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Am J Physiol Regul Integr Comp Physiol 278: R215-R225, 2000;
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Vol. 278, Issue 1, R215-R225, January 2000

Short-term and long-term blood pressure and heart rate variability in the mouse

Ben J. A. Janssen, Peter J. A. Leenders, and Jos F. M. Smits

Department of Pharmacology, Cardiovascular Research Institute Maastricht, Universiteit Maastricht, Maastricht 6200 MD, The Netherlands


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Knowledge on murine blood pressure and heart rate control mechanisms is limited. With the use of a tethering system, mean arterial pressure (MAP) and pulse interval (PI) were continuously recorded for periods up to 3 wk in Swiss mice. The day-to-day variation of MAP and PI was stable from 5 days after surgery. Within each mouse (n = 9), MAP and PI varied by 21 ± 6 mmHg and 17 ± 4 ms around their respective 24-h averages (97 ± 3 mmHg and 89 ± 3 ms). Over 24-h periods, MAP and PI were bimodally distributed and clustered around two preferential states. Short-term variability of MAP and PI was compared between the resting (control) and active states using spectral analysis. In resting conditions, variability of MAP was mainly confined to frequencies <1 Hz, whereas variability of PI was predominantly linked to the respiration cycle (3-6 Hz). In the active state, MAP power increased in the 0.08- to 3-Hz range, whereas PI power fell in the 0.08- to 0.4-Hz range. In both conditions, coherence between MAP and PI was high at 0.4 Hz with MAP leading the PI fluctuations by 0.3-0.4 s, suggesting that reflex coupling between MAP and PI occurred at the same frequency range as in rats. Short-term variability of MAP and PI was studied after intravenous injection of autonomic blockers. Compared with the resting control state, MAP fell and PI increased after ganglionic blockade with hexamethonium. Comparable responses of MAP were obtained with the alpha -blocker prazosin, whereas the beta -blocker metoprolol increased PI similarly. Muscarinic blockade with atropine did not significantly alter steady-state levels of MAP and PI. Both hexamethonium and prazosin decreased MAP variability in the 0.08- to 1-Hz range. In contrast, after hexamethonium and metoprolol, PI variability increased in the 0.4- to 3-Hz range. Atropine had no effect on MAP fluctuations but decreased those of PI in the 0.08- to 1-Hz range. These data indicate that, in mice, blood pressure and its variability are predominantly under sympathetic control, whereas both vagal and sympathetic nerves control PI variability. Blockade of endogenous nitric oxide formation by NG-nitro-L-arginine methyl ester increased MAP variability specifically in the 0.08- to 0.4-Hz range, suggesting a role of nitric oxide in buffering blood pressure fluctuations.

autonomic control; baroreflex; circadian rhythm; set point; spectral analysis


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE PROGRESSION IN recombinant DNA technology has permitted the development of genetically altered animals. This technology is increasingly used in cardiovascular research. For practical reasons, most genetically altered animal models are generated in mice, although other species can be used. Currently, many mouse models are available in which genes controlling hormones or receptors are overexpressed or disrupted to study the possible role of the respective gene product in cardiovascular disease (4, 16, 21). Concomitantly, this process has incited the miniaturization of techniques to assess cardiovascular function in the various phenotypes of mice (4, 7, 10). Presently, knowledge about the normal physiological characteristics of the murine cardiovascular system is still limited.

Arterial blood pressure levels have been compared in several genetically altered mice and their various control strains either by the indirect tail-cuff method (20) or directly via arterial catheterization (6, 16). However, many of these direct measurements were done during or shortly after anesthesia, and generally only for short-term periods, to compare blood pressure levels between different groups or strains of mice (7). Recently, using chronically implanted catheters, Mattson and Krausi (24, 25) described the feasibility of long-term measurements of arterial blood pressure in mice. However, continuous 24-h recordings to assess the spontaneous variation of blood pressure in this time frame have not yet been performed in the mouse.

The aim of this study was to characterize the long- and short-term spontaneous variations of blood pressure and heart rate (HR) in conscious unrestrained mice. Using an adapted version of a chronic perfusion technique, which was developed in rats (13), we investigated 24-h blood pressure and HR rhythms in Swiss mice. The reproducibility of these measurements was tested by comparing two full 24-h periods on a beat-to-beat basis. Spectral analysis was used to characterize the short-term variation of blood pressure and HR. In addition, pharmacological experiments were conducted to classify the frequency components at which the autonomic nervous system influences blood pressure and HR variability (22, 34, 35). In addition, the possible involvement of nitric oxide in buffering blood pressure fluctuations (8, 17, 27) was tested by determining the effect of NG-nitro-L-arginine methyl ester (L-NAME) on the spectral components of blood pressure.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Animals

Adult male outbred Swiss mice weighing 25-35 g were used. The mice were purchased from the Broekman Instituut (Someren, The Netherlands). Experiments were performed according to the guidelines of the Universiteit Maastricht and were approved by the institutional animal ethics committee. The animals were kept on a 12:12-h light-dark cycle in a temperature-controlled (21 ± 2°C) room. After surgery, animals were housed individually (cage size: length, 23 cm; width, 16 cm; height, 14 cm), with ad libitum access to standard food pellets (type SRMA-1210, Hope Farms, Woerden, The Netherlands) and water.

