Published online before print July 8, 2002, doi: 10.1161/01.HYP.0000027279.69240.75
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(Hypertension. 2002;40:207.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Heart Rate Variability and Baroreflex Function in AT2 Receptor-Disrupted Mice
From the Max-Delbrück-Center for Molecular Medicine (V.G., R.P., M.O.), Helios-Klinikum-Berlin; Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University (J.T., J.J., F.C.L.), Berlin, Germany; and General Clinical Research Center, Vanderbilt University (A.D.), Nashville, Tenn.
Correspondence to Friedrich C. Luft, MD, Franz Volhard Clinic, Wiltberg Strasse 50, 13125 Berlin, Germany. E-mail luft{at}fvk-berlin.de
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Abstract |
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We adapted telemetry and sequence analysis employed in humans to mice and measured heart rate variability and the spontaneous baroreflex sensitivity in angiotensin II type 2 (AT2) receptor–deleted (AT2 -/-) and wild-type (AT2 +/+) mice with either deoxycorticosterone acetate (DOCA)-salt hypertension or N
-nitro-L-arginine methylester hydrochloride (L-NAME) hypertension. Mean arterial pressure leveled during the day at 101±1 mm Hg and during the night at 109±1 mm Hg in AT2 receptor–deleted mice, compared with 98±2 mm Hg (day) and 104±2 mm Hg (night) in wild-type mice. Mean arterial pressure increased in AT2 receptor–deleted mice with L-NAME to 114±1 mm Hg (day) and 121±1 mm Hg (night), compared with 105±2 mm Hg (day) and 111±2 mm Hg (night), respectively. DOCA-salt also increased day and night blood pressures in AT2 receptor–deleted mice to a greater degree than in wild-type mice. Heart rate variability in the time and frequency domain was not different between AT2 receptor–deleted mice and AT2 receptor–deleted mice at baseline. Systolic blood pressure variability in the low frequency band was lower in AT2 receptor–deleted mice (0.6±0.1 ms2 versus 3.9±1.3 ms2) than in wild-type mice. Baroreceptor-heart rate reflex sensitivity was significantly increased in AT2 receptor–deleted mice compared with wild-type mice (3.4±0.6 versus 2.1±0.5 ms/mm Hg). These differences remained after DOCA-salt and L-NAME treatments. We conclude that activation of the AT2 receptor impairs arterial baroreceptor reflex function, probably by a central action. These data support the existence of an inhibitory central effect of the AT2 receptor on baroreflex function.
Key Words: mice • receptors, angiotensin II • baroreflex • L-NAME • deoxycorticosterone
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Introduction |
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Angiotensin II (Ang II)–related effects are mediated by at least 2 receptor isoforms (AT1 and AT2). The AT1 receptor mediates vasoconstriction, aldosterone secretion, regulation of glomerular and renal tubular function, and cardiovascular hypertrophy. Although not yet as clearly delineated as the AT1 receptor, the AT2 receptor may be responsible for counterregulating the effects induced by the AT1 receptor.1 In accord with this view, disruption of the AT2 receptor caused increased blood pressure in mice and increased vasopressor responses to Ang II.1–5 In experimental and human hypertension, the sensitivity of the baroreceptor control of heart rate is reduced and has been associated with an overactivity of the renin-angiotensin system.6 Endogenous Ang II affects the baroreceptor function through the AT1 receptor7,8 and the AT2 receptor via central tonic inhibitory effects.9,10 Therefore, the AT2 receptor gene–disrupted (-/-) mouse could be a useful model for studying the involvement of the AT2 receptor in baroreceptor function. In man, the combined computer analysis of spontaneous blood pressure and heart rate fluctuations allows the assessment of baroreflex function without invasive or provocative interventions. We adapted telemetry to AT2 receptor -/- and wild-type (+/+) mice to study blood pressure and continuous spontaneous baroreflex function in the mouse. To our knowledge, this report is the first in which these clinically accepted methods are applied to mice.
