Ca were measured in an air-acetylene flame.
Pharmacokinetic model. A kinetic model
was generated by using ModelMaker 3.0 (Cherwell Scientific, Oxford, UK)
and used to predict the appearance of Tm (as detected by AAS) in urine
with time after an initial intravenous infusion of 0.15 mmol of
TmDOTP5 Statistical data analysis. All data
are means ± SD. Statistical significance was determined by using
ANOVA or the Student t-test, as
appropriate. A P value < 0.05 was
considered significant.
TmDOTP5
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
in rat tissue
was compared with CoEDTA,
an anionic complex previously used as a marker of extracellular space.
Heart, liver, muscle, blood, and urine were collected from rats after
infusion of either complex and were quantitatively analyzed by atomic
absorption spectroscopy. Although total
TmDOTP5 in blood and tissue
was consistently lower (0.88 ± 0.04;
n = 6) than
CoEDTA after an identical
infusion protocol (presumably because of some association of the
phosphonate complex with bone), a comparison of blood and tissue
contents indicated that the two anionic complexes distributed into
identical extracellular spaces. Relative extracellular space in the in
vivo liver, as determined by
TmDOTP5 and
CoEDTA, was 0.18 ± 0.02 and 0.15 ± 0.01, respectively. The corresponding relative
extracellular space values for the in vivo heart reported by the two
agents were identical (0.11 ± 0.02). Experiments were also
performed to evaluate the washout kinetics of
TmDOTP5 from anesthesized
rats. In rats given a total dose of 0.16 mmol TmDOTP5, 81% appeared in
urine by 180 min, <2% was found in all remaining soft tissue,
leaving ~18% undetected. The rate of Tm appearance in urine was fit
to a standard pharmacokinetic model that included four tissue
compartments: plasma, one fast equilbrating space, one slow
equilibrating space, and one very slow equilibrating space (presumably
bone). The best fit result suggests that the highly charged
TmDOTP5 complex is cleared
from plasma more rapidly than is the typical lower charged Gd-based
contrast agents and that release from bone is slow compared with renal clearance.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
,
a gamma-emitting isotope of cobalt, has been used as an ECS marker and
found to measure the same space as
[14C]sucrose (7).
Nonradioactive CoEDTA has
also been successfully used to measure ECS, with Co being determined by
AAS (25).
6 as an ECS marker has been
used both in isolated cell studies (28) and in perfused tissues (1, 13). 31P-NMR methods, first
demonstrated by Kirk and Kuchel (15), using a combination of neutral
phosphorus-containing markers that distribute into all water space and
of charged phosphonates markers that are restricted to the ECS, have
also become popular (9).
)
was compared with CoEDTA as
a marker of ECS in the in vivo heart and liver. The concentrations (marked by brackets) of Tm, Co, and Na in tissue and blood were determined by AAS, and the
[Tm]tissue/[Tm]plasma
ratio (or
[Co]tissue/[Co]plasma ratio) was used to determine the volume of the ECS. Given the ECS and
relative dry weight (rDW) of the tissue, intracellular Na
concentration
([Na+]i)
was evaluated by measuring the difference between total tissue and
plasma Na, as originally described by Scheufler and Peters for perfused
hearts (25). Additional experiments were performed to compare the
biodistribution of TmDOTP5
and CoEDTA and to measure
the rate of clearance of
TmDOTP5 from live animals.
The later kinetic data agreed well with an established pharmacokinetic
model for clearance of negatively charged contrast-agent complexes from
three tissue compartments.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
or 80 mM
CoEDTA. Stock solutions of
TmDOTP5 and
CoEDTA were prepared from
Na4HTmDOTP (Magnetic Resonance
Solutions, Dallas, TX) and KCoEDTA (10), respectively.
were infused at 2 ml/h (6 min), 4 ml/h (6 min), 6 ml/h (6 min), 8 ml/h (6 min), and 6 ml/h (81 min) while the blood samples were periodically withdrawn for
determination of total Tm, Na, Mg, and Ca by AAS. In the second, either
80 mM TmDOTP5 or 80 mM
CoEDTA was infused at 2 ml/h (6 min), 4 ml/h (6 min), 6 ml/h (6 min), and 8 ml/h (6 min).
