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Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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This study
describes a technique for the direct daily measurement of arterial
blood pressure, sampling of arterial blood, and continuous intravenous
infusion in free-moving, conscious, Swiss-Webster mice. Catheters were
chronically implanted in the femoral artery and vein, tunneled
subcutaneously, exteriorized at the back of the neck in a lightweight
tethering spring, and attached to a swivel device at the top of the
cage. Time-control experiments (n = 8)
demonstrated stable values of mean arterial pressure (MAP, 116 ± 1 mmHg) and heart rate (HR, 627 ± 21 beats/min) for up to 35 days
after catheter implantation. It was further observed that restraining
mice (n = 7) increased MAP by 10 ± 3 mmHg and HR by 78 ± 8 beats/min from the values observed under free-moving conditions. To demonstrate the chronic use of the venous
catheter, intravenous infusion of
NG-nitro-L-arginine
methyl ester (L-NAME, 8.6 mg · kg
1 · day1,
n = 6) for 5 days significantly
increased MAP from 117 ± 4 to 131 ± 4 mmHg without altering HR.
In a final group of mice (n = 5), oral
L-arginine (2% in drinking
water) increased plasma arginine concentration from 90 ± 7 to 131 ± 17 µM and prevented L-NAME hypertension. These
experiments illustrate the feasibility of long-term intravenous
infusion, direct arterial blood pressure measurements, and arterial
blood sampling in conscious mice.
hypertension; nitric oxide; arginine
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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MODERN MOLECULAR BIOLOGY techniques have permitted the generation of a number of different animal models in which targeted genes of interest are overexpressed or deleted using recombinant DNA technology (2, 3, 20, 21). The majority of these genetic alterations have been performed in the mouse. Despite the development of a large number of mouse models in which genes involved in the regulation of cardiovascular function have been manipulated (Refs. 7, 9, 11, 12, 16, 19, and many others), the techniques to directly monitor blood pressure, sample arterial blood, and continuously infuse pharmacological agents into free-moving, conscious mice have not been fully developed. In the absence of techniques to perform these types of manipulations, the complete characterization of cardiovascular parameters and experimental use of these animals is limited. Recent studies to examine blood pressure in genetically engineered mice have relied on direct pressure measurements in anesthetized mice (1, 8, 23), indirect blood pressure measurements by tail-cuff plethysmography in restrained conscious mice (9, 11), or direct arterial pressure measurements in restrained mice (10, 16, 22). Although a blood pressure value can be obtained with each of these techniques, these methods do not allow for long-term recording (days to weeks) of blood pressure, sampling of arterial blood before and after experimental manipulations in the animals, or continuous intravenous infusion of pharmacological agents.
The goal of this study was to develop techniques to directly measure arterial pressure, sample arterial blood, and continuously infuse compounds intravenously to conscious, freely moving mice. These techniques were then used to determine the influence of chronic intravenous infusion of NG-nitro-L-arginine methyl ester (L-NAME) on blood pressure in mice. Additional experiments were subsequently performed to determine the consequences of dietary arginine supplementation (by administering 2% L-arginine in drinking water) on the plasma levels of L-arginine in conscious mice and the development of L-NAME hypertension.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Experiments were performed on adult Swiss Webster mice (28-44 g) obtained from Taconic Farms (Germantown, NY). The mice were housed in the Animal Resource Center at the Medical College of Wisconsin with normal food and tap water provided ad libitum. All animal procedures were approved by the Medical College of Wisconsin Animal Care Committee, and the mice were closely monitored to ensure that none experienced undue stress or discomfort.