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Methods |
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Experiments were performed on 8 adult male AT2 receptor–deleted (AT2 -/-) and 7 male wild-type (AT2 +/+) mice. All animals used in this study were from Vanderbilt University Medical Center (Nashville, TN; courtesy of Dr T. Inagami). The animals were allowed free access to standard chow (0.25% sodium, SNIFF Spezialitäten GmbH) and drinking water ad libitum. The protocol was approved by the local council on animal care and corresponds to requirements of the American Physiological Society.
Before implantation of the TA11PA-C20 blood pressure device (Data Sciences International), the zero offset of the instrument was measured and the unit was soaked in 0.9% NaCl. Mice were anesthetized with enflurane (Baxter Deutschland GmbH). The mice were shaved on the ventral abdomen, and the surgical area was denuded further with a depilatory cream. During surgery and in the recovery period, the mice were placed on a heated table to maintain body temperature. After a 2- to 3-cm midline abdominal incision and retraction of the intestines, the aorta was dissected from the surrounding fat and connective tissue and separated from the vena cava below the left renal artery. A suture (6x0) was placed around the aorta. Before insertion of the transmitter catheter into the aorta, the vessel was rinsed with 2% lidocaine. After vessel occlusion, the catheter was inserted into the aorta through a small hole made with a 29 G needle and advanced 5 to 6 mm. Thereafter, the catheter was sealed in place with Vetbond tissue adhesive and the aorta was rinsed with more 2% lidocaine to avoid vessel spasm. After careful replacement of the intestine, the body of the transmitter was fixed on the abdominal wall and the cavity was closed with sutures. During the surgery the intestine was kept moist by rinsing the cavity with prewarmed 0.9% saline. The rapid procedure prevented ischemic neurologic injury. The mice were moved to their home cages without any signs of paralysis.
The mice were synchronized to a light-dark schedule of 12:12 hours with lights on at 06:00 AM. All mice were allowed 10 days recovery from surgery before any measurements were made. At this time the mice had regained their circadian blood pressure and heart rate rhythm. Thereafter, baseline values were continuously recorded for 3 days. During the recovery period and during recording of baseline values, the mice received normal chow (0.25% NaCl) and tap water. In the following week, the mice were given a 5 mg/10 mL dose of N-nitro-L-arginine methylester hydrochloride (L-NAME) in their drinking water for 1 week. The retrospective calculation of L-NAME uptake for both strains revealed an L-NAME uptake of 0.1 mg/g per day during the time period as blood pressures and heart rates were measured and the baroreceptor function determined. After L-NAME treatment the mice were maintained with tap drinking water for 1 week. Thereafter, all mice underwent light ether anesthesia, and a 50-mg deoxycorticosterone acetate (DOCA) pellet (Innovative Research of America) was implanted subcutaneously. The mice also received 1% NaCl as drinking water and were given standard chow for 2 weeks. We measured body weight twice a week. All mice appeared healthy and could not be distinguished from mice not carrying the TA11PA-C20 blood pressure device.