Surgery

The implantation of the arterial catheter for the long-term recording of blood pressure in the mouse was adapted from a technique we developed in rats (13). The arterial catheter was constructed from a 45-cm piece of PE-25 tubing (0.4 mm ID, 0.8 mm OD) that was heat-sealed to a 4-cm piece of PE-60 tubing (0.76 mm ID, 1.22 mm OD). The free end of the PE-25 tubing was heat-stretched above a soldering iron to obtain a 2-cm piece with an inner diameter of ~0.1 mm and outer diameter of ~0.15 mm. This heat-stretched part was bent into a J-shape 1.3 cm from its tip to provide proper angulation of the catheter during implantation. Under aseptic conditions, surgery was performed during pentobarbital sodium anesthesia (100 mg/kg ip) and with buprenorphine (2 mg/kg) as an analgesic agent. A small incision was made in the groin to expose the femoral artery. Via a small hole cut with iris scissors, the catheter was advanced into this vessel so that the tip was ~0.5 cm above the aortic bifurcation. The catheter was secured to the leg muscle and tunneled to the back of the mouse where a small incision was made 1.5 cm above the tail. Here, a small block (length, 8 mm; width, 8 mm; height, 5 mm) of silicone rubber (Sylgard 184, Dow Corning, Wiesbaden, Germany) was tightly sutured to the muscles of the back of the mouse with the aid of Mersilene gauze (type RM 3030, Ethicon, Norderstedt, Germany). Then, to this silicone block, a 40-cm steel spring (2.4 mm OD) was fixed, through which the arterial catheter was guided.

The venous catheter was made of a 1-cm piece of Silastic (0.12 mm ID, 0.25 mm OD) sealed to a 45-cm piece of PE-10. The venous catheter was implanted via the right jugular vein, guided subcutaneously to the back of the mouse, and exteriorized through the steel spring. The wounds were then closed with fine intracutaneous stitches. The venous catheter was filled with heparinized saline (5 U/ml) and plugged with a metal pin. The steel spring was led to the outside of the cage through a hole made at the base level and connected to a hydraulic swivel (model 375/20, Instech Labs, Plymouth Meeting, PA). The arterial catheter was connected to the swivel and hence to a low-volume displacement pressure transducer (micro-switch, model 156PC 156WL, Honeywell, Amsterdam, The Netherlands). The arterial cannula was kept patent by a continuous arterial infusion of heparinized saline solution (30 U/ml) at a rate of 0.5 ml/day. This setup allowed us to measure blood pressure continuously and to administer drugs without disturbing the mice. The catheter is protected from damage, and the mouse drags the spring through the cage without having to bear its weight. The mice habituate to this spring within a few hours.

Data Acquisition

The arterial pressure transducer was connected to an amplifier that delivered a high-voltage signal to an analog-to-digital converter board (model 2814, Data Translation, CN Rood, Rijswijk, the Netherlands) mounted in an IBM 486-compatible computer. The blood pressure signal was sampled at 2,000 Hz (~200 data samples/beat). The detection limit of blood pressure changes was <0.1 mmHg. The electrical drift in the pressure monitoring system was <1 mmHg/wk (13). Because of the length of the catheter and the elastic properties of its material, the pressure signal was dampened, and pulse pressure was only 20-30 mmHg. Therefore, we chose to utilize mean arterial pressure (MAP) only. Beat-to-beat values of MAP were calculated as the area under the curve of each pressure wave using the end-diastolic value to determine the interbeat or pulse interval (PI). The data acquisition software package (HDAS) was developed by the Engineering department of the Universiteit Maastricht.

Protocols

Long-term variation. To determine the effect of anesthesia and surgery on the 24-h variation of MAP and PI, measurements were started right after surgery and continued until the amplitude of the 24-h variation of MAP and PI became fully expressed and stable. During these measurements, 30-min average values of MAP and PI were saved on hard disk. Once the 24-h rhythms of MAP and PI were stable, the reproducibility of the 24-h variation of MAP and PI was determined. For this purpose, beat-to-beat values of MAP and PI were written to hard disk for two periods of 24 h, resulting in ~900,000 pairs of data points per 24 h for each mouse. The first measurement took place on day 6 or 7 after surgery (day 1). The second recording was made on day 9 ± 2 (range 7-14 days) after surgery (day 2). This protocol was completed in nine mice.