Mice were preanesthetized with methoxyflurane and then administered pentobarbital sodium (50 mg/kg ip) to induce anesthesia. Supplemental anesthesia was administered as needed. With the use of aseptic techniques, catheters were placed in the femoral artery for the measurement of arterial pressure and in the femoral vein for infusions. The arterial and venous catheters consisted of a 4- to 5-cm length of Micro-Renathane tubing (0.025 in. ID, 0.040 in. OD; Braintree Scientific) stretched over hot air to give a tip 300-500 µm in diameter. The Micro-Renathane tubing was coupled with a 23-gauge stainless steel pin to a 25-cm piece of polyethylene tubing (PE-50; 0.023 in. ID, 0.038 in. OD; Clay-Adams). The catheters were tunneled subcutaneously and exteriorized through a 15-cm piece of lightweight spring (Instech); the tethering spring was attached to the back of the animal by sewing a 1-cm-diameter stainless steel button into the strap muscles between the scapulae. The free end of the spring was connected to a swivel device at the top of the cage. During and after surgery, the animals were kept warm on a heated surgical table. The mice were allowed to recover for 5-7 days before the experimental protocol. Any animal exhibiting pain or distress was euthanized with an overdose of pentobarbital sodium intravenously or intraperitoneally. With this preparation, the mice were observed to regain full use of the catheterized limb and moved easily throughout their cages while being continuously infused intravenously or having blood pressure monitored through the indwelling catheters.
Except when specified in the description of the individual protocol, the catheters were filled with 500 U heparin in saline, sealed, and only opened when they were used for recording. The only animals that were continuously infused were those in protocols 3 and 4, in which saline (3 ml/day) or saline with drug was infused intravenously. The infusion was delivered through either commercially available single-channel swivels (model 375/22; Instech Laboratories, Plymouth Meeting, PA) or single-channel swivels fabricated in our laboratory. The mice were able to easily turn the swivels providing the lever arm between the end of the spring and the swivel was ~3 cm or longer.
Arterial pressure was measured with solid-state pressure transducers (Cobe Laboratories, Lakewood, CO) and a general-purpose amplifier built in the Department of Physiology electronics shop. Amplified data was fed into an analog-to-digital convertor (Significat, Boston, MA) and to an Apollo DN3500 computer. The computerized data-acquisition software reduces pulsatile blood pressure signals collected at 100 Hz to periodic (1 min) averages of systolic, diastolic, and mean arterial blood pressure and heart rate (HR). All data were obtained in this way except for the raw data described in Fig. 1, which were obtained with a personal computer using CODAS data-acquisition software (AT-CODAS; DATAQ Instruments, Akron, OH).
Protocol 1: Direct measurement of blood pressure in freely moving, conscious mice. An initial group of mice (n = 8) was instrumented as described above to evaluate this technique to directly measure arterial pressure in conscious mice. Beginning on the seventh day after surgery, direct measurements of arterial pressure were performed periodically over the next 4 wk to determine the longevity and patency of the implanted arterial catheters. Direct measurements of arterial pressure were obtained from this group of mice on postsurgical days 7, 10, 12, 14, 17, 19, 21, 24, 26, 28, 31, 33, and 35. Blood pressure was monitored for 2-3 h on each recording day as the conscious mice rested in their home cages.
Protocol 2: Comparison of direct arterial pressure measurements in restrained and unrestrained conscious mice. A separate group of mice (n = 6, 35 ± 2 g body wt) were prepared as described above and allowed 5-7 days to recover from surgery. Daily blood pressure recordings were made from the mice in their home cages. After an initial 60- to 100-min control recording period during which the mice were allowed to move freely about the cage, the mice were placed in Plexiglas restrainers and blood pressure and HR were again measured during an additional 60- to 100-min period. The restrainer used in these experiments was 3 cm high and 2.5 cm wide, with an adjustable length and an 8-mm groove cut into the removable top. The mice could therefore be placed directly into the restrainer without disconnecting or bending the tethering spring. Daily pressure recordings were made on 6 consecutive days to compare the blood pressure and HR values obtained under free-moving and restrained conditions.
