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Department of Anatomy and Cell Biology, College of Medicine, University of Iowa, Iowa City, Iowa 52242
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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blood pressure; heart rate; telemetry; circadian; pregnant; transgenic mice; gene targeting; gestation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Until recently, arterial blood pressure (BP) in mice has been measured either indirectly using tail cuff plethysmography (8, 16) or directly using indwelling fluid-filled catheters (4, 9, 10). Plethysmography measures only systolic pressure and requires extensive animal training, heating, and restraint. The fluid-filled catheter method requires that mice are tethered, and catheter patency limitations prevent long-term measurements (more than 1–2 wk). The recent development of miniature implantable radiotelemetric devices offers the possibility for long-term, hands-off BP measurement in untethered mice living in their home cages (12). However, limitations associated with abdominal aortic implantation of the transmitter, the surgical approach originally developed for this technology (10), have prevented broad implementation of this technology so far. First, the size of the pressure-sensing catheter prevents placement of it in the abdominal aorta without obstruction of blood flow to the lower extremities except in larger-than-average adult mice (must be at least 30 g) (1, 12). Second, perhaps due to lengthy anesthesia periods and trauma associated with abdominal surgery, there is high morbidity and mortality using the conventional abdominal aorta method (1, 12). Third, since catheter placement using this approach potentially compromises uterine blood flow, it is not feasible in pregnant mice.
Since we are interested in studying cardiovascular regulation during pregnancy, we wanted to develop an alternative method for reliable and continuous measurement of BP before, during, and after pregnancy in mice using radiotelemetry. Since female mice of reproductive age weigh on average 22 g, the secondary goal was to develop the radiotelemetric technique for application in smaller mice. Carlson and Wyss (1) recently reported a protocol for implantation of radiotelemeters in mice weighing on average 28 g. With carotid placement of the catheter tip and midscapular region placement of the transmitter body, they report a much higher success rate compared with the conventional abdominal aorta technique. Here we describe an alternate approach that we have developed in which thoracic aortic (via the left carotid artery) implantation of the pressure-sensing catheter is combined with subcutaneous placement of the transmitter body along the right flank. Our results document that this is an extremely reliable procedure for accurately measuring basal mean arterial pressure (MAP) and heart rate (HR) in mice weighing 22 g on average, but as small as 17 g. Additionally, we show that continuous radiotelemetric recording of cardiovascular parameters using this technique does not interfere with pregnancy.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Telemetry Probe Implantation Procedure
Pressure-sensing catheter implantation.
The components of the radiotelemetry system (Data Sciences International, St. Paul, MN), including the mouse BP telemetry device, have been described in detail previously (12). Female C57 or BPH/5 mice were anesthetized with ketamine (90 mg/kg ip) and ace promazine (1.8 mg/kg ip), and the neck was shaved and disinfected. Animals were placed on their backs on a heated surgical surface with forelimbs secured using tape and the head held parallel to the body by a small piece of tubing looped around the upper incisors and anchored to the surface. This allows easier access to the region to be dissected. A ventral midline skin incision was made from the lower mandible posteriorly to the sternum (
3 cm), and the submaxillary glands were gently separated using sterile cotton swabs. The left common carotid artery was isolated using fine forceps, with care being taken to avoid disturbing nerve fibers running parallel to the artery. The left carotid is preferable, since the right brachiocephalic artery branches off of the right carotid artery, potentially compromising blood flow to this region. Two silk ligatures (7–0, Braintree) were passed under the vessel and used for both ligation and retraction (Fig. 1A). The anterior silk suture (Fig. 1A, a), placed just caudal to the bifurcation of the interior and exterior carotid arteries (see Fig. 1E, inset E1), was used to ligate the artery. The posterior suture (Fig. 1A, b), placed loosely about 0.5 cm from the anterior tie, was used for temporary occlusion of the artery during catheter insertion. Gentle tension was applied to both ligatures to slightly retract and lift the vessel (Fig. 1A) before making a tiny incision in the carotid artery just posterior to suture a using Vannas spring micro-scissors (Fine Science Tools, catalog no. 15610-08). After carefully removing the protective cover from the tip of the catheter, the catheter was gently grasped using vessel cannulation forceps (Fine Science Tools, catalog no. 00608-11) and inserted into the carotid artery with the aid of fine forceps used to hold the vessel incision open. The occlusive posterior suture b was released, and the catheter was advanced to the point where the small notch on the tubing (the transition between the thin-walled tubing and remaining outer tubing, 10 mm from the tip) resided at the vessel opening (even with suture a, see Fig. 1, B and E, inset E1). Inserting the catheter up to this landmark notch assures the critical placement of the pressure-sensing tip just inside of the thoracic aorta (see Fig. 1E, inset E2). The notch also serves as a useful tool for anchoring the catheter into the vessel; the loose ends of suture a were tied securely around the catheter at the notch. The loose ends of the occlusive posterior suture b were also brought up and tied securely around the vessel/catheter (Fig. 1, B and E1). A single microdrop of Nexaband veterinary adhesive was applied to the site of catheter insertion into the vessel (Fig. 1B, arrow). It should be emphasized that that only a very small amount of adhesive is required, and that care should be taken to avoid undue application of adhesive to surrounding tissues and nerve fibers.