Short-term variation. The dynamic characteristics of MAP and PI were analyzed by spectral analysis. For the comparison of MAP and PI fluctuations between the active and resting phase, two periods of ~15 min (~10,000 beats) were selected from each 24-h period. One data segment was obtained during the resting phase between 10 and 11 AM (lights-on period). The other data segment was taken during the active phase between 1 and 2 AM (lights-off period). The values obtained on days 1 and 2 were compared to estimate the reproducibility of these data. The data handling and spectral analysis method are explained in detail in Data Analysis.

To determine the frequency ranges at which the autonomic nervous system influences blood pressure and HR variability in the mouse, beat-to-beat values of MAP and PI were recorded after injection of autonomic blockers. The pharmacological experiments were conducted in random order during the resting phase of the mice (between 10 and 12 AM) at 48-h intervals. Muscarinic blockade was obtained by atropine methylnitrate (1 mg/kg), beta 1-blockade by metoprolol (2.5 mg/kg), alpha 1-blockade by prazosin (0.1 mg/kg), and ganglionic blockade by hexamethonium bromide (25 mg/kg). All agents were dissolved in saline and given as intravenous bolus injections in volumes of 15-25 µl followed by 40 µl saline to wash the cannula. When, after the injection, hemodynamics had stabilized (~10 min), beat-to-beat measurements of MAP and PI were performed for 15 min. In the mice that had received metoprolol, combined cardiac autonomic blockade was induced by additional administration of 0.5 mg/kg metoprolol plus 1 mg/kg atropine. The efficacy of cardiac autonomic blockade was tested by comparing the effects of bolus injections of phenylephrine or sodium nitroprusside before and after cardiac autonomic blockade (see Fig. 1). In control conditions, the reflex response of PI may vary considerably due to arousal of the mouse after an injection. During autonomic blockade, this variation was less pronounced. The data obtained for change in MAP (Delta MAP) and PI (Delta PI) are as follows (±SD): phenylephrine control (n = 7): Delta MAP, 20 ± 8 mmHg, Delta PI, 30 ± 18 ms; after atropine: Delta MAP, 24 ± 8 mmHg, Delta PI, 1 ± 5 ms; sodium nitroprusside control (n = 7): Delta MAP, -22 ± 10 mmHg, Delta PI, -17 ± 6 ms; after metoprolol: Delta MAP, -24 ± 9 mmHg, Delta PI, -1 ± 7 ms. A comparable degree of reflex inhibition of PI was obtained after intravenous injection of hexamethonium bromide. The degree of blockade of adrenergic receptors by metoprolol and prazosin was not determined. However, because higher doses of metoprolol and prazosin did not further increase PI or lower MAP, respectively, it may considered to be near-maximally effective. Finally, the contribution of nitric oxide to buffering short-term fluctuations in arterial pressure was examined. For this, mice were given a bolus injection of 10 mg/kg L-NAME (20 µl + 40 µl saline) and, after a 10- to 15-min stabilization period, beat-to beat data of MAP and PI were recorded for 15 min.


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  		Fig. 1.   Representative example of the effects of intravenous injections of phenylephrine (phe; 2 µg/kg) and sodium nitroprusside (snp; 5 µg/kg) on mean arterial pressure (MAP; thick line) and pulse interval (PI; thin line) in conscious unrestrained mice before (A) and after blockade with atropine (1 mg/kg) (B) as well as before (C) and after blockade with metoprolol (2.5 mg/kg) (D).

The data on atropine, metoprolol, and L-NAME were obtained in the same group of mice in which the differences between the active and resting period were compared. Hence, the values obtained in the resting period were taken as control values. The effects of prazosin and hexamethonium were recorded in another group of Swiss mice. The control values of MAP (91 ± 3 mmHg) and PI (96 ± 4 ms) in this second group of animals were not different from those obtained in the first group of mice (MAP, 86 ± 2 mmHg; PI, 98 ± 2 ms). Measures of variability of MAP and PI were also not different between these groups.

Data Analysis

Long-term variation. The reproducibility of the 24-h measurements of MAP and PI was determined over different time scales. For each mouse, averages of beat-to-beat values of MAP and PI were compared when calculated over periods of 24, 12, and 1 h. Furthermore, as a measure of 24-h rhythmicity, the maximal 24-h amplitude of MAP and PI was defined as the difference between the lowest and highest 1-h average value of MAP and PI occurring in that 24-h period. Then, for each measure, the reproducibility was calculated as the relative difference between the first (day 1) and second day (day 2) of the beat-to-beat recordings. Data were averaged over nine mice.

To illustrate the long-term mutual interaction of MAP and PI, two-dimensional frequency distributions were constructed by counting the specific combinations of MAP and PI over 12:12-h light-dark periods and the full 24-h period (see Fig. 3). The bin widths for MAP and PI were set at 1 mmHg and 1 ms, respectively. Topographical altitude maps were made by plotting lines through bins with equal amounts of occurrences (multiples of 400). The advantage of such plots over time course graphics is that they 1) illustrate in more detail the range of the spontaneous variations of parameters and 2) reveal clusters of preferred combinations between parameters that are not visible in time course graphics. In all mice, MAP and PI were clustered around two different states, and the values of MAP and PI with the highest frequency were identified. We have used these techniques to illustrate our modified view on the concept of a set point and the concept of autoregulation (13, 31).