The design of this protocol arose from preliminary experiments in which the control levels of mean arterial pressure (MAP) and HR were compared between two separate groups of restrained and unrestrained mice on a single day. The first group (n = 6, the control data from mice in protocol 3) was prepared as described above with the catheters exteriorized at the back of the neck and protected in a stainless steel spring. The second group (n = 5) was also chronically catheterized, except that the free ends of the catheters were anchored to the back of the neck with dental acrylic. Direct measurements of blood pressure could therefore only be made in the second group during restraint. It was observed that there was no significant difference in MAP pressure between these groups (119 ± 4 mmHg in restrained mice vs. 117 ± 4 mmHg in unrestrained mice), but HR was significantly elevated in the restrained group (709 ± 22 beats/min vs. 602 ± 26 beats/min). Although these preliminary data pointed to a difference in the HR measurements obtained under restrained and unrestrained conditions, the comparison of measurements obtained on a single day between two separate groups of mice could be misleading. The present paired design was therefore carried out on 6 consecutive days to eliminate these possible sources of error.
Protocol 3: Influence of chronic intravenous
L-NAME infusion on blood pressure in
conscious mice.
After a 5- to 7-day recovery period from surgery, during which time the
mice (n = 6, 39 ± 2 g
body wt) were continuously infused intravenously with saline (3.0 ml/day), daily blood pressure measurements were made during a 2- to 3-h
period. After two stable control days,
L-NAME was added to the
intravenous infusate to deliver 8.6 mg · kg1 · day1
in saline. Daily blood pressure measurements were obtained as the
L-NAME infusion was continued
for 5 days. Additional pressure measurements were made during 2 postcontrol days when the L-NAME infusion was stopped and saline alone was infused intravenously.
Protocol 4: Influence of
L-arginine supplementation on
L-NAME hypertension in mice.
After a 5- to 7-day recovery period from surgery, daily blood pressure
measurements were taken in an additional group of conscious mice
(n = 6, 38 ± 1 g body wt)
continuously infused intravenously with saline (3 ml/day) and
maintained on an oral intake of
L-arginine (2% wt/vol) in
drinking water. After 2 stable control days,
L-NAME (8.6 mg · kg1 · day1)
was added to the intravenous infusate for 5 days. Daily pressure measurements were made throughout the control period, during the L-NAME infusion period, and
during 2 postcontrol days when saline alone was infused intravenously.
-alanine,
which served as an internal standard. The samples were then mixed well,
centrifuged at 10,000 g for 15 min to remove the precipitated protein, and derivatized
with an equal volume of
o-phthaldialdehyde (1 mg/ml). The
individual samples were separated by reverse-phase HPLC with a system
consisting of a Bio-Rad AS-100 Auto Sampler, Hitachi L-7100 Gradient
Pump, Waters (15 cm × 3.9 mm, 5 µm) column, Waters 474 Fluorescence Detector (excitation: 338 
, emission: 425 ), and a
Hitachi D-2500 Integrator. Validation experiments demonstrated a clean
separation of a standard cocktail consisting of 17 amino acids. With
six repeated injections, the coefficient of variation (CV) for the arginine peak was 0.3% for retention time, 3.3% for peak area, and
1.65% for peak height. Peak area and peak height were linear for any
given amino acid over the range of 30 nM to 10 µM
(r2 = 0.99 for
arginine peak height and
r2 = 0.99 for
arginine peak area). A plasma pool injected 23 times on 6 different
days yielded a mean of 109 µM for arginine (CV = 4.9%) and 74 µM
for citrulline (CV = 5.3%).
Statistical methods. Data are
expressed as means ± SE. The within-group changes were evaluated
with a one-way analysis of variance (ANOVA) for repeated measures with
a Duncan post hoc test. Between-group comparisons were made with a
two-way ANOVA with a Duncan post hoc test. A probability level of
P < 0.05 was considered significant
for all statistical tests.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Protocol 1: Direct measurement of blood pressure in freely moving, conscious mice. An arterial blood pressure recording from a single mouse on representative days from 1 to 5 wk after catheter implantation is presented in Fig. 1. The catheters in all eight original mice in the group remained functional until day 17; catheters of six mice remained functional until day 21, five until day 28, and four until day 35. The cause of catheter failure was variable. One mouse was found dead in his cage of unknown causes, one of the mice was euthanized because the catheterized leg became necrotic, and the arterial catheters in the two remaining mice became blocked and could no longer be used to measure blood pressure. The catheters in the remaining mice were all functional on the final day of the experiment when the mice were euthanized. The summarized MAP, pulse pressure, and HR values from this time-control group of chronically instrumented mice are presented in Fig. 2. Both MAP and HR were stable after the first several days of recording and were not different from the day 35 values of 116 ± 1 mmHg and 627 ± 21 beats/min throughout the protocol. Pulse pressure fell from 37 ± 3 mmHg on day 7 to 25 ± 4 mmHg on day 12, but was not significantly altered from that value throughout the remainder of the experiment, indicating patency of the catheters. The mean weight of the mice averaged 40 ± 1 g at the beginning of the experiment and was unaltered from that value throughout the experimental period.