Animals were then killed, and the heart, liver, one kidney, and one
thigh muscle were freeze-clamped and weighed. All urine was collected
from the bladder, a sample of blood was taken, and one femur removed
and cleaned free of tissue. The tissues were dissolved in a 5:1:1
mixture of nitric, sulfuric, and perchloric acids, respectively, and Tm
or Co in each tissue type (expressed as a percentage of total metal ion
infused) was determined by AAS. The femur appeared to dissolve
completely in hot acid, but an insoluble precipitate that later
formed precluded quantitation of Tm and Co in this tissue.
were infused at 2 ml/h (6 min), 4 ml/h (6 min), 6 ml/h (6 min), and 8 ml/h (6 min),
followed by infusion of normal saline at 6 ml/h for an additional
period of 156 min. This experiment was performed to evaluate washout of
TmDOTP5 from tissues and
appearance of TmDOTP5 in
urine. During prolonged infusions, 100 µl of anesthetic were injected
into a muscle every 30 min to maintain proper anesthesia. All animals
were positioned supine on a small heating pad to maintain normal body
temperature. The bladder was catheterized to collect urine samples.
Blood samples were withdrawn from the arterial line before, during, and
after the infusion period. All tissue samples were blotted to remove
excess blood, weighed wet, dried at 60°C overnight, then reweighed
to determine a dry-to-wet ratio.
at a known rate.
The model was equivalent to that of Wedeking et al.
(31), who described the pharmacokinetics of
GdDTPA2 and
99MTcDTPA in rats and included
three exchanging compartmental spaces: plasma, a fast exchanging space
(FES), and a slow exchanging space (SES) plus a urine compartment. The
kinetic rate constants for movement of
TmDOTP5 between these
compartments and into urine were initially set equal to those given by
Wedeking et al. (31) and later altered to optimize the fit to our
experimental data.
RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
infusions over extended
periods.
As reported previously (2, 3, 26), infusion of 80 mM
TmDOTP5 into rats by using
the infusion protocol outlined in MATERIALS AND
METHODS produces a modest decrease in mean arterial
blood pressure. Blood samples removed from rats during such a protocol have been analyzed for total Tm, Ca, and Mg by AAS; those results are
shown in Fig. 1. Although total
concentations of Ca and Mg ([Ca2+]tot
and
[Mg2+]tot,
repectively) in blood tended to drop during early periods of
TmDOTP5 infusion (compare
0- to 10- vs. 13- to 18-min infusion periods), these
differences were not significant. Thereafter,
[Mg2+]tot
remained constant throughout the remaining infusion periods, whereas
[Ca2+]tot
increased in proportion to total concentration of
TmDOTP5 (Fig.
2). A linear regression of the
[Ca2+]tot
data shown in Fig. 2 (n = 12 animals)
indicated that
[Ca2+]tot = 0.30 ± 0.05 TmDOTP5
concentration + 1.81 ± 0.13.
View larger version (20K):
[in a new window]
Fig. 1.
Average values of total Tm, Mg, and Ca in plasma from animals during
infusion of TmDOTP5 by
using standard protocol outlined under MATERIALS AND
METHODS. Value represented by each bar represents mean ± 1 SD for blood samples collected
(n = 6) during intervals shown (time
at which blood samples were collected for each animal varied
slightly).
View larger version (15K):
[in a new window]
Fig. 2.