Short-term variation. Spectral power of MAP and PI was determined from the 15-min periods using a Fast Fourier transform algorithm. To obtain equidistant signals, the 15-min periods of beat-to-beat data of MAP and PI were resampled by linear interpolation at 40.96 Hz. Spectral power was then calculated on 50% overlapping consecutive blocks of 4,096 data points (each 100 s). Before calculation of the power, each segment was subjected to linear trend removal and cosine tapering. Spectral power was expressed in absolute units and averaged over the sequential data sets. In addition, the transfer gain, phase, and coherence between MAP and PI were calculated.

We have restricted our analysis to frequency ranges commonly used in rodents (>0.03 Hz). The spectra were divided into four different frequency domains on the basis of their appearance: 1) a high-frequency range (3-10 Hz), 2) a mid-frequency range (1-3 Hz), 3) a low-frequency range (LF; 0.08-1 Hz), and 4) a very-low-frequency range (<0.08 Hz). Based on the results (see Figs. 5-7), we have subdivided the LF band in two regions, namely, LF1 (0.08-0.4 Hz) and LF2 (0.4-1 Hz).

Because of the inverse relation between PI and HR, the spectra of PI and HR are not necessarily similar, and different results may be obtained (3). We have chosen to use PI rather than HR, because in the mouse species the distribution of PI data is smaller and less skewed than for HR. This may be easily seen when the range of values is compared at which PI (80-135 ms) and HR (444-750) varies. Comparison of the power spectra of PI and HR after all autonomic blockers yielded qualitatively similar results (data not shown).

Statistics

Data are presented as means ± SE unless stated otherwise. Statistical significance of the differences between the resting state, active state, and those caused by the administration of the autonomic blockers was tested by ANOVA, using post hoc Dunnett's and Bonfferoni's t-tests to indicate the level of significance between the resting control state and the other states, respectively. Statistical significance was accepted at P < 0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Long-Term Variation of MAP and PI

Figure 2 shows the spontaneous variation of MAP and PI as recorded in a mouse for 13 days after surgery. Figure 2 illustrates that it took at least 4 days after the surgical intervention and tethering to the recording system before the 24-h rhythms of MAP and PI became fully expressed. From then on, the amplitudes of the 24-h rhythms of MAP and PI were fairly constant. Similar findings were obtained in other mice. In some cases the PI rhythm was established 1 or 2 days sooner; however, in each mouse, MAP increased until days 2-3 after surgery and then declined to become constant from day 5 on. For this reason, all further data on MAP and PI variability were taken from postsurgery day 5.


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  		Fig. 2.   Example of a tracing of half-hour average values of PI and MAP recorded in a mouse for 14 days. Note that the 24-h rhythms of MAP and PI become stable after 5 days of surgery. Solid and open bars indicate 12-h periods of light and dark, respectively. Another tracing is shown in Fig. 4 of Ref. 7.

The day-to-day reproducibility of the measurements of average values of MAP and PI over several periods of time is summarized in Table 1. The average day-to-day variability of 1-, 12-, or 24-h averages of MAP and PI was ~5%. This value is lower than the coefficients of variation found for MAP and PI (~10%) over 1-h time periods. The greatest source of the within-hour variation of MAP and PI is behavioral activity. Although mice are nocturnally active animals, they are to some extent active during the lights-on period and were observed to eat and drink occasionally in this period. Blood pressure then increased to very similar values as those found during the lights-off period, when the mice display most of their activity. Consequently, the frequency distribution of MAP and PI showed a bimodal pattern during both these periods (see Fig. 3). In each mouse, 24-h beat-to-beat values of MAP and PI were clustered around two modes, associated with the resting and the active state. As indicated in Fig. 3, the day-to-day variability of these most preferred values of MAP and PI was fairly constant and was smaller than 3%. Furthermore, these preferred states differed significantly from the calculated 24-h average values of MAP and PI.

                              
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  		Table 1.   Reproducibility of the long-term recordings over several periods of time



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  		Fig. 3.   A and D: frequency distributions of MAP vs. PI in a mouse during the 12-h lights-on period (A) and 12-h lights-off period (D). B and E: contour plots of 24-h distributions of MAP and PI on 2 different days in the same mouse (B: day 1; E: day 2). C: modes of MAP and PI found in 9 mice. F: average 1-h values of MAP and PI over 24 h as recorded on day 1. Error bars indicate average within 1-h SD.

Short-Term Variation of MAP and PI

Resting state vs. active state. The average steady-state values of MAP and PI in the data segments selected from the resting and active periods are summarized in Fig. 4. In addition, overall variability, expressed as the standard deviation, is indicated. MAP and MAP-SD were significantly higher in the active state than in the resting state. Steady-state values of PI were significantly lower in the active state, whereas PI-SD values were not different from values obtained in the resting state.