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Protocol 2: Comparison of direct arterial pressure measurements in restrained and unrestrained conscious mice. MAP and HR in a group of mice under free-moving and restrained conditions on 6 consecutive days are graphed in Fig. 3. MAP averaged 120 ± 2 mmHg, and HR averaged 639 ± 17 beats/min on the initial day of pressure measurements under control conditions. Both blood pressure and HR were relatively constant throughout the 6-day recording period, although MAP was significantly decreased from the initial value on day 3 and HR was different on days 3 and 6. In contrast to the control values obtained under unrestrained conditions, MAP was significantly increased by restraint on 4 of the 6 recording days and HR was increased above control values on all 6 days. In addition, both the MAP and HR values obtained during restraint significantly increased from the day 1 value by days 4-6. On the initial days of this experiment, it was difficult to place the mice in the restrainers, and the animals were visibly agitated during the recording period. By the second or third day of the experiment, the animals could be placed in the restrainer much more readily and rested quietly during the recording period. Despite the apparent "conditioning" of the mice to the restrainer, the largest differences in blood pressure and HR were observed on the final days of this experiment.
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To address the possibility that the time of restraint (60-100 min) led to the differences in HR and blood pressure observed, the raw data for each mouse for each measurement period under both restrained and unrestrained conditions were separated into four equal periods of 15-25 min each and individually analyzed with a two-way ANOVA. Comparison of the mean values of MAP and HR for these individual periods demonstrated that neither MAP nor HR was consistently altered between the initial 15-25 min of each period and the final 15-25 min of each recording period in either the restrained or unrestrained condition. The only significant changes observed were a decrease in MAP from 123 ± 7 to 113 ± 7 mmHg on day 5 in unrestrained mice, an increase in HR from 612 ± 35 to 641 ± 29 beats/min on day 1 in unrestrained mice, a decrease in MAP from 126 ± 5 to 120 ± 4 mmHg on day 5 under restraint, and a decrease in HR from 744 ± 21 to 710 ± 14 beats/min on day 3 under restraint. The time of restraint therefore did not appear to influence the results of this experiment.
Protocol 3: Influence of chronic intravenous L-NAME on blood pressure in conscious mice. The influence of chronic intravenous L-NAME infusion on blood pressure in conscious mice is presented in Fig. 4. MAP averaged 117 ± 4 mmHg and HR averaged 602 ± 26 beats/min on the second control day. Intravenous infusion of L-NAME increased arterial pressure to 126 ± 5 mmHg after 1 day of infusion. MAP was elevated throughout the 5-day L-NAME infusion and reached a maximum of 137 ± 6 mmHg on day 4. HR was unaltered from control values throughout the L-NAME infusion period. By the first day of the postcontrol period, MAP fell to levels not different from control, and averaged 112 ± 2 mmHg on postcontrol day 2.