Plot of total concentrations of
Ca2+ ( 
) and
Mg2+ (
) vs.
total concentration of
TmDOTP5 in plasma samples
obtained from a larger group of animals
(n = 12) during infusion of shift
reagent when using protocol described in MATERIALS AND
METHODS.
or 80 mM
CoEDTA was infused into
live animals for 24 min by using the protocol described in
MATERIALS AND METHODS. The infusions
were then discontinued, and the heart, liver, one thigh muscle, and one
kidney were removed, a blood sample was collected, and urine was
collected from the bladder. All tissues were analyzed for total Co and
Tm by AAS. Total Tm and Co levels in all skeletal muscle were
determined from the thigh muscle analyses by assuming that skeletal
muscle was 45% of total animal body weight (8). Similarly, total Tm and Co concentrations in blood were determined by assuming that total
blood volume was 6.5% of total body weight (11). Those results,
expressed as percentage of total
TmDOTP5 or
CoEDTA infused at 24 min,
are shown in Fig. 3. These data show that the tissue distribution of the two ECS markers paralleled one another,
but percent Tm was typically lower than percent Co (this was especially
evident in those tissues containing greater amounts of ECS marker, such
as kidney, muscle, blood, and urine). The average Tm/Co in kidney,
muscle, blood, and urine was 0.88 ± 0.04. Because the amount
detected in heart and liver was relatively small, the Tm/Co ratio was
not significantly different from unity in those tissues.
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, but not of
CoEDTA. To examine this
question further, we measured the washout kinetics of
TmDOTP5 from tissue after
an initial infusion of the ECS marker for 24 min, followed by continued
infusion of normal saline for an additional 156 min. The experimental
data for appearance of Tm in urine during infusion of saline are shown
in Fig. 4 (experimental points on top
curve). At 180 min, the infusion was discontinued, and tissues were removed and analyzed as described above. An analysis of those data
indicated that ~81% of the total
TmDOTP5 infused after 24 min (0.15 mmol) was found in urine, but <2% was found in liver,
thigh muscle, kidney, heart, and blood at 180 min. Thus ~18% of the
TmDOTP5 could not be
accounted for in those tissues examined at 180 min. This is shown as
the single data point on the curve labeled "bone" in Fig. 4 (see
below).
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[Na+]i
and relative ECS in tissue.
Although the absolute amount of
TmDOTP5 and
CoEDTA in the various
tissues does appear to differ after an identical infusion period, the
ratio of marker in tissue to blood plasma was constant. Assuming that
[Tm]plasma = [Tm]ECS,
[Co]plasma = [Co]ECS, and [Na]plasma = [Na]ECS after a
suitable equilibration period, the relative ECS (rECS), and hence the
[Na+]i,
could be determined by using the method outlined in Scheufler and
Peters (25). The relevant equations are as follows
![rECS = [Tm]<SUB>tissue</SUB>/[Tm]<SUB>plasma</SUB> or [Co]<SUB>tissue</SUB>/[Co]<SUB>plasma</SUB>](/content/vol85/issue5/fulltext/1800/img001.gif)
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(1) |
![[Na<SUP>+</SUP>]<SUB>i</SUB> = [Na<SUP>+</SUP>]<SUB>tissue</SUB>](/content/vol85/issue5/fulltext/1800/img002.gif)
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![− (rECS × [Na<SUP>+</SUP>]<SUB>plasma</SUB>)]/(1 − rECS − rDW)](/content/vol85/issue5/fulltext/1800/img003.gif)
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(2) |
or CoEDTA are summarized in
Table 1. These parameters were not
significantly different (P < 0.05)
for the two ECS markers in either heart or liver (although values for
the two tissues did differ). Both markers indicated that rECS was
larger and rDW was smaller in heart than in liver. Despite these
differences,
[Na+]i
did not differ between the two tissues.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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TmDOTP5 has been shown to
be effective as an in vivo shift reagent for resolving
23Na-NMR signals of intra- and
extracellular Na+ (2, 3, 19, 22,
26). Prior NMR experimental results suggest that this compound
distributes into all ECS and does not cross the blood-brain barrier
(2). The highly charged phosphonate surface of this molecule does,
however, clearly alter Ca2+
homeostasis. Although free Ca2+
concentration (as measured by a Ca-specific electrode; see Ref. 3) has been shown to decrease by ~10-20% during
infusion of TmDOTP5 into
rats, the data shown here indicated that
[Ca2+]tot
does increase in parallel with total shift reagent concentration in
blood (see Fig. 2). The shift reagent is also known to
bind divalent Mg2+ (with a lower
affinity than Ca2+; see Ref. 23),
but analysis of total blood Mg2+
indicated that the concentration of this ion was not substantially altered during infusion of
TmDOTP5 into live rats.
