Influence of Tail Versus Cardiac Sampling On Blood Glucose and Lipid Profiles in Mice

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Original Article

Influence of tail versus cardiac sampling on blood glucose


and lipid profiles in mice

Yih Kai Chan1, Paul F Davis2,3, Sally D Poppitt1,4, Xueying Sun5, Nicholas S Greenhill2,3,
Rita Krishnamurthi5, Aneta Przepiorski5, Anne-Thea McGill1,6 and Geoffrey W Krissansen5
1
Human Nutrition Unit, The University of Auckland, Auckland, New Zealand; 2Bioactivity Investigation Group, Department of Medicine,
University of Otago, Wellington, Wellington South, New Zealand; 3Trinity Bioactives Ltd, Wellington, New Zealand; 4School of Biological
Sciences, The University of Auckland, Auckland, New Zealand; 5Department of Molecular Medicine & Pathology, Faculty of Medical and
Health Sciences, University of Auckland, New Zealand; 6School of Population Health, The University of Auckland, Auckland, New Zealand
Corresponding author: G W Krissansen. Email: gw.krissansen@auckland.ac.nz

Abstract
Blood is collected during animal experimentation to measure haematological and metabolic parameters. It cannot be
assumed that circulating blood has the same composition irrespective of its location, and indeed, differences in the
composition of blood sampled from the arterial and venous compartments have been reported. Here we investigated whether
blood collected by cardiac puncture (CP) versus that collected following removal of the distal 1 mm of the tail tip (TT) differs
with respect to glucose and lipid profiles in male C57BL/6J mice at 4, 7, 20 and 28 weeks of age. Blood was first collected
from the TT of unanaesthetized mice, which were then immediately anaesthetized using ketamine/xylazine, and a second
blood sample was collected by CP. The CP glucose concentration was significantly higher than TT glucose by a positive bias
averaging þ80% (P , 0.01), irrespective of the age of the mice. Conversely, the concentrations of the CP lipids, including total
cholesterol, high-density lipoprotein cholesterol and triglyceride were lower than TT lipids by a negative bias averaging 225%
(P , 0.05). These observations highlight the difficulty in measuring and comparing metabolic parameters such as glucose and
lipid between one blood compartment and another. They illustrate the need to standardize sampling sites, especially when
repeated blood sampling is required.

Keywords: Metabolic parameters, blood sampling site, glucose, lipids, C57BL/6 mice

Laboratory Animals 2012; 46: 142– 147. DOI: 10.1258/la.2011.011136

Assessment of blood parameters is often used to monitor Rodents and humans share a similar cardiovascular circu-
animal health and to determine the success of dietary and latory system where the venae cavae carry deoxygenated
pharmacological intervention in preclinical animal models. blood from the tissues to the heart, which then pumps the
Cardiac puncture (CP) of anaesthetized animals is routinely blood via the pulmonary artery to the lungs. The oxyge-
used in rodent studies to collect large volumes of good nated blood is pumped back to the heart via the pulmonary
quality central circulatory blood from the heart at the ter- veins, and then to the rest of the body via the aorta. In the
mination of an experiment. Smaller aliquots of peripheral tail of the mouse, there are three veins and one artery,
blood are commonly obtained by removal of the distal hence blood collection from the TT yields both venous
1 mm of the tail tip (TT) of conscious, unanaesthetized and arterial blood.1,2 Blood collected from the heart can
animals. Sampling blood from the TT is a less invasive pro- yield venous or arterial blood or a mixture depending on
cedure that allows repeated blood collection from the same the volume taken and site of puncture. Differences in the
animal without the confounding effects of anaesthesia. It is composition of the blood in an artery or a vein have been
important to consider whether haematological and meta- widely addressed in clinical medicine and clinical
bolic measurements might differ in relation to different studies;3,4 however, direct comparison remains less well
blood sampling sites, and/or use of anaesthesia at the known in animal studies and is often ignored. In humans,
time of blood collection. More than one blood collection inconsistent differences in lipid and lipoprotein concen-
site may be used concurrently during a study, which trations in arterial and venous blood have been reported.
would potentially confound the results. Further, metabolic Miles et al.5 reported that venous plasma triglyceride
parameters are sometimes compared across studies. (TAG) concentrations were significantly lower than arterial

Laboratory Animals 2012; 46: 142 –147


Chan et al. Blood sampling site affects metabolic measurements 143
................................................................................................................................................