The data from the TA11PA-C20 device were transmitted via radio frequency signals to a receiver below the home cage and thereafter collected using the Dataquest A.R.T. system, version 1.1 (Data Sciences International), which allowed us to detect, collect, and analyze signals from several animals simultaneously. The data were sampled every 5 minutes for 10 seconds, continuously day and night, with a sampling rate of 1000 Hz and stored on a hard disk. Systolic (SBP) and diastolic blood pressure (DBP), mean arterial pressure (MAP), and heart rate (HR) were recorded using the Dataquest software. For statistical analysis, the values for 3 consecutive days were analyzed as the 12-hour mean (day/night) of mean arterial pressure (MAP) and heart rate (HR). Because in mice the fluid and electrolyte homeostasis is achieved efficiently within 2 days after altering salt balance,11 we performed statistics with all values from days 4 to 7 after adding L-NAME to the drinking water or from days 4 to 7 and 11 to 14 after DOCA and 1% saline. In an earlier study, we found that, at this time point, sodium excretion does not increase further in DOCA-salt hypertensive mice.12
For further evaluation of cardiovascular function, the baroreceptor heart rate reflex was investigated using spontaneous changes in blood pressure and heart rate. For this purpose, on the third day of each recording period, signals were sampled beat-by-beat during a 2-hour daytime period (8:00 AM to 10:00 AM). This period of day, when the mice are quietly resting, was chosen to minimize the influence of physical activity or cortical arousal. The baroreceptor heart rate reflex was calculated using the sequence method over the whole 2-hour period; the sequence method is described elsewhere.13,14 Briefly, the spontaneous baroreflex slope (BRS) was calculated as the slope of the linear regression lines between the SBP and the subsequent RR intervals, with a delay of 0, 1, or 2 heartbeats, using the sequence technique. Because the number of sequences found was highest for the delay of 1 heartbeat in both strains, we used only values calculated with this delay for further analysis. Sequences with at least 3 intervals, 0.5 mm Hg blood pressure changes, and 5 ms RR interval changes were analyzed only if the correlation coefficients were >0.85. BRS was calculated as the mean value of the significant slopes obtained.
Power spectral analysis has provided useful information about the temporal fluctuations of different hemodynamic parameters such as heart rate variability in animal and human studies.15,16 Cross spectra were used to capture interrelationships between parameters in the time and frequency domain. Therefore, we calculated the power spectra of SBP and RR interval time series using fast Fourier transformation (segment length 32 s, resampling with 4 Hz, resolution 0.004 Hz, mean values of 3 to 5 segments) and the cross spectra.17 The baroreflex gain was determined as mean value of the transfer function in the very low, low, and high frequency bands (VLF=0.015 to 0.250 Hz; LF=0.250 to 0.600 Hz; HF=1.0 to 3.0 Hz). BRS was considered significant if the coherence in the analyzed frequency band was >0.8. The frequency bands were adapted for analysis in mice considering the ranges of heart rate and breathing frequencies. The data analysis was performed by use of PV-WAVE software (VisualNumerics). Representative 256 seconds were chosen according to the following criteria: (1) steady state conditions, (2) no large sudden changes of blood pressure, (3) no artifacts, and (4) high heart rate variability. Data are presented as means±SEM. Differences were tested by ANOVA for repeated measures, the Bonferroni t test, and the Mann Whitney U test. Probability values <0.05 were considered statistically significant.
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Results |
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Figure 1 shows that 4 to 5 days after transmitter placement, heart rate and systolic and diastolic blood pressure again exhibited a normal daytime variation. Therefore, we are confident that blood pressure regulation was not affected by the surgical procedure. Figure 2 shows the spontaneous changes in blood pressure and heart rate used to analyze baroreflex function. Shown is a 2-hour beat-to-beat registration period. The figure illustrates the profound spontaneous oscillations of RR intervals and arterial blood pressure recorded in a representative AT2 -/- mouse. The AT2 +/+ mice had patterns that were not different. The figure underscores the marked range of baroreflex function, even in resting, unperturbed mice. The lower panel of Figure 2 shows blood pressure and heart rate spectra obtained for 32 seconds in the same mouse. Note the similar characteristic peaks as obtained in humans, only different in the frequency scale. This supports the hypothesis that blood pressure control in mice has major similarities to that in other mammals. We believe that this state of affairs indicates that spontaneous baroreflex sequences represent physiological rather than chance interactions also in mice. Figure 3 shows that the number of sequences was highest for the delay of one heartbeat. The sequence number at the 2-heartbeat delay was significantly lower. The strains did not differ in that regard.
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Body weight averaged 30±0.8 g in AT2 -/- mice and 31±0.6 g in AT2 +/+ mice before surgery. After surgery the weights decreased by 2 to 3 g. One week later, the mice showed slightly reduced but stable body weights. The body weights increased continuously and averaged 29±0.6 g in AT2 -/- and 30±0.6 g in AT2 +/+ mice at the baseline period and 29±0.5 g in AT2 -/- and 32±1.0 g in AT2 +/+ mice at the end of the protocol.