This apparent difference in homeostasis between Ca2+ and
Mg2+ parallels the affinity of
TmDOTP5 for these two ions
(23).
The tissue distribution of
TmDOTP5 in live
anesthetized rats parallels the distribution of
CoEDTA in heart, liver,
kidney, muscle, blood, and urine after infusion of identical amounts of
each ECS marker (Fig. 3). Although the absolute amount in each tissue
was lower for TmDOTP5 than
for CoEDTA, these data show
that both compounds act as typical low- molecular-weight extracellular
agents. The AAS results (Table 1) indicate that both compounds were
equally effective as markers of ECS in heart and liver. rECS was
smaller in the in vivo hearts (average 0.16) than in isolated perfused
hearts (1), reflecting the known tendency of isolated, perfused hearts
to become edematous. rECS, as measured by either marker in the in vivo
rat liver (0.11 ± 0.02), was significantly lower than rECS for the
in vivo heart (0.16 ± 0.03), but
[Na+]i
in the two tissues was identical. Mavroudis et al. (20) have reported
values of rECS = 0.15 and
[Na+]i = 20.2 mM for in vivo rat heart using radioactive inulin as an ECS
marker. Both agree well with values found here with the use of either
TmDOTP5 or
CoEDTA as an ECS marker.
Blum et al. (4) and Bansal et al. (2) have measured
[Na+]i
in the in vivo rat liver using NMR techniques, finding values of 26 ± 7 and 21 ± 6, respectively. Again, both agree well with the
values determined here by AAS.
The in vivo clearance rate of
TmDOTP5 has been measured
previously by NMR in rat kidney (26), liver (3), and skeletal muscle
(2). The shift reagent was found to clear with similar time constants
from kidney and liver (12-13 min) but with a longer time constant
from muscle (53 min). These results were consistent with elimination of
TmDOTP5 from at least two
tissue compartments with different time constants, similar to that
observed for anionic MRI contrast agents (31). Data presented here
indicate that ~18% of the total
TmDOTP5 infused into
animals was not detected in the tissues after 180 min. Because highly
charged phosphonates of this type are known to localize on bone
surfaces (29), a reasonable assumption is that much of the missing
TmDOTP5 remained bound to
bone after the 180-min washout period (we were unable to fully dissolve
bone for quantitative analysis by AAS). G. Kiefer (unpublished
observations) has examined the biodistribution of
159GdDOTP5
in rats and found that 55% of the total injected radioactive dose was
localized on bone surfaces after 30 min. When this experiment was
repeated by using
159GdDOTP5
doped with millimolar quantities of unlabeled
GdDOTP5, ~25% was found
tightly bound to bone after 2 h (G. Kiefer, unpublished observations).
This suggests that the binding sites for these highly charged complexes
on bone surfaces may be saturable.
The clearance data of Fig. 4 appear to be minimally biphasic,
consistent with a combined rapid clearance of
TmDOTP5 from blood plus
slower clearance from less highly perfused tissue such as muscle and,
perhaps, bone. Using the kinetic constants reported by Wedeking et al.