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Protocol 4: Influence of L-arginine supplementation on blood pressure response to L-NAME in conscious mice. MAP averaged 120 ± 3 mmHg (Fig. 5) and HR 648 ± 13 beats/min on the second control day as these mice were maintained on 2% (wt/vol) L-arginine drinking water. Daily water intake averaged 7.2 ± 1.5 ml/day, to provide an average arginine intake of 120 ± 37 mg/day on the second control day. Water intake was significantly increased from that value during L-NAME infusion, averaging 13 ± 2 ml/day (263 ± 40 mg/day arginine) on the first day of L-NAME infusion. This oral route of L-arginine administration increased plasma arginine concentration from 90 ± 7 µM before L-arginine administration to 131 ± 17 µM on the final day of the experiment. The oral L-arginine also significantly increased plasma citrulline levels from 32 ± 3 to 54 ± 6 µM and ornithine from 58 ± 9 to 110 ± 21 µM. Intravenous infusion of L-NAME to these arginine-treated mice did not alter MAP or HR from control values throughout the 5-day L-NAME infusion, averaging 118 ± 7 mmHg and 649 ± 26 beats/min, respectively, on the fifth day of L-NAME infusion. On both days of the postcontrol period, MAP was significantly decreased from the control and experimental values, averaging 110 ± 4 mmHg on the last day of the experiment.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The present study demonstrates the feasibility of chronically implanting femoral arterial and venous catheters in mice for the long-term measurement of arterial blood pressure, sampling of arterial blood, and continuous intravenous infusion. This technique should aid in the performance of long-term cardiovascular studies in the unique genetic models presently available in the mouse and lead to a better understanding of the multiple systems that control cardiovascular function. The initial experiments demonstrated the stability and the longevity of the chronically implanted catheters in mice. Five weeks after implantation, the arterial catheters were still functional in one-half of the original group of animals. The values of MAP and HR were constant in these animals over the final 3 wk of the recording. There was little problem maintaining patency of the catheters as illustrated by the average pulse pressure which exceeded 15 mmHg on postsurgical day 35. The general health of the mice also remained good throughout the experiment, as indicated by the maintenance of constant body weight, stable blood pressure and HR, and overall appearance of the animals. As further evidence of the general health of the animals, preliminary data (not presented in this manuscript) have shown that mice instrumented in this way achieve sodium balance on sodium intakes ranging from 100 to 1,000 µeq/day.
A number of different studies have directly measured arterial pressure in conscious, restrained mice (10, 16, 22). To determine whether the measurement of arterial pressure using the system described in this paper offered an advantage over the measurement of blood pressure and HR in restrained mice, blood pressure and HR were compared in a single group of animals under restrained and free-moving conditions. MAP and HR were measured for a 60- to 100-min control period when the mice were allowed to move freely about their cages. Immediately after this period, the mice were placed in a Plexiglas restrainer and MAP and HR were again measured during a second 60- to 100-min period. Restraint of the mice led to a significant elevation of HR on each of the 6 days of recording. Interestingly, blood pressure was unaltered between the control and restrained period on the initial day of the experiment, but MAP was significantly elevated from control by restraint on 4 of the final 5 days of the experiment. These data indicate that both blood pressure and HR are elevated by restraint, even in animals trained to sit quietly in the Plexiglas restrainers. In addition, both MAP and HR values in the restrained mice increased as the experiment progressed; in contrast, these parameters were largely unaltered under free-moving conditions. Placing mice in restrainers, even when they have been "conditioned" to the restrainer, leads to an elevation of MAP and HR, which may limit the detection of subtle changes in cardiovascular parameters in restrained animals.
To demonstrate the feasibility of chronic intravenous infusion in
conscious mice, the nonspecific nitric oxide synthase (NOS) inhibitor
L-NAME (8.6 mg · kg1 · day1)
in saline (3 ml/day) was administered to an additional group of mice.
Intravenous infusion of L-NAME
led to a 19-mmHg increase in mean arterial blood pressure, which was
readily reversible after cessation of the
L-NAME infusion. This experiment
demonstrated that the long-term hypertensive effects of
L-NAME are qualitatively similar
to those previously reported in the rat (6, 15, 17) and dog (14). In
addition, the absolute increase in arterial pressure was not
statistically different from the value that we have previously reported
with the same dose of L-NAME in
conscious rats (17). To test for nonspecific effects of
L-NAME on blood pressure, a
separate study was performed in which exogenous NOS substrate,
arginine, was administered in the drinking water. Pretreatment of the
mice with oral L-arginine, which
elevated circulating arginine levels by 46%, prevented the development
of L-NAME-induced hypertension. This experiment indicated that the hypertensive effects of
L-NAME were specific to NOS
inhibition. These studies demonstrate that this system can be used to
continuously infuse compounds intravenously and lead to sustained
alterations in blood pressure in mice. The arterial catheters also
enable the sampling of arterial blood in the same animals under
different experimental conditions.