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  		Fig. 4.   Steady-state values of MAP and PI as measured under different conditions. Values are means of the 15-min periods from which MAP and PI variability were assessed by spectral analysis. Overall variability of MAP and PI under each condition is indicated by SD. L-NAME, NG-nitro-L-arginine methyl ester. * P < 0.05, significantly different from resting control state.

During the resting and the active states, spectral power of PI was for a major part (~65%) confined to the respiratory frequency, which was found at 3-4 Hz during the resting state and at higher frequencies (4-6 Hz) during the active state (Fig. 5). In contrast, spectral power of MAP was related only to a small extent (~5%) to the breathing cycle. Spectral power of MAP and PI increased with lower frequencies, with individual peaks occurring at 0.08-0.6 Hz and sometimes at lower frequencies. The double logarithmic plots of averaged power of MAP and PI vs. frequency showed marked transitions at ~3 and 0.4 Hz, and a minor transition at 1 Hz. This suggests that within the frequency ranges segregated by these marks, different control mechanisms may be active. During activity, spectral power of MAP was elevated in the 0.08- to 3-Hz range. In contrast, spectral power of PI was decreased from 0.08 to 0.4 Hz. Coherence between MAP and PI was not only high at the respiratory frequencies, but also at 0.4 Hz, with MAP leading the PI fluctuations by ~0.3-0.4 s (see Fig. 8). This suggests that reflex coupling between blood pressure and HR occurs in this frequency range in mice. Remarkably, the coherence of MAP and PI around 0.4 Hz was significantly higher during the active than resting period. As shown in Fig. 5, these findings were not different between recordings made on different days.


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  		Fig. 5.   Comparison of average spectral powers of MAP and PI during resting and active phases. A: day 1. B: day 2. Average powers obtained during the resting phase are indicated by thick line. Thin line gives average powers found during the active phase. Average frequency-dependent changes in coherence (COH) between MAP and PI are given in the third plot. Note relatively high coherence at ~0.4 Hz. Power spectra were subdivided into 5 frequency ranges as indicated by dotted lines: VLF, very low frequency (0-0.08Hz); LF, low frequency (LF1: 0.08-0.4 Hz; LF2: 0.4-1 Hz); MF, mid frequency (1-3 Hz); HF, high frequency (>3 Hz). Reproducibility of these measurements was tested by comparing these data with average powers and coherence of data segments obtained on another day. With ANOVA, no significant differences between days were found. * P < 0.05 significant difference between the active and resting phase.

Effects of autonomic blockade. The steady-state values of MAP and PI during the various pharmacological interventions are given in Fig. 4. The spectral powers of MAP and PI are compared in Figs. 6 and 7, respectively.


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  		Fig. 6.   Comparison of average power spectra of MAP during 6 pharmacological interventions. A: atropine. B: prazosin. C: metoprolol. D: hexamethonium. E: atropine plus metoprolol. F: L-NAME. Power spectra obtained during blockade (thick line) are compared with those obtained in resting control conditions (thin line). * P < 0.05, significant difference between control and blocked states.



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  		Fig. 7.   Comparison of average powers spectra of PI during 6 pharmacological interventions. A: atropine. B: prazosin. C: metoprolol. D: hexamethonium. E: atropine plus metoprolol. F: L-NAME. Power spectra obtained during blockade (thick line) are compared with those obtained in resting control conditions (thin line). * P < 0.05, significant difference between control and blocked states.

ATROPINE. After muscarinic blockade with atropine, steady-state values of MAP did not change. PI values decreased slightly but not significantly from 98 ± 2 to 95 ± 2 ms. Whereas spectral power of MAP remained unaltered, administration of atropine reduced the PI fluctuations in the 0.08- to 1-Hz range.

METOPROLOL. When metoprolol was administered, PI increased from 98 ± 2 to 123 ± 3 ms. MAP was not altered. Total power of PI increased by a factor of ~2. PI became especially more variable from 0.4 to 3 Hz. Changes in spectral power of MAP were not significant.

METOPROLOL PLUS ATROPINE. After the combined administration of atropine and metoprolol, the steady-state values of MAP and PI were not different from those obtained in the control condition. As during atropine alone, PI power was significantly reduced in the 0.08- to 0.4-Hz range. Spectral power of MAP was not different from control.

PRAZOSIN. Although prazosin reduced MAP to values of 69 ± 3 mmHg, PI fell only slightly from 98 to 92 ± 3 ms. Prazosin reduced spectral power of MAP in the 0.08- to 1-Hz range. Spectral power of PI was not different from control.