(31) for charged contrast-agent complexes, we initially modeled the
data of Fig. 4 to a three-compartment model, including plasma, a FES,
and a SES. That model predicted that the appearance of Tm in urine
would continually increase with time (even after 180 min) and not level
off as the experimental data show. This means that either the kinetic
rate constants reported by Wedeking et al. (31) are too slow to model
the TmDOTP5 data well or
the model is too simple. Subsequently, a fourth, even slower
exchanging, space was added to the model [labeled as bone in Fig.
4, based on the biodistribution data of G. Kiefer (unpublished
observations)], and the kinetic constants were adjusted so that
total Tm on bone at 180 min equaled the missing 18% (0.028 mmol) that
we failed to detect in the remaining tissues in our experiments. The
solid curves of Fig. 4 show the time-dependent distribution of
TmDOTP5 predicted by this
model. The kinetic rate constants for distribution between the plasma,
FES, SES, and urine were double those reported by Wedeking
et al. (31), and the rate of
TmDOTP5 removal from bone
was an order of magnitude slower than the remaining kinetic constants.
Because we do not have plasma levels of Tm during the 180-min washout
period, we cannot say with any certainty that this kinetic model is
unique, but the general shape of the appearance of
TmDOTP5 in urine agrees
reasonably well with that observed. The poorest agreement between the
results predicted by this kinetic model and the experimental data comes
at the early time points. This may be due to a short time delay between
collection of TmDOTP5 in
the tubules of the kidney and its actual appearance in the bladder.
Two other pieces of experimental evidence suggest that the model
presented in Fig. 4 is reasonable. First, the time constants for
washout of TmDOTP5 from
liver (3) and kidney (26) have been measured at 12-13 min, whereas
the time constant for washout from muscle was considerably longer (53 min; Ref. 2). These time constants are similar to those predicted by
the kinetic model for washout of
TmDOTP5 from the FES (17 min) and SES (38 min), respectively. Second, if one estimates the blood
volume of a 225-g rat at 14.6 ml (6.5%; Ref. 11), then the
concentration of TmDOTP5 in
plasma at 24 min according to the model would be ~1.7 mM, similar to
that found experimentally (Fig. 1).
In summary, we have shown that
TmDOTP5 can be used as a
marker of all ECS in various rat tissues in vivo. The analytical
comparisons with CoEDTA,
the rates of TmDOTP5
appearance in urine, and the pharmacokinetic modeling results all
indicate that a significant fraction of
TmDOTP5 is bound to bone in
vivo. This, however, does not detract from its potential usefulness as
an ESC marker in vivo. Although the tissue samples were destroyed for
analytical purposes in the experiments reported here, the NMR hyperfine
shift properties of TmDOTP5
potentially make this a unique ECS marker for in vivo applications. We
have shown that 31P-NMR signal of
TmDOTP5 is easily detected
in tissue at levels comparable to those used here (26), so the total
amount (µmol) of ECS marker in any given volume of tissue can be
determined by 31P-NMR.
Furthermore, the magnitude of the hyperfine shift induced in the
extracellular 23Na resonance has
been shown (32) to be directly proportional to the concentration
(µmol/ml) of TmDOTP5 in
the ECS. Thus the combination of these two measurements provides a
direct measure of the ECS volume without destroying the tissue. This
unique feature of TmDOTP5
has allowed us to monitor both the extracellular and intracellular concentrations of Na+ in vivo
(32).
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ACKNOWLEDGEMENTS |
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The technical help of Andrea Wiethoff and Martha Germann is gratefully acknowledged.
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FOOTNOTES |
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This research was supported in part by a Division of Research Resources Biomedical Magnetic Resonance Facility Grant P41-RR-02584, a grant from the Robert A. Welch Foundation (AT-584), and by a Clinical Investigator Award from the Department of Veterans Affairs.
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. D. Sherry, Dept. of Radiology, The Mary Nell & Ralph B. Rogers Magnetic Resonance Center, Univ. of Texas Southwestern Medical Center, 5801 Forest Park Rd., Dallas, TX 75235-9085.
Received 27 January 1998; accepted in final form 14 July 1998.
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
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