Although the present techniques allow for direct arterial pressure measurements for a number of days in conscious mice, a number of limitations are inherent in these types of techniques. At present, the minimum size mouse that may be successfully catheterized is not known. The present experiments were performed in mice that averaged ~40 g, although catheters were implanted in mice as small as 28 g. An additional concern is the influence of chronic catheterization, an invasive technique, on the animals. The catheters and instruments used are sterilized, and the mice survive for up to 5 wk after surgery with a stable body weight and blood pressure, but it is possible that some adverse effects on function or health occur in response to the chronic instrumentation of the mice. Another potential problem is the daily values for blood pressure and HR that are obtained from a 2- to 3-h daily measurement period. Although this period is at the same time each day, important changes in blood pressure and HR that occur throughout the day and night may not be detected as the system is presently used. Related to this issue, data collection at 100 Hz, as used in this protocol, may dampen the arterial pressure signal, particularly under conditions when the HR would be expected to be elevated. It may therefore be desirable to acquire data at higher collection rates when precise measurements of diastolic and systolic pressure are needed. A final consideration is the volume of blood that may be drawn from a mouse without altering blood pressure. It was assumed that the 100 µl of blood drawn in the present experiment would have a minimal effect on blood pressure; however, the influence of blood sampling on systemic hemodynamics and the possible need for blood replacement should be considered for any analysis that requires blood withdrawal from conscious mice. Particular attention should be made to the possible effects of serial blood withdrawal from a single mouse in a limited time period. Despite these concerns, this method appears to be worthwhile to chronically monitor pressure and infuse substances intravenously to conscious mice.
A number of technical problems were noted as these animals were surgically prepared and studied. Several important factors appear to be necessary for a successful catheterization. First, the tip of the arterial catheter should be advanced into the lower portion of the abdominal aorta if the arterial pressure is to be measured for more than 3-4 days. Second, the Micro-Renathane tubing is soft and flexible so it does not tear or cut through the vessels, but it is also stiff enough that the catheters can be advanced. Third, the catheters were carefully flushed after use to ensure that blood did not remain in the tip before sealing. Special care was also taken to ensure that the mice would recover quickly from surgery and regain function in the catheterized limb. The recovery from surgery and reestablishment of use of the catheterized limb was much quicker in animals in which the time of surgery was minimized, in which limited amounts of lidocaine were used to dilate the vessels, and in which minimal disturbance to the femoral nerve occurred. Finally, despite chronic catheter implantation, the system was not used for 24-h recording of blood pressure. Although we had limited success in preliminary attempts at 24-h recording in mice, it was observed that the patency of the catheters declined much more rapidly when pressure was continually monitored than when pressure was only sampled for a 2- to 3-h period daily. In addition, for the intravenous infusion experiments, continuous blood pressure monitoring will require the use of a multiple-channel swivel.
In conclusion, we describe a technique for the measurement of arterial pressure in conscious, free-moving mice. The principle advantage of this technique is that it allows for long-term intravenous infusion, direct arterial blood pressure measurements, and arterial blood sampling in conscious mice over many days. This technique can hopefully be used in the future to utilize the unique genetic models developed in the mouse to further understand the long-term regulation of blood pressure and cardiovascular function.
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ACKNOWLEDGEMENTS |
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The author thanks A. W. Cowley, Jr., F. Park, and W. G. Hope for valuable discussions regarding this manuscript.
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FOOTNOTES |
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This work was partially supported by National Heart, Lung, and Blood Institute Grant HL-29587.
Address for reprint requests: D. L. Mattson, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226.
Received 16 June 1997; accepted in final form 23 October 1997.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Significant difference
(P < 0.05) from the value obtained
under identical conditions on day 1 (D1).