values in eight healthy male subjects. In contrast, Kupke diet (refer to Table 1). The temperature of the room
et al.6 reported that the concentrations of lipids and lipopro- during the study was maintained at between 18 and 228C,
teins measured in arterial blood serum were lower than in humidity of 50 and 65% and the lighting on a 12 h light
venous blood, and concluded that venous and arterial and 12 h dark cycle. Ethical reviews were undertaken by
blood serum cannot be used interchangeably for these Animal Ethics Committees of the University of Auckland
estimations. and Wellington School of Medicine. All procedures and
There are little published animal study data on how levels care administered to the animals were in accordance with
of haematological and metabolic parameters differ in arter- the institutional animal ethics approval.
ial and venous blood. Nevertheless, differences in the levels
of glucose obtained from arterial versus venous blood have
been documented in humans since the 1920s.4,7 – 10 The Collection of blood samples
levels of venous glucose generally reflect that of arterial TT blood: Blood samples were collected from the TT of con-
glucose under fasting conditions; however, arterial and scious, unanaesthetized mice at 4, 7, 20 and 28 weeks of age.
venous glucose levels can deviate in a similar but unpredict- Mice were fasted for 4 h on the morning of blood collection.
able manner after feeding or under a glucose load. The Animals were placed in a restrainer and the tail section was
arterial value may be anywhere from 2% higher during covered with a clean gauze swab leaving the last 5 mm
fasting to as much as 70% higher in the postprandial clear. The last 1 mm of the tip of the tail was then
state.4,7 – 10 Other haematological parameters such as removed using sterilized surgical scissors. The tail was
packed cell volume, haemoglobin, white blood cell, red placed in a serum separator tube (Becton Dickinson Cat.
blood cell and haematocrit have been reported to be No. 365956; Becton, Dickinson and Co, Franklin Lakes, NJ,
higher in venous blood samples compared with blood USA), and gently milked to ensure an adequate blood
samples obtained from the retro-orbital sinus or arterial flow. Approximately 200 mL of blood was collected on
heart of mice and rats.11 – 15 In C57BL/6 mice the total leuko- each occasion.
cyte counts obtained by CP were reported to be significantly
lower as compared with blood sourced from the saphenous Cardiac puncture: Following collection of the TT sample, the
vein, tail and foot.16 mice were immediately anaesthetized by intraperitoneal
Anaesthesia may affect the concentrations of a number of injection with ketamine (100 mg/kg body weight) and xyla-
circulating metabolites. There are reports of higher levels of zine (5 mg/kg body weight). They then underwent laparot-
glucose in blood collected from rats anaesthetized with omy and a 22 G needle attached to a 1 mL syringe was used
ether, pentobarbitone sodium or fentanyl plus droperidol to puncture through the diaphragm into the heart and
compared with manually restrained unanaesthetized 800 mL of blood was collected, representing most of the ani-
rats,17 and similar findings have been observed in keta- mal’s blood volume, and expected to be a mix of venous
mine/xylazine anaesthetized rats.18 Saha et al.19 reported and arterial blood. The blood was placed in a serum separa-
that anaesthesia with ketamine/xylazine caused acute tor tube (Becton Dickinson Cat. No. 365956).
hyperglycaemia associated with decreased insulin, adreno-
corticotropic hormone and corticosterone in fed, but not
fasted, rats. Hyperglycaemia and hypoinsulinaemia have Analyses
also been documented during ketamine/xylazine anaesthe- The blood samples were centrifuged at 3000 rpm for 10 min,
sia in thoroughbred horses.20 Hence, some commonly used and the sera were collected and transferred to fresh micro-
anaesthetics can differentially affect a number of blood par- tubes, and stored at 2808C until analysed. Blood biochem-
ameters in animal studies. istry was analysed using a Vitalab Flexor clinical chemistry
The aim of the present study therefore was to determine analyser (Vitalab Flexor E, AC Dieren, The Netherlands).
whether different blood sampling sites had a significant The serum levels of glucose were measured by the
effect on measurements of circulating concentrations hexokinase method;21 total cholesterol (TC) was measured
of glucose and lipids in male C57BL/6J mice. Blood by an enzymatic method using cholesterol esterase and
samples were collected from the TT of unanaesthetized cholesterol oxidase/peroxidase; TAG was measured by the
animals and then immediately from CP of ketamine/ lipase/glycerol kinase method; and high-density lipoprotein
xylazine anaesthetized animals at 4, 7, 20 and 28 weeks cholesterol (HDL-C) was measured by an enzymatic
of age. method using Roche assay kits (Roche Diagnostics GmbH,
Mannheim, Germany).