In AT2 -/- mice, the 12-hour mean of MAP leveled during the day 101±1 mm Hg and the night 109±1 mm Hg compared with 98±2 mm Hg (day) and 104±2 mm Hg (night) in AT2 +/+ mice. The heart rate leveled in AT2 -/- mice 502±7 (day) and 530±8 beats per minute (bpm, night) compared with 507±7 (day) and 538±7 bpm (night) in AT2 +/+ mice. Figure 4 shows the changes in MAP and HR after L-NAME and DOCA-salt treatments during day and night. L-NAME increased blood pressure more in AT2 -/- than in AT2 +/+ mice, so that MAP leveled in AT2 -/- mice at 114±1 (day) and 121±1 (night) compared with 105±2 mm Hg (day) and 111±2 mm Hg (night), respectively. In the following week with tap water vehicle, all parameters returned to levels measured before L-NAME treatment. The DOCA-salt regime induced an increase in blood pressure that was also more pronounced in AT2 -/- mice than in AT2 +/+ mice. The increases in blood pressure after DOCA-salt and L-NAME treatments were not significantly different, indicating that similar degrees of hypertension were achieved with both regimens. The blood pressure increases after L-NAME and DOCA-salt treatments were accompanied by decreases in heart rate in both strains.
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Heart rate variability in the time domain (coefficient of variation, CV) was similar in the two mouse strains and not affected by the interventions with the exception of DOCA-salt mice. CV in DOCA-salt–treated AT2 -/- mice was 9.7±1.9% compared with 5.6±0.6% in DOCA-salt–treated AT2 +/+ mice. Heart rate variability in the frequency domain (power spectral density in the very low [VLF], low [LF], and high frequency [HF] bands) in AT2 -/- mice was also similar to that in AT2 +/+ mice. However, the coefficient between LF and HF spectral power density, which is presumed to reflect sympathovagal balance in heart rate control,18 was significantly reduced in L-NAME–treated AT2 -/- mice compared with L-NAME–treated AT2 +/+ mice (1.3±0.3% compared with 2.7±0.7%).
Systolic blood pressure variability in terms of standard deviation was similar in the 2 strains. Shown in Figure 5 are systolic blood pressure variability in the low frequency band (SBPLF), the baroreflex sensitivity calculated as the mean value of the transfer function between systolic blood pressure and RR intervals in the low frequency band (BRSLF), and baroreflex sensitivity calculated with the sequence technique for upslopes of systolic blood pressure (BRSup) in untreated AT2 -/- and AT2 +/+ mice. The SBPLF was significantly reduced in AT2 -/- mice at 0.6±0.1 ms2 compared with 3.9±1.3 ms2 in AT2 +/+ mice (Figure 5, top). BRSLF (cross-spectral analysis) was 6.3±1.2 in AT2 -/- mice and 2.3±0.6 ms/mm Hg in AT2 +/+ mice (Figure 5, middle). The BRSup (sequence technique) was increased in AT2 -/- mice compared with AT2 +/+ mice. The values were 3.4±0.64 and 2.15±0.52 ms/mm Hg (Figure 5, bottom). Irrespective of the analysis used, the AT2 -/- mice showed higher baroreflex sensitivity values compared with AT2 +/+ mice. Surprisingly, hypertension-producing treatments did not significantly affect baroreflex sensitivity parameters (BRSLF and BRSup) in either strain.
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Discussion |
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The important observation in our study was that systolic blood pressure variability was reduced in AT2 -/- mice compared with AT2 +/+ mice. Moreover, the baroreflex sensitivity calculated by use of the sequence analysis and cross-spectral analysis was increased in AT2 receptor -/- mice compared with AT2 +/+ controls. These differences were sustained during the development of secondary hypertension in these mice.
