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Am J Physiol Regul Integr Comp Physiol 286: R108-R113, 2004. First published September 11, 2003; doi:10.1152/ajpregu.00405.2003
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REGULATION IN GENETICALLY MODIFIED ANIMALS

Dbh(-/-) mice are hypotensive, have altered circadian rhythms, and have abnormal responses to dieting and stress

Steven J. Swoap,1 David Weinshenker,2 Richard D. Palmiter,2 and Graham Garber1

1Department of Biology, Williams College, Williamstown, Massachusetts 01267; and 2Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, Washington 95195

Submitted 21 July 2003 ; accepted in final form 10 September 2003


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
We used mice deficient in dopamine {beta}-hydroxylase [Dbh(-/-)] and their littermate controls [Dbh(+/-)] to examine the role of epinephrine (Epi) and norepinephrine (NE) in the maintenance of cardiovascular parameters during 7 days of caloric restriction and acute exposure to environmental stress. Cardiovascular parameters of the mice were monitored using blood pressure radiotelemeters at an ambient temperature of 29°C. Under normal conditions, Dbh(-/-) mice had a low heart rate, were severely hypotensive, and displayed an attenuated circadian blood pressure rhythm. Upon 50% caloric restriction, Dbh(+/-) mice exhibited decreases in heart rate and mean blood pressure. However, the blood pressures of Dbh(-/-) mice did not fall significantly in response to caloric restriction, and the bradycardia associated with caloric restriction was attenuated in these mice. In response to an open-field test, the blood pressure and heart rate of Dbh(+/-) mice increased substantially and rapidly, whereas Dbh(-/-) mice had blunted changes in blood pressures and no change in heart rate. These data suggest a primary role of Epi and NE in mediating the hypotension induced by dieting. Furthermore, Epi and NE play a smaller, but still significant, role in the bradycardia induced by caloric restriction. In contrast, Epi and NE are required for the tachycardia in an open field but are not required for the increase in blood pressure.

hypertension; blood pressure; food restriction; sympathetic nervous system; radiotelemetry; dopamine {beta}-hydroxylase-deficient mice

ONE OF THE MAJOR COMORBIDITIES with obesity is high blood pressure (11). Restriction of caloric intake has been known for many years to be an effective tool for lowering blood pressure in hypertensive humans, hypertensive rats, and even normotensive mice (8, 18, 27, 35, 40, 39, 42). Both leptin signaling and insulin signaling have been suggested as mediators of the hypotensive effect of caloric restriction (12, 19). Although the extent to which these hormones mediate obesity-related hypertension and diet-induced amelioration of hypertension remains somewhat controversial, the suggested signaling pathways for both of these hormones converge on the sympathetic nervous system (SNS). In fact, the hypotensive effect of caloric restriction has long been thought to be mediated through the SNS based on correlative reductions in catecholamine levels, sympathetic outflow, and blood pressure during a calorie-restricted regime (4, 8, 10, 16, 18, 41).

The primary aim of this study was to directly test the hypothesis that the chronic absence of the sympathoadrenergic catecholamines epinephrine (Epi) and norepinephrine (NE) would result in the lack of change in blood pressure and heart rate observed during caloric restriction. Epi and NE are synthesized from dopamine by dopamine {beta}-hydroxylase (DBH). Mice with a targeted disruption of the Dbh gene have been generated that completely lack Epi and NE (30). It is clear that the sympathetic branch of the autonomic nervous system plays a dominant role in the regulation of chronic blood pressure in rats (6) and mice (reviewed in Ref. 14). Some cardiovascular dysfunction has been noted in that smooth musculature surrounding peripheral vessels in DBH-deficient mice [Dbh(-/-)] do not show the appropriate vasoconstrictor activity in response to cold, contributing to the cold-intolerant phenotype (31). However, Dbh(-/-) mice display normal left ventricular systolic and end-diastolic pressures under anesthesia (2). We used radiotelemetry in these Dbh(-/-) mice to assess the cardiovascular parameters in conscious, freely moving animals and in response to a bout of caloric restriction.

A secondary goal of this study was to characterize the cardiovascular response of the mouse in an often-used stress test, the open-field test. Catecholamines have long been known to play an important role in the stress response in humans and rats (1, 3, 21, 32-34). Use of these Dbh(-/-) mice allowed us further to examine the role of Epi and NE in mediating the stress response in mice in the open-field test.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. Homozygous control mice [Dbh(+/-)] and Dbh(-/-) mice (6 mo old, ~22 g) were bred at the University of Washington and shipped to Williams College for cardiovascular assessment. Animals were maintained on a 12:12-h light-dark cycle, dark from 5:00 P.M. to 5:00 A.M. All animal studies were approved by the Williams College Institutional Animal Care and Use Committee. Dbh(+/-) mice have normal catecholamine levels (29, 31) and were used as controls for all experiments.