Materials and methods Statistical methods


Animals and housing All data are expressed as mean + standard error of the
C57BL/6J mice were sourced from the Jackson Laboratory, mean (SEM) unless otherwise stated. Cross comparisons
Bar Harbor, Maine, USA. Twenty-one-day-old male between the blood collection sites were calculated using a
C57BL/6J mice weighing between 6 and 12 g were housed paired t-test. Pearson’s correlation coefficients were calcu-
under standard conditions at five mice per conventional lated to determine associations between the blood sampling
cage with wood shavings as bedding. They had unrestricted sites and the various blood parameters. Linear regression
access to water and either the AIN93M or AIN93G rodent analyses were used to determine the partial R 2 (Microsoft
144 Laboratory Animals Volume 46 April 2012
................................................................................................................................................

Table 1 Differences in glucose, total cholesterol, triglyceride (TAG) and high-density lipoprotein cholesterol (HDL-C) concentrations between
cardiac puncture (CP) and tail tip (TT) blood
Age No. of Total cholesterol
(weeks) animals Diet Glucose (mmol/L) (mmol/L) TAG (mmol/L) HDL-C (mmol/L)
  
4 40 AIN93M control diet 10.56 (26.87 to 22.34) 20.82 (21.38 to 0.99 ) 20.38 (20.95 to 0.81 ) 20.62 (21.17 to 0.65)
(10 en% fat)
7 10 AIN93G control diet 7.43 (4.89 to 9.02) 20.92 (21.01 to 20.45) 20.18 (20.45 to 0.39)NS 20.58 (20.93 to 20.36)
(17 en% fat)
20 20 AIN93M control diet 6.41 (5.24 to 12.93) 20.47 (21.71 to 0.65) 20.13 (0.35 to 20.33)NS 20.30 (21.13 to 0.38)#
(10 en% fat)
28 20 AIN93M control diet 10.99 (8.38 to 17.09) 20.94 (20.47 to 21.22) 20.27 (20.04 to 20.32) 20.74 (20.76 to 0.2)
(10 en% fat)

Values are expressed as mean difference (range) between CP and TT bleeds


NS: not significant as compared with the TT group of mice

P , 0.01, #P , 0.05

Office Excel 2007, Professional Edition, Microsoft TT blood, yielding a mean negative bias of approximately
Corporation). P , 0.05 was considered statistically 225% (mean, SD) across all concentrations.
significant.