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Fluid-Filled Catheter Implantation Procedure
In a separate cross-validation experiment, female C57 mice (n = 7) were surgically instrumented with fluid-filled carotid arterial catheters for direct measurement of MAP and HR according to methods described by us previously (4). Briefly, animals were prepared as above, and sterile heparinized saline-filled catheters were inserted into the left common carotid artery. Catheters were tunneled subcutaneously, exteriorized, and sutured in place as described before (4). Lines were flushed daily with dilute heparinized saline.
Experimental Protocol
Telemetry experiments.
Following full recovery from anesthesia, mice were returned to their home cages (placed atop telemetry receivers), where they continued to be monitored daily throughout the study for general condition, body weight, food and water intake, state of surgical wound healing, and any signs of morbidity. Radiotelemeters were magnetically activated immediately upon return to the home cage, and BP (pulsatile waveforms and MAP), HR, and locomotor activity were recorded continuously for 12 days.
The pregnancy study, carried out only in C57 mice, began on day 13 postsurgery. At this time, the telemeters were magnetically switched off, and male C57 breeders were placed with females. Each morning females were examined for the presence of a vaginal plug. Upon detection of a plug, males were removed, radiotelemeters were turned on again, and female mice were weighed daily. If a significant weight gain was not observed by 7 days postplug, then a male was returned to the cage and the process repeated. MAP and HR were recorded continuously during pregnancy and then intermittently (to conserve transmitter battery life) every 3 days (for 24-h intervals) for 2–3 wk postpartum. Mice were weighed daily throughout the experiments, and litter sizes and pup weights were recorded during the postnatal period. Female C57 mice (n = 7) that had not been implanted with radiotelemeters served as controls. They were similarly bred, weighed, and observed during and after pregnancy.
Fluid-filled catheter experiments.
MAP and HR were recorded in conscious freely moving female C57 mice both at 3 days and again 7 days following implantation of fluid-filled carotid catheters as described (4). After connection of the arterial line to a PowerLab (ADInstruments, PowerLab/4S)-coupled pressure transducer, mice were allowed 60 min stabilization period before obtaining baseline MAP and HR recordings for 60 min.
Data Acquisition and Analysis
Radiotelemetry data were collected continuously (sampling every 5 min for 10-s intervals) as indicated and stored using the Dataquest ART data acquisition system (Data Sciences International) as described in detail previously (12). MAP, HR, and locomotor activity data collected from the first 12 consecutive days following surgery were plotted as mean values over each hour. All other data are expressed as means ± SE calculated for the day postsurgery or over the stage of pregnancy indicated [pre, early (6–8 days), middle (11–13 days), late (18–20 days), post (2–3 wk postdelivery)]. Differences in MAP and HR at the different time points, between methods for recording (radiotelemetric vs. fluid-filled catheters) and/or between strains were analyzed by repeated measures ANOVA followed by the Student’s modified t-test with Bonferroni correction for multiple comparisons between means using the modified error mean square term from the ANOVA. Student’s t-test was used to compare litter sizes, average pup sizes, and weight gain during pregnancy between mothers with and without radiotelemetry implants.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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MAP and HR Measurements During Recovery from Surgery
All reported telemetry data were collected from C57 and BPH/5 mice with right flank-implanted transmitters. We began recording MAP, HR, and locomotor activity immediately following surgical implantation of the device to establish the time point at which daily circadian rhythms returned. Data from the first 12 consecutive days following surgery were plotted for each animal and inspected visually. A typical 24-h rhythm in a C57 mouse over 4 consecutive days starting a few hours after recovery from anesthesia, and again 1 wk (6.5 days) after surgery, is shown in Fig. 3. For the first several days following surgery, the circadian rhythms appeared disorganized with regard to the light cycle. It was not until 5–7 days after surgery (5.7 ± 0.8 days, n = 17) that circadian organization of MAP, HR, and activity, defined previously in mice as a diurnal rhythm with peak values at the onset of the active dark period and minimum values during the quiescent light period (9), returned. The time course of recovery of circadian patterns was similar for both strains.