Implantation of blood pressure telemeters. Mice (n = 7 for each group) were anesthetized initially with 5% isofluorane in an oxygen stream and maintained on 1-2% isofluorane. Mice were kept on a heating pad (38°C) throughout implantation of blood pressure transducers (PAC20; Data Sciences International) in the left common carotid artery (26). Mice were maintained on a heating pad for 48 h after the surgery and then housed at 29°C for 1 wk to allow time for recovery.

Baseline and caloric restriction cardiovascular data collection. Data from the blood pressure telemeters were recorded at 500 Hz. Between 5:00 P.M. and 4:00 P.M. on the next day, 2-min data streams were obtained every 10 min. From the pressure waveform analysis, the following cardiovascular parameters were obtained: heart rate, systolic blood pressure, diastolic blood pressure, mean blood pressure, pulse pressure, and the SD of the interbeat interval (SDIBI). Activity of the animals was also monitored. Between 4:00 P.M. and 5:00 P.M., data were not taken while the animals were cared for (watered, fed, bedding change, etc.) The dark-cycle cardiovascular parameters were averaged from data collected between 5:00 P.M. and 4:00 A.M., and the light-cycle parameters were averaged from data collected between 5:00 A.M. and 4:00 P.M. Baseline data reported are the averages of two consecutive dark cycles or two consecutive light cycles. During this period, mice were fed ad libitum a diet consisting of the following: 45% carbohydrate (cornstarch), 35% fat (24% corn oil and 11% lard), and 20% protein (casein), supplemented with vitamins, minerals, and fiber (cellufil). The mice were then calorically restricted (50% of normal caloric intake supplemented with vitamins and minerals to match the intake of the precaloric restriction diet) for 1 wk. The temperature of 29°C was chosen for the following two reasons: 1) the cold sensitivity of the Dbh(-/-) mice (31) and 2) to prevent entry of these mice into torpor during the bout of caloric restriction (9, 26, 39). Data were collected over the last 2 days of caloric restriction.

Open-field data collection. The mice were fed ad libitum after the caloric restriction bout for 7-9 days. Mice were tested between 9:00 A.M. and 11:00 A.M. (4-6 h into the light cycle) on three successive mornings (each animal was tested only one time). The open-field test consisted of the following three phases: rest, in the open field, and recovery. During the rest phase, the mouse was in its home cage for a duration of 5 min. The animal was then gently moved in the open-field arena, which consisted of a white box (3 ft. x 3 ft. x 3 ft.) illuminated to 600 lux. The receivers for the telemetry were set in an array beneath the box to allow for cardiovascular data collection from all points within the box. After 5 min, the animal was retrieved and allowed to recover for 5 min in its home cage. The data were collected continuously throughout the 15 min.

Statistics. Data for the variables studied are reported as means and SE. Statistical analysis for baseline and caloric restriction cardiovascular parameters included a three-factor ANOVA (genotype, fed state, light-dark cycle) followed by a post hoc least-significant difference (LSD) test. Statistical analysis for the open-field test included a repeated-measures ANOVA followed by a post hoc LSD test. The 0.05 level of confidence was accepted for statistical significance.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Baseline cardiovascular parameters. Dbh(-/-) mice exhibited striking differences in cardiovascular parameters compared with heterozygote littermates. A typical blood pressure tracing is shown in Fig. 1A, taken during the dark cycle for both animals. Systolic, mean, diastolic, and pulse pressures were significantly lower in Dbh(-/-) mice compared with Dbh(+/-) littermates (Table 1) within both the dark cycle (active period) and light cycle (inactive period). The Dbh(+/-) mice exhibited normal circadian rhythms, with elevated heart rate, blood pressures, and activity during the dark cycle (Fig. 1B and Table 1). In contrast, although the Dbh(-/-) mice showed circadian rhythms in heart rate and activity, the differences in blood pressure between the light and dark cycle were minimal but statistically significant. The SDIBI was calculated from the blood pressure tracings. The SDIBI of Dbh(-/-) mice was significantly higher than in Dbh(+/-) mice during both the dark and light cycles (Table 1).



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  		Fig. 1. Blood pressure of a mouse deficient in dopamine {beta}-hydroxylase [Dbh(-/-)] and its littermate control [Dbh(+/-)]. A: representative blood pressure (BP) waveform of a Dbh(+/-) mouse and a Dbh(-/-) mouse. The blood pressure tracings shown are 2-s segments during the dark cycle. B: pressure waveforms were collected for 2-min bouts every 10 min. Mean blood pressure and heart rate were averaged over that 2-min bout and plotted. Activity was calculated based on pressure telemeter movements within the cage. Lights were off from 5:00 P.M. to 5:00 A.M. Arb. units, arbitrary units.