HEXAMETHONIUM. Acutely after ganglionic blockade with hexamethonium, MAP fell to values of ~55 mmHg, but then stabilized for ~20 min at 64 ± 3 mmHg. In contrast, values of PI fell gradually over time and stabilized at 130 ± 7 ms. As found for prazosin, spectral power of MAP was significantly reduced in the 0.08- to 1-Hz range. Similar to metoprolol, and in contrast to the results obtained with atropine, spectral power of PI increased in the 0.4- to 3-Hz range. This suggests that ganglionic blockade resulted in a sympatholytic rather than parasympatholytic cardiac effect.

L-NAME. After injection of L-NAME , MAP increased within 15 min to 128 ± 5 mmHg and PI increased to 126 ± 4 ms. These changes in steady-state values were associated with specific changes in the spectral plots of MAP. Fluctuations of MAP increased specifically in the 0.2- to 0.3-Hz range and from 1 to 3 Hz. PI power was increased over all frequencies.

To further investigate the reflex coupling between MAP and PI, we compared the transfer gain and phase relation between MAP and PI in the 0.08- to 1-Hz range as obtained in the various conditions. The results are summarized in Fig. 8. As can be seen in Fig. 8, the magnitude of the transfer gain by itself is not a very suitable estimate of the baroreflex function. In conditions when the cardiac baroreflex was suppressed (i.e., after the injections of hexamethonium and metoprolol plus atropine), the gain was not different from control values. This suggests that in addition to reflex mechanisms, other factors influence the magnitude of fluctuations in this frequency range. In contrast to what was found by comparing the gain values, the phase relation appeared to indicate more accurately the situations when reflex coupling between MAP and PI was altered. In the conditions of suppressed reflex function, the phase shift between MAP and PI changed significantly from about -0.4 s to ~0, indicating that fluctuations of PI were not longer following those of MAP but occurred now simultaneously. Similar changes in the phase relation were observed after atropine, but not after metoprolol, suggesting that this was mediated by vagal rather than sympathetic withdrawal.


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  		Fig. 8.   Comparison of average transfer gain (A) and phase relation (B) between fluctuations of MAP and PI in the LF range (0.08-1 Hz) with a mid-frequency range of 0.4 Hz. A negative phase value indicates that MAP fluctuation is leading corresponding PI change. * P < 0.05, significantly different from resting (control) state.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

In studying the function and interactions of elements of the cardiovascular system, different strategies have been applied. In the most common approach, the physiological consequences of the elimination or stimulation of a single factor (or gene) are explored. In these types of experiments much effort is paid to minimize the variation brought about by other factors. In contrast to this approach, this study unraveled aspects of the cardiovascular system by studying the dynamic behavior and interaction of two principal parameters under circumstances that allowed maximal naturally occurring lability. With mathematical tools that examine in detail the spontaneous variation of these parameters, one may obtain supplementary information on the organization and function of the cardiovascular system (30). With the use of these techniques, this study characterized the stability and harmonic oscillations of blood pressure and HR controlling mechanisms in the mouse.

Long-Term Control of Blood Pressure and HR

Five days after the mice underwent surgery and were tethered to the continuous perfusion system, 24-h blood pressure and HR rhythms became stable, and their measurement became reproducible. The average 24-h values of blood pressure and PI in Swiss mice were in the range of values found in the study of Mattson (24) and in several other control strains of mice (6, 16). The initial disturbance of circadian rhythmicity is probably due to the stress imposed by the surgery (19). Recently, using a telemetric device in mice, Johansson and Thorén (15) found that the diurnal rhythms of HR, locomotor activity, and body temperature were regained no sooner than 4 days after the surgery.

In the present study, in terms of 1-h average values, the amplitude of the 24-h blood pressure rhythm was ~22%. That of the HR rhythm was ~19%. These values are not different from those obtained in other studies in mice and rats either by telemetry (15, 38) or by chronic catheterization (13). To what extent the attachment of the steel spring to the lower back of the mouse limits the natural behavior of the animal is not known. However, the advantage of tethering the protective spring to the lower back of the animal instead of to its neck is that it allows free movement of the head and that it does not hinder grooming behavior. We observed that, with the spring attached, the mice seemingly easily climbed the roof of their cage to feed. This suggests, as confirmed by the circadian patterns of blood pressure and HR, which run in parallel with those of activity (12, 15), that the present setup did not hamper the activity pattern of the mouse. Another possible drawback of this model may be that the continuous intra-arterial infusion of heparinized saline may affect the circadian blood pressure and HR levels. However, the amount of volume (0.5 ml) that is infused over 24 h is ~10% of the daily water intake in these mice (36). Therefore, the present chronic catheterization technique is a suitable method to continuously record blood pressure over long-term periods in mice in a reproducible manner.

The two-dimensional frequency distributions constructed from beat-to-beat pairs of MAP and PI showed that both parameters were bimodally distributed and associated with a state of activity and state of rest. As found before in the rat (13), there seems to be no single controlled set point of blood pressure; rather, in both species, there is a limited number of what we have called before (13, 29) preferred "homeodynamic" states between which the cardiovascular system switches. A consequence is that the dynamics of the control mechanisms must differ between these states. Therefore, it is important to standardize physiological blood pressure measurements in the mouse, especially when recording only for short time periods.