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10 ± 4 mmHg, n = 17; Fig. 5, bottom). One C57 mouse exhibited a sudden loss of the signal during the second week following surgery. Inspection of the device upon explant revealed a thrombus at the catheter tip.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Our findings are consistent with those of Carlson and Wyss (1) in that we also found the carotid artery placement to be tremendously more reliable and successful than the abdominal aorta method for mice smaller than 30 g. Although not presented here, we initially struggled with the abdominal placement as well, and our low success rate with it in part led to our development of the approach in the current study. In contrast to the report of Carlson and Wyss (1), however, we did not have success with placement of the transmitter body on the back at the midscapular region. In addition to limiting head movement and general locomotor activity, the mice had access to the back incision with their hind legs and scratched it excessively. This, perhaps combined with activity during breeding, led to wound opening and exteriorization of the probes in most cases. We had much better success with placement of the transmitter body subcutaneously along the right flank. Not only is it more convenient in that the entire implantation procedure can be carried out through a single small incision, also, the animals cannot easily access the inner right flank region through scratching. The implants remained relatively undisturbed over the months of implantation. The smaller size of mice in our study, along with the added stress of the breeding protocol, may account for differences in success with the midscapular placement between our study and that of Carlson and Wyss (1).
In addition to being reliable, our results indicate that radiotelemetry is also a highly accurate method for baseline BP phenotyping. Cross-validation of telemetric recordings with those obtained by fluid-filled catheters in separate mice demonstrated nearly identical MAP values by these two techniques. Similar findings were reported for validation of telemeters against Millar transducer-tipped catheters (12). An additional important finding from this part of our study that we believe has broad implications for BP phenotyping in general is that mice do not fully recover from anesthesia and surgery, as indicated by the return of normal circadian patterns, for 5–7 days. In both C57 and BPH/5 strains, circadian patterns remained disorganized with regard to the light cycle until about 6 days following implantation of the telemetry device. The effects of surgery/anesthesia seem to also be reflected in altered baseline cardiovascular values in both strains. Compared with values obtained a week after surgery, both MAP and HR were significantly elevated for several days following surgery in C57 and BPH/5 mice. Although the time course for recovery of the circadian rhythms was similar in both strains, the relative effect of anesthesia/surgery on baseline MAP and HR values differed between C57 and BPH/5. A relatively greater increase in MAP during the first several days following surgery in C57 than in BPH/5 mice (compared to values 7 days after surgery) appeared to have masked the significant difference observed in this parameter in animals that are fully recovered. In fact, a significant difference in baseline MAP between these two strains was not detected until 5 days following surgery. This is also the amount of time it took for baseline MAP in C57 mice to reach a stable level. Taken together, these findings suggest that recordings taken prior to 5 days after surgery (i.e., a typical time for so-called conscious recordings in mice) may not provide accurate cardiovascular phenotyping and that a 5- to 7-day recovery period is critical. The strain-related differences in recovery revealed in this study underscore the importance of this waiting period, especially in studies of genetically altered or inbred strains of mice. Our basal MAP and HR data recorded in C57 mice at 7 days postsurgery by both telemetry and fluid-filled catheters are in close agreement with other reports using either method (1, 9). Thus we believe that the fluid-filled catheter method does provide an accurate short-term BP phenotyping method, as long as catheters can be kept patent to allow for adequate time for recovery from surgery. If this is not possible or when experimental paradigms require continuous direct recording over weeks or months, then radiotelemetry is a crucial tool.