Discussion
Results
In the present study, we showed firstly that the commonly
Measurement of blood glucose concentrations measured metabolic parameters of glucose, TC, HDL-C
The mean glucose concentration was significantly different and TAG differed significantly between the two sampling
between blood obtained from the TT and by CP, irrespective sites irrespective of the age of the mice, with higher circulat-
of the age of the animals (Figure 1a; Table 1). CP glucose ing glucose and lower circulating lipid concentrations in CP
was significantly higher than TT glucose in 4-week-old blood. Secondly, that when all age groups were combined
(23.56 + 1.34 versus 13.00 + 0.29 mmol/L, P , 0.01), there were significant positive correlations between TT
7-week-old (20.55 + 0.70 versus 13.13 + 0.38 mmol/L, P , and CP blood as lipid concentrations increased, but conver-
0.01), 20-week-old (16.57 + 1.24 versus 10.16 + 0.60 mmol/ sely no significant correlation between concentrations of
L, P , 0.01) and 28-week-old (20.88 + 1.63 versus 9.89 + glucose when collected from the TT and by CP. When
0.54 mmol/L, P , 0.01) mice. CP glucose concentrations working with rodents, blood is commonly collected from
for all age groups combined exhibited a wide range of both the TT and/or heart. However, the choice of method
values (range 8.63 –33.98 mmol/L) compared with TT and source of blood collection may vary, and hence differen-
glucose (range 8.15 – 15.69 mmol/L), and there was no corre- tially affect a number of blood parameters.11 – 15,18,22,23 It is
lation between the two sampling sites (glucose R 2: 0.098, therefore important to consider any possible disparity in
P . 0.05) (Figure 2a). Further, more than 95% of the measured blood constituents caused by the technique of
paired determinations had a higher glucose concentration collection, to avoid untoward experimental bias.
in the blood obtained by CP than from the TT. The mean The glucose concentrations in blood samples obtained by
bias of the CP glucose concentrations versus TT glucose con- CP were determined to be higher than those obtained from
centrations was approximately þ80% (mean, SD) across all the TT. The current understanding is that under conditions
concentrations. of basal, steady-state glucose metabolism, the glucose con-
centration in the artery is consistently higher than that
in the vein. Henry24 predicted on a physiological basis
Measurement of blood lipid concentrations that arterial glucose concentrations are approximately
In contrast to the glucose results, the levels of TC, HDL-C 0.20 mmol/L higher than venous values in fasting individ-
and TAG in arterial blood collected by CP from anaesthe- uals. In the present study, the combined mean difference
tized mice at 4, 7, 20 and 28 weeks of age were consistently for all animals across all age groups was 8.85 mmol/L
lower than venous blood obtained from the TT (Figures 1b, (80% bias individual sample), hence we speculate that
c and d). These effects were significant irrespective of the either such extreme differences between the two sampling
age of the mice, with the exception of TAG at 7 and 20 site are either not entirely physiological, or this represents
weeks where there was no significant difference between a physiological difference between humans and mice.
the two sampling sites (Table 1). Higher blood glucose levels were reported from anaesthe-
There was a positive correlation between levels of TC, tized rodents compared with unanaesthetized manually
HDL-C and TAG measured from TT blood and those restrained counterparts.17 Recent studies by Rodrigues
obtained by CP under anaesthesia (TC r 2: 0.27, P , 0.01; et al.18 and Saha et al.19 also showed similar findings
TAG r 2: 0.27, P , 0.01; HDL-C r 2: 0.34, P , 0.01; combined where anaesthesia with ketamine/xylazine caused
data from 4-, 7-, 20- and 28-week-old mice) (Figures 2b, c significant hyperglycaemic effects in non-fasted Sprague –
and d). Approximately 90% of the paired determinations Dawley rats after 20 min that continued to increase for
of TC, TAG and HDL-C were lower in CP blood than in 3 h post-anaesthesia via an a2-adrenoceptor pathway.
Chan et al. Blood sampling site affects metabolic measurements 145
................................................................................................................................................

Figure 1 Levels of (a) glucose, (b) total cholesterol, (c) triglyceride (TAG) and (d) high-density lipoprotein cholesterol (HDL-C) in serum samples of male C57BL/
6J mice from blood collected from the tail tip (TT) and by cardiac puncture (CP) at 4 (n ¼ 40), 7 (n ¼ 10), 20 (n ¼ 20) and 28 (n ¼ 20) weeks of age. n ¼ number of
animal samples; values are expressed as mean + SEM.  P , 0.01 and #P , 0.05 as compared with the TT group of mice

Interestingly, ketamine/xylazine-induced anaesthesia did that fasted rats subjected to the standard shock procedure
not cause hyperglycaemia in fasted rats, though there was consisting of tail bleeding can mobilize glucose into the
a small and insignificant increase in blood glucose levels. blood stream and cause severe hyperglycaemia indepen-
In the present study, the mice were fasted for 4 h on the dent of their initial glucose reserve. It is also possible
morning of blood collection and the time between keta- that our mice may have experienced some form of haemor-
mine/xylazine-induced anaesthesia and cardiac bleeding rhagic shock following the initial TT procedure which trig-
was less than 2 min, hence it is unlikely that the anaesthesia gered the mobilization of glucose into the blood stream
induced hyperglycaemia, though it cannot be ruled out as and caused an increase in blood glucose concentrations
partly explaining why the TT and CP glucose levels are so prior to the second CP procedure. Hypoperfusion is a
different. known factor in the underestimation of point-of-care
When external stimuli such as stress, even from routine glucose testing, especially in critical care individuals.30
laboratory procedures including animal handling and Alternatively, milking the tail to collect a sufficient
blood collection, are applied to animals, significant physio- volume of blood could have led to dilution of blood by
logical changes correlated with stress have been reported in interstitial fluid as a contributory factor for the lower
a number of studies, in particular stress-mediated increases glucose concentrations.
in serum or plasma concentrations of corticosterone, The widely used C57BL/6J mouse strain is susceptible to
glucose, growth hormone or prolactin, heart rate and obesity and atherosclerosis, which is exacerbated when the
blood pressure.25,26 Periorbital puncture resulted in a dra- mice are fed a high-fat diet.31 – 34 It is increasingly used as a
matic increase in blood glucose in conscious mice indicating diet-induced fatty mouse model of the metabolic syndrome
that this is a stressful procedure.27 Tail puncture resulted in that mimics high fat/energy-fed humans.34 The present
an increase in blood glucose in conscious mice, compared study shows that the levels of TC, HDL-C and TAG in
with saphenous venepuncture indicating that this is a blood obtained by CP from anaesthetized mice at 4, 7, 20
stressful procedure.28 Further Strawitz et al.29 showed and 28 weeks of age were consistently lower than levels
146 Laboratory Animals Volume 46 April 2012
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Figure 2 Deviations of the levels of (a) glucose, (b) total cholesterol, (c) triglyceride (TAG) and (d) high-density lipoprotein cholesterol (HDL-C) in serum samples
from blood collected from the tail tip (TT) and by cardiac puncture (CP) (n ¼ 90); NS: not significant