 

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  		Table 1. Cardiovascular parameters of Dbh(+/-) and Dbh(-/-) mice during the dark and light cycles

 

Caloric restriction. Previous reports by us (26) and others (38, 39) have demonstrated decreases in mouse heart rate and blood pressure in the dark cycle in response to 7 days of 50-60% caloric restriction. We used the Dbh(-/-) mice and littermate controls to determine whether Epi and NE were required for altered cardiovascular parameters during caloric restriction. Dbh(+/-) mice ate 11.8 ± 0.5 kcal/day, whereas Dbh(-/-) mice ate a nonsignificantly different amount of 12.3 ± 0.3 kcal/day during the ad libitum feeding. Mice were calorically restricted at 50% of normal intake (6 kcal/day) for 7 days at 29°C. Dbh(+/-) mice lost 2.4 ± 0.6 g body wt and the Dbh(-/-) lost 2.3 ± 0.5 g body wt over the 7 days. For analysis of cardiovascular parameters, data from the last two 24-h periods during caloric restriction were averaged and compared with baseline data listed in Table 1. Dbh(+/-) mice exhibited significant drops in all blood pressure values (mean blood pressure shown in Fig. 2) and heart rate (Fig. 2) in the dark cycle in the absence of any significant changes in loco-motor activity. Mean blood pressure fell an average of 13.7 ± 3.6 mmHg and heart rate fell an average of 126 ± 23 beats/min in the dark cycle. In agreement with earlier studies of wild-type mice (38), blood pressures of Dbh(+/-) mice were not changed during the light cycle with caloric restriction. Dbh(-/-) mice, however, exhibited no statistical change in blood pressures in response to caloric restriction (P > 0.05 vs. precaloric restriction pressures), although there was a trend for lowered mean blood pressure during both the light and dark cycles. In contrast to the observation that caloric restriction induced a drop in heart rate of ~25% in the dark and 16% in the light in Dbh(+/-) mice (Fig. 2), Dbh(-/-) mice had a blunted heart rate response. These mice exhibited a small, but significant, reduction in heart rate of ~9% in both the dark and light cycles in response to caloric restriction (Fig. 2). Interestingly, SDIBI of Dbh(-/-) mice significantly increased only in the light cycle in response to caloric restriction, whereas SDIBI of Dbh(+/-) mice increased in both the light and dark cycles (Fig. 2).



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  		Fig. 2. Change in cardiovascular parameters for Dbh(+/-) and Dbh(-/-) mice after a 7-day bout of caloric restriction. Mean blood pressure, heart rate, activity, and SD of the interbeat interval (SDIBI) were averaged over the dark cycle (5:00 P.M.-4:00 A.M.) or the light cycle (5:00 A.M.-4:00 P.M.) over 2 days during ad libitum feeding (Table 1). Caloric intake was then restricted to 50% of the calories normally eaten for 7 days, and data were averaged over the last 2 days for both the light and dark cycles. The difference between the last 2 days of the caloric restriction period and the last 2 days before the caloric restriction period was calculated for each animal and averaged. *P < 0.05 testing ad libitum vs. calorie restriction within the same genotype and within the same light-dark cycle. a.u., Arbitrary units.

 

Open field. Exposure of rats to stressful open-field conditions has been shown to induce tachycardia and elevate blood pressure (32-34). However, the cardiovascular response of mice to the open field has not been characterized. Therefore, we characterized the response of Dbh(+/-) mice to an open field and then compared Dbh(+/-) and Dbh(-/-) mice to examine whether the cardiovascular response requires Epi and NE. As seen in a representative example in Fig. 3 and quantified for all mice in Fig. 4, the response to exposure to an open field is notably atypical in Dbh(-/-) mice. Whereas the heart rate and mean blood pressure of Dbh(+/-) increased ~235 beats/min and 29 mmHg in response to exposure to the open field, Dbh(-/-) mice underwent minimal changes in cardiovascular parameters (no change in heart rate and 12 mmHg increase in blood pressure) in the open field. Both genotypes responded with an increase in scurrying throughout the open field, as assessed by the increase in activity seen in Figs. 3 and 4. The cardiovascular data quantified and shown in Fig. 4 represent an average over the last 2 min in each condition.



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  		Fig. 3. Cardiovascular parameters of Dbh(+/-) and Dbh(-/-) mice before, during, and after exposure to an open field. Mean blood pressure, heart rate, and activity were continuously monitored in these representative mice. "Rest" is the 5-min period in the mouse's home cage before exposure to the open field. "Open field" is the 5-min period during which the mouse is placed in a 3 ft. x 3 ft. x 3 ft. white box flooded with light. "Recovery" is the 5-min period in the mouse's home cage immediately after exposure to the open field.