This is not to say that implementation of radiotelemetry is without caveats. Certainly, one consideration is cost. The initial investment in equipment is relatively substantial. Additionally, there are recurrent costs for refurbishment of transmitter batteries and pressure-sensing catheters. However, attention to conservation of battery life and efforts to maximize transmitter reuse can reduce these recurrent costs considerably. Battery life with continuous use is about 1.5 mo, but the time course of a study and/or the life of the transmitter can be extended by magnetically switching the transmitters off and on repeatedly over time to conserve the battery. For example, we have analyzed MAP and HR over a 6-mo period in mice by recording for 24-h intervals every 4 days. Extension of battery life by this method even in studies with shorter time courses (typically using shorter "off" intervals), in combination with transmitter explant and reuse, has also helped us reduce refurbishment costs. We have been relatively successful with reusing transmitters one or two times, but have had limited success beyond that. An inability to completely remove all adhesive debris and difficulties with the catheter gel have been the primary limitations.
At least two concerns might reasonably be raised about implantation of the pressure-sensing catheter in the thoracic aorta via the carotid artery. First, this procedure prevents the left carotid sinus from directly seeing arterial pressure, raising the possibility that baroreflex function might be comprised. While this is a concern, previous studies in dogs have shown that even after total denervation of both left and right carotid sinus baroreceptors, baroreflex function returns to normal within 1 wk as a result of compensatory effects of the remaining baroreceptors (12). Although we have not directly evaluated baroreflex function in mice with telemeters, our preliminary baroreflex studies in mice with fluid-filled catheters implanted in the left carotid artery appear to support these findings. Investigations are ongoing.
The other concern associated with carotid placement of the telemeter is that of inducing cerebral ischemia due to ligation of the carotid artery. Although our studies did not assess this possibility directly, we did not observe changes in behavior attributed to ischemia such as twisting, body rotations (in a direction contralateral to the damaged hemisphere), or diminished locomotor activity (3). Indeed, behaviorally, mice with carotid catheters (either transmitters or fluid-filled) were indistinguishable from unoperated controls. It should be noted, however, that some studies have identified strain-related differences in susceptibility to ischemia induced by bilateral carotid artery occlusion in mice, perhaps related to differences in cerebrovascular anatomy (5). Future studies investigating the effects of unilateral carotid occlusion and the potentially confounding role of genetic background would be useful.
Finally, an additional goal of this study was to establish a method for continuous stress-free recording of cardiovascular parameters in mice during pregnancy. Previous studies in pregnant rats or mice have utilized indwelling fluid-filled catheters in anesthetized animals (6, 13) or the tail-cuff method with preheating and restraint (16, 17), but we were concerned about the potentially confounding influences such manipulations could have. We reasoned that the long-term, hands-off recording potential of radiotelemetry would allow us to implant the transmitters before the mice were bred, allow adequate recovery time, and then record MAP and HR continuously before, during, and after pregnancy without interruptions such as restraint, handling, or anesthesia/surgery. Indeed, our results indicate that the transmitter device did not interfere with conception, gestation, delivery, or postnatal care of the pups. Furthermore, we were able to continuously track changes in MAP and HR throughout pregnancy and during the postpartum period in C57 mice. Interestingly, the significant drop in MAP at midgestation followed by a return to normal during late pregnancy and the marked increase in HR throughout pregnancy are consistent with what occurs in women during pregnancy (11). To our knowledge, this is the first report of normal baseline cardiovascular data collected over the entire course of pregnancy and postpartum period under stress-free conditions in rodents. This approach may have important applications in future studies designed to understand the pathogenesis of pregnancy-related cardiovascular diseases such as preeclampsia.
The emerging field of functional genomics has a goal to link the delineation of the genome to the function of the whole organism and organ systems in health and disease. One prerequisite for the successful achievement of this critical goal is the development and optimal deployment of tools that allow accurate, reliable, and high-throughput phenotyping. We believe that radiotelemetry, as described in detail and utilized in this study, is an important such tool and represents a key step in cardiovascular phenotyping in mice. The ubiquitousness of murine models in genetic research and of cardiovascular disease in the developed world indicates the potential significance of this particular tool in a broad range of future cardiovascular functional genomic research.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. L. Davisson, Dept. of Anatomy and Cell Biology, College of Medicine, Univ. of Iowa, Iowa City, IA 52242 (E-mail: robin-davisson{at}uiowa.edu).
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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