in TT blood. In contrast to glucose, this difference cannot in the liver to be secreted into the circulation via the
be accounted for by simple dilution of venous blood hepatic vein, whereas lipids will be released from both
with interstitial fluid in the TT sample due to milking the liver and peripheral adipose tissues into the blood.
the tail since the levels of lipids derived from TT blood Glucose extraction in the periphery may mean lower
were significantly higher than those obtained by CP. The glucose levels in the tail and limbs than centrally.
increasing age of the mice did not seem to influence this Whatever the exact reason for the consistent differences
pattern with the exception of circulating TAG at 7 and seen, the current observation suggests a probable true bio-
20 weeks where it was just insignificant between the two logical difference in lipid concentrations existing between
sampling sites. The overall inter-individual variations these two sampling sites, and consequently we suggest
(combined data) of CP blood lipid levels were narrower, that TT and CP blood should not be used interchangeably
and around 90% of the paired determinations measured when assessing the levels of serum glucose and/or lipids
were lower than those for TT blood yielding an average within one experimental model.
negative bias of approximately 225% across all concen- In conclusion, the present study demonstrated that the
trations irrespective of the age of the animals. We also blood sampling site can profoundly influence a number of
found that circulating concentrations of TC, HDL-C and commonly tested blood parameters such as glucose and
TAG collected from the TT were positively associated lipid profiles including TC, HDL-C and TAG. Our findings
with the levels obtained by CP; however, the correlations emphasize the need to standardize the sampling site and
were weak and TT values could not be used to predict collection method, especially in longitudinal research
CP concentrations of any lipid or lipoprotein component. studies where multiple and repetitive routine blood
In the fasting state used here glucose will be synthesized samples are required.
Chan et al. Blood sampling site affects metabolic measurements 147
................................................................................................................................................

ACKNOWLEDGEMENTS 16 Doeing DC, Borowicz JL, Crockett ET. Gender dimorphism in differential
peripheral blood leukocyte counts in mice using cardiac, tail, foot, and
The authors gratefully acknowledge Yih-Chih Chan, Carol saphenous vein puncture methods. BMC Clin Pathol 2003;3:3
Zhu and Katy Wiessing for their technical assistance. We 17 Upton PK, Morgan DJ. The effect of sampling technique on some blood
parameters in the rat. Lab Anim 1975;9:85 –91
thank staff members of the Biomedical Research Unit 18 Rodrigues SF, de Oliveira MA, Martins JO, et al. Differential effects of
(BRU), University of Otago, Wellington, and at the Vernon chloral hydrate- and ketamine/xylazine-induced anesthesia by the s.c.
Jansen Unit (VJU), University of Auckland for their assist- route. Life Sci 2006;79:1630 –7
ance with daily animal husbandry. We thank staff of the 19 Saha JK, Xia J, Grondin JM, Engle SK, Jakubowski JA. Acute
Bioactivity Investigation Group and Trinity Bioactives Ltd, hyperglycemia induced by ketamine/xylazine anesthesia in rats:
mechanisms and implications for preclinical models. Exp Biol Med
Wellington for technical assistance. This study was sup- 2005;230:777 – 84
ported by funding from the Foundation for Research 20 Tranquilli WJ, Thurmon JC, Neff-Davis CA, et al. Hyperglycemia and
Science and Technology, and the Fonterra Co-operative hypoinsulinemia during xylazine-ketamine anesthesia in thoroughbred
Group via the consortium Lactopharma, New Zealand. horses. Am J Vet Res 1984;45:11 – 14
21 Neese JW, Duncan P, Bayse D, Robinson M, Cooper T, Stewart C.
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