 


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  		Fig. 4. Cardiovascular parameters of all Dbh(+/-) and Dbh(-/-) mice tested before, during, and after exposure to an open field. Mice (n = 7 for each genotype) were exposed to an open field as described in Fig. 3. The last 2 min of each condition (rest, open field, recovery) were averaged for each animal. P < 0.05 vs. rest (a) and vs. the open field (b).

 


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Using mice deficient in DBH, an enzyme that is required for synthesis of Epi and NE, we determined the impact of the lack of these catecholamines on the cardiovascular response to a bout of caloric restriction. A secondary goal was to characterize the cardiovascular response of mice to an open-field stressor. One limitation in these studies is that, in addition to release from the adrenal medulla and sympathetic nerve endings, Epi and NE are neurotransmitters in the central nervous system (reviewed in Ref. 7). Thus the present experiments cannot differentiate whether it is the lack of central nervous system signaling or lack of peripheral SNS signaling that is responsible for the altered cardiovascular parameters exhibited by the Dbh(-/-) mice. It is likely because of the latter, however, given the strong link between chemical sympathectomy and chronic low blood pressure (reviewed in Ref. 43).

Cho et al. (2) have previously reported that Dbh(-/-) mice have normal left ventricular systolic and diastolic pressures. However, these measurements were obtained from anesthetized mice. In contrast, we found here using radiotelemetry in conscious and freely moving animals that the blood pressures of Dbh(-/-) mice were astonishingly low (Table 1 and Fig. 1). The hypotension in Dbh(-/-) mice closely mirrors DBH deficiency in humans, who exhibit hypotension and severe orthostatic intolerance (25). These mice also exhibit both a low heart rate and low pulse pressure. The severe hypotension in Dbh(-/-) mice is consistent with earlier findings suggesting that blood pressure in mice is heavily influenced by the SNS (13, 14, 17). An interesting aspect of the baseline cardiovascular parameters of the Dbh(-/-) mice is the attenuated circadian blood pressure variability in the DBH-deficient mice. Humans (23), rats (15, 22, 37), and mice (20, 26, 36, 39) all exhibit higher blood pressure values and heart rate during the active cycle (light for humans, dark for rodents) relative to the resting cycle. The circadian oscillating system from the suprachiasmatic nucleus appears to be responsible for the circadian cardiovascular parameters, and some studies in the rat have implicated the autonomic nervous system as the mediator of this rhythm (15, 22, 37). In the current study, Dbh(+/-) mice exhibited blood pressures 13-14 mmHg higher during the dark cycle than the light cycle (Table 1), much like that previously described for wild-type mice. However, the blood pressure difference between the dark and light cycle of Dbh(-/-) mice was blunted to only 4-5 mmHg (Table 1), even though these animals display a normal circadian rhythm in activity levels. Furthermore, the Dbh(-/-) mice have a normal circadian rhythm in heart rate (Table 1). These data suggest that sympathoadrenergic catecholamines, and not spontaneous cage activity, play a principal role in the circadian difference in blood pressure. This is consistent with the finding of the circadian rhythm in circulating catecholamines (elevated during the dark cycle) in rodents (5). In contrast, the heart rate difference between the dark and light cycle must be the result of some other cause than Epi and NE and is likely activity related, as has been previously suggested in a rat study using chemical sympathectomy (22).

The drop in blood pressure that is associated with caloric restriction has long been known to be associated with a drop in SNS activity in rodents and humans (4, 8, 10, 16, 18, 41). With the use of the Dbh(-/-) mice, we were able to test directly whether Epi and NE are required for such a cardiovascular change. We found that the mean blood pressure of Dbh(-/-) mice did not drop significantly upon caloric restriction (Fig. 2). This was also true for systolic, diastolic, and pulse pressures (data not shown). It is possible that the blood pressures of the Dbh(-/-) mice were already so low before the caloric restriction that they could not drop further and still maintain adequate perfusion pressure, somewhat of a "basement" effect. It is of interest that the drop in blood pressure in Dbh(+/-) mice associated with caloric restriction (Fig. 2, 13-14 mmHg) is roughly the same as that associated with the difference between the dark and light cycle (Table 1, also 13-14 mmHg). In addition, the lack of a prominent cardiovascular circadian rhythm and lack of caloric restriction-induced hypotension in Dbh(-/-) mice provides circumstantial evidence that the circadian rhythm and diet-induced low pressure utilize the same mechanism, and that mechanism requires Epi and NE for realization. The bradycardia that is associated with caloric restriction