Cardiovascular reflexes play an important role in the regulation of circulation in both physiological and pathophysiologic states. In contrast to baroreflex control of blood pressure or peripheral resistance, which has been reported to be normal in humans with essential hypertension or in experimental models of hypertension,19 baroreflex control of heart rate has been shown to be impaired in hypertension and is associated with the risk of cardiovascular events.20 This state of affairs is the basis for the interest in these parameters. The technique of recording heart rate and arterial pressure on a beat-to-beat basis allowed us to analyze "spontaneous" baroreflex control of heart rate under free-living daily conditions.21
To account for changes in baroreceptor input, we calculated BRS using the sequence technique over 2 hours. We also used cross-spectral analysis as a second method of BRS analysis for selected periods of 32 seconds each. Both methods showed similar results. We are aware that spontaneous BRS reflects only one point of the baroreflex response curve. However, investigations in humans have shown a close correlation between invasive and different noninvasive methods, such as the cross-spectral and the sequence techniques.22 All methods have advantages and limitations. The traditional pharmacological technique (phenylephrine and nitroprusside) can induce changes in the mechanical properties of the arterial wall where the baroreceptors are located. This potential confounder may interfere with physiological baroreceptor stimulation. Therefore, differences between the results obtained by these methods would be expected. We believe that invasive and noninvasive approaches should be regarded as complementary approaches.23 To our knowledge, this study is the first to use blood pressure telemetry to calculate BRS repeatedly under different pathophysiological situations in the mouse.
Functional investigations show that angiotensin II modulates the baroreceptor reflex in the nucleus tractus solitarii (NTS) via the AT1 receptor.24–26 Furthermore, the AT2 receptor has been reported to have a tonic inhibitory effect on the baroreceptor reflex. This effect is believed to have origins within the central nervous system.9,10 Microinjections of Ang II and Ang III into the NTS lead to a tonic inhibition of the baroreceptor reflex. The action of Ang II is confined to the AT1 receptor, whereas the action of Ang III is mediated via both the AT1 and AT2 receptor subtypes.9,10,27 Furthermore, at the site of the rostral nucleus reticularis ventrolateralis, both Ang II and Ang III may promote a tonic suppression of the spontaneous baroreceptor reflex via the AT2 receptor.9 Our study suggests that Ang II attenuates the baroreceptor reflex via the AT2 receptor. The AT2 -/- mice clearly exhibited baroreflex sensitivity that was increased compared with AT2 +/+ mice. Therefore, in wild-type +/+ mice, the net effect of Ang II on both the AT1 and AT2 receptors may have depressed baroreflex activity. Moreover, the more effective baroreflex in AT2 -/- mice may enable these mice to decrease their blood pressure variability because of dampening blood pressure changes. This interpretation is supported in part by the changes of heart rate variability in the time (CV) and frequency domains (LF/HF) in these mice. However, the HRV parameters did not reach statistical significance because of the high inter- and intraindividual variability normally found in free-moving, conscious mice. We were very surprised to observe such a high degree of variability in resting, unperturbed mice.
On the other hand, Ang II acting within the NTS may depress the baroreceptor reflex via release of NO.28 These observations prompted us to investigate baroreceptor function in L-NAME hypertensive mice with blocked NO synthesis and to compare these mice with DOCA-salt hypertensive mice. In DOCA-salt hypertensive mice, the NO system is stimulated.29 Hypertension, induced either by L-NAME or DOCA-salt treatment, increased blood pressure similarly in both strains. The present results are in good agreement with other reports showing that chronic administration of L-NAME causes arterial hypertension in rats30 and mice.31,32 In L-NAME-hypertensive rats, both a decrease and an increase in baroreflex sensitivity have been reported.28,30,33 NO synthesis in mice resulted in an enhancement of baroreflex sensitivity in an earlier study.31 In our study, L-NAME treatment increased blood pressure to a greater degree in AT2 -/- than in controls, suggesting an augmented sensitivity of AT2 -/- mice to L-NAME. The baroreflex sensitivity was not affected by L-NAME in our study. This result contradicts the observation of Peotta et al,31 who found an increase in baroreflex sensitivity after L-NAME treatment by use of the phenylephrine and sodium nitroprusside technique in urethane-anesthetized mice, which decreases mean arterial blood pressure. The differences may be related to the fact that we measured arterial baroreflex control of heart rate in the conscious state under free-living conditions without pharmacological interventions. This result would support the view that the influence of NO on baroreceptor sensitivity is small under these circumstances.