Effects of Autonomic Blockers on Steady-State Levels of MAP and PI

In resting conditions, blood pressure fell ~35 mmHg after blockade by hexamethonium and prazosin but did not change when atropine or metoprolol was given. This suggests that in normal mice adrenergic tone is important in the control of blood pressure. Mattson and Krausi (25) found that in normotensive mice blood pressure was also sensitive to angiotensin-converting enzyme inhibition. The potent hypotensive response to captopril appeared to be due in part to increased urinary excretion of sodium. The present data suggest that part of that response could be due to the sympatholytic effects of captopril too.

Resting values of PI were not significantly altered by atropine, corroborating data obtained in other strains of mice where atropine failed to accelerate HR (23) or only increased it modestly (5-7%) (6). In contrast, in this study, PI values increased considerably after injection of hexamethonium and metoprolol and fell only slightly when blood pressure was lowered 35 mmHg by prazosin. These data indicate that, in this experimental setup, HR was predominantly under sympathetic control. Remarkably, PI values were not similar after hexamethonium or the combination of metoprolol and atropine. The reason for this is unclear. It may be that control of HR depends partly on the endogenous release of (nervous) factors other than norepinephrine and acetylcholine (5, 26). The fact that L-NAME had a strong bradycardic effect in the mouse may indicate that nitric oxide directly influences the membrane potential of cardiac myocytes and hence the sinus rhythm (26). Preliminary observations in mice (n = 4) indicate that PI declines even further to ~149 ± 8 ms when L-NAME was added to hexamethonium and blood pressure returned to control values (97 ± 4 mmHg). Taken together, these data indicate that the adrenergic nerves play an essential role in the control of MAP and PI. However, the contribution of other nerves or factors, especially to the control of PI, may not be neglected.

Effects of Activity and Autonomic Blockers on the Dynamics of MAP and PI

Short-term variability of MAP and PI was different in the resting and active states, emphasizing the importance of standardizing conditions during hemodynamic recordings in mice. Most of the difference between the resting and active state was caused by an increase in 0.08- to 3-Hz fluctuations of blood pressure. MAP fluctuations in the 0.08- to 1-Hz range were suppressed after the administration of hexamethonium or prazosin. This suggests that, in the active state, part of the increase of MAP fluctuations is related to increased sympathetic tone to resistance vessels (0.08- to 1-Hz range). However, activity-related changes in body posture may not be excluded. These are possibly reflected by the increase of the 1- to 3-Hz fluctuations of MAP.

The short-term variability of PI was slightly different between the resting and active states. During activity, PI variability decreased in the 0.08- to 0.4-Hz range. With regard to the effects of atropine on this frequency range in resting conditions (see Fig. 7), the observed reduction in PI may be due to activity-related vagal withdrawal. These data indicate that, although atropine did not alter steady-state PI, its variability is under vagal control.

Remarkably, and in contrast to the effects of atropine, both ganglionic blockade and beta 1-blockade increased PI variability in the 0.4- to 3-Hz range. There are several explanations for this observation. First, the increase in PI variability could be a consequence of the increase in steady-state PI. However, if this were the case, then 1) a nonspecific increase of variability over all frequency bands would have been expected, and 2) relative measures of PI variability should not be different from control. However, compared with values found in control conditions (4.1 ± 0.3%), the coefficient of variation of PI was 4.8 ± 0.4% (P = 0.1) after metoprolol and 5.0 ± 0.6% (P = 0.1) after hexamethonium. This suggests that part of the change in PI variability is a consequence of sympathetic blockade. Our findings are compatible with previous reports obtained in other strains of mice. Mansier et al. (23) reported that HR variability increased after beta -blockade by propranolol in transgenic mice in which atrial beta 1-receptors were overexpressed. Conversely, in mice with a cardiac-specific overexpression of Gsalpha -proteins, HR variability was depressed (37). In other words, sympathetic overdrive diminishes HR variability. This is compatible with our observation that the elimination of sympathetic influences enhances HR variability. Finally, the increase of PI variability in the 0.3- to 4-Hz range after sympathetic blockade may be due to unmasking of other modulating factors. As mentioned above for the steady-state changes, the influence of nonadrenergic and noncholinergic nerves may not be neglected. Possibly, as discussed below, also nitric oxide may have some direct effects on the sinus node in the mouse. Direct recordings of nerve activity are necessary to distinguish between these possibilities.