DOCA-salt also increased blood pressure in both strains. However, again the blood pressure increase in AT2 -/- mice was greater than in AT2 +/+ mice. The mechanisms of DOCA-salt hypertension are not fully understood. However, changes in hormonal and neural pressor mechanisms, including bradykinin, nitric oxide, altered neural Ang II, and vasopressin activity, elevated sympathetic drive, endothelin-related mechanisms, and a distorted baroreflex response, all appear to contribute to DOCA-salt hypertension.34–39 DOCA-salt–treated mice in our study had similar responses as L-NAME–treated mice, even though their NO-related mechanisms were presumably stimulated. The findings suggest that NO-related influences on baroreflex regulation did probably not have a major impact on our findings. We assume that the stronger blood pressure increase to L-NAME and DOCA-salt treatment in AT2 -/- may be caused by the missing AT2-mediated vasodilatory effect normally opposing the AT1-mediated vasoconstriction and may be also accelerated by the upregulated AT1 receptor in AT2 -/- mice.5,40,41 In contrast, the normally synergistic inhibitory central action of the AT1 and AT2 receptors may be responsible for the improved baroreflex function seen under baseline conditions that were not further influenced by L-NAME and DOCA-salt treatment. The approximately 10 to 15 mm Hg increase of mean arterial blood pressure after L-NAME and DOCA-salt treatment may be not sufficient to induce the expected reduction of the baroreflex-mediated heart rate control caused by hypertension.
Another important observation of our study was the finding that telemetric measurements required a week’s recovery before the normal cardiovascular responses, particularly circadian cycles, were restored. General anesthesia is required for placement of intra-arterial catheters in mice. We suggest that baroreflex and similar measurements in conscious mice should not be performed acutely. A weakness in our study is that we included only a relatively small number of mice (AT2 -/- n=8, AT2 +/+ n=7). However, under the view of telemetric chronic studies, these numbers are relatively high. We elected the intra-abdominal placement of our transmitters to avoid the confounding effects of carotid catheterization in our mice.42 The mortality of abdominal placement is higher, and the technical difficulty involved is greater. However, the amount of data we analyzed in our chronic study was substantial. The animals have a heart rate of 500 to 600 bpm, and we collected data for days at a time. Thus, we were able to measure blood pressure over weeks and to apply repeated-measures analyses.
Perspectives
We suggest that future perspectives provided by our data include research into the central role of the AT2 receptor in baroreflex activation. A tonic suppression effect by AT2 receptors on baroreflex sensitivity has been suggested. However, additional mechanistic studies will be necessary to verify this possibility. Also poorly explained is why AT2 receptor–deficient mice developed a greater increase in blood pressure than did controls and yet exhibited responses suggesting superior baroreflex sensitivity in response to 2 vastly different forms of secondary hypertension. Reconciling these findings in future studies may lead to a new appreciation of baroreflex-related mechanisms. Finally, our application of computerized baroreflex analyses that were designed for humans to mice with heart rates 10-fold higher and with much more divergent blood pressure and heart rate responses may open further avenues of investigation.
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Acknowledgments |
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This study was supported by a grant-in-aid from the Deutsche Forschungsgemeinschaft to Volkmar Gross. We are grateful to Sabine Grüger and Ilona Kamer for technical assistance.
Received February 12, 2002; first decision March 20, 2002; accepted June 11, 2002.
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