The autonomic blockers did not influence PI variability at frequencies >3 Hz, which were related to the respiration. Both the vagal and sympathetic nervous systems seem too sluggish to modulate fluctuations at these high frequencies (14, 35). Therefore, we suggest that the fast HR fluctuations are mainly determined by mechanical factors exerted on the heart by the respiratory movement. As observed in rats (1), PI fluctuations at 0.4 Hz seem to be partly mediated by the baroreflex. The coherence between MAP and PI at this frequency was relatively high, with MAP oscillations leading those of PI by 0.4 s. Cardiac autonomic blockade by atropine and metoprolol decreased these PI fluctuations at 0.4 Hz. However, this reduction in PI variability had no consequences for blood pressure variability. Therefore, these data suggest that the cardiac component of the baroreflex is not a dominant blood pressure controller in the mouse.

After the administration of L-NAME, changes in spectral power of MAP were typically restricted to two frequency domains. The enhancement of fluctuations in the 0.08- to 0.4-Hz range is probably due to opening up of the control loop by which nitric oxide attenuates blood pressure fluctuations as described in detail by Persson (30). The magnitude of this response (an increase by a factor of 2) is comparable to those found in dogs (17), rats (28), and endothelial nitric oxide synthase knockout mice (33). If this would be an aspecific effect due to the increase of pressure (9), the frequency distribution of its components should remain constant. Alternatively, with regard to the rise in pressure, an influence of the baroreflex may not be excluded. The mechanism underlying the increase of MAP fluctuations from 1 to 3 Hz is unclear. These relatively fast fluctuations may have been caused by changes in locomotor activity of the mice, since this frequency range matches the frequency range of amplified pressure oscillations when the active and resting state were compared. Finally, with the large increase of PI variability at this range taken into account, enhanced fluctuations of cardiac output may have contributed too. Studies on the contribution of cardiac output to pressure fluctuations are underway (32).

An interesting finding of the present study is that the ranges of the sympathetic-mediated changes in MAP and PI were not similar. Frequency-dependent changes in MAP were found to decrease in the range of 0.08-1 Hz, whereas those of PI increased at 0.4-3 Hz. With the assumption that the postsynaptic nerve fibers in the heart and blood vessels were similarly suppressed by ganglionic blockade with hexamethonium, the difference in the frequency response of these organs is probably due to different sympathetic coupling characteristics at the level of the effector organ (cardiac pacemaker cell and vascular smooth muscle). This means that at sympathetic firing rates >0.4 Hz the ability of the heart to follow these oscillations becomes impaired and that, in response to the pulsatile release of norepinephrine, the pacemaker cells increase their rate while modulation decreases. In contrast, the resistance vessels seem to be able to follow the sympathetic fluctuations in the 0.08- to 1-Hz range by corresponding contractions and relaxations. Above 1 Hz, the vessels probably respond with a tonic contraction (11). These frequency-response characteristics of the heart and vessels are comparable to those observed by Stauss et al. (35) in rats. If one compares the known low-frequency oscillations in sympathetic nerve firing across species and scales them linearly to HR [0.1 vs. 1.2 Hz in humans (18), 0.3 vs. 4 Hz in rabbits (11), and 0.4 vs. 5 Hz in rats (2)], then one should expect the postganglionic sympathetic nerve fluctuations in mice at ~0.8 Hz, in view of their 10-Hz HR. However, on the basis of the appearance of the power spectra of MAP and PI and the frequency response to the sympathetic blockers, it appears that this frequency occurs also at 0.4 Hz in the mouse. This suggests that the time constants in the sympathetic pathways are similar in mice and rats and have reached their minimum values. However, direct recordings of sympathetic nerve firing are necessary to validate this hypothesis.

In summary, using a chronic catheterization technique, we were able to record arterial blood pressure continuously in conscious mice for periods of 2-3 wk. Over 24-h periods, MAP and PI were bimodally distributed and clustered around preferential states associated with rest and activity. Blood pressure and its variability were found to be predominantly under sympathetic control, whereas both vagal and sympathetic nerves controlled PI variability. In addition, the frequency ranges at which the sympathetic nerves modulate arterial resistance and HR cardiac function differ. Blockade of endogenous nitric oxide formation by L-NAME increased MAP variability at ~0.2 Hz, suggesting a role of nitric oxide in buffering blood pressure fluctuations.

Perspectives

The number of techniques that can be used to test cardiovascular function in mice is increasing, and these are helpful in the detection of physiological adaptations after genetic modification in this species (7). This study shows that the impact of surgery in these small animals is considerable and that extensive recovery periods are necessary for physiological assessments. Furthermore, the study shows that blood pressure and HR dynamics were different over the day and varied between resting and active states. Therefore, hemodynamic data obtained during or shortly after anesthesia or during restraint should be interpreted with care. Finally, HR was found to be largely under sympathetic control, which is at variance with especially human data, and hence questions the relevance of the use of this species in assessing mechanisms of human cardiac disease.


    FOOTNOTES

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 and other correspondence: B. J. A. Janssen, Dept. of Pharmacology, Universiteit Maastricht, PO Box 616, Maastricht 6200 MD, The Netherlands (E-mail: b.janssen{at}farmaco.unimaas.nl).

Received 13 July 1998; accepted in final form 3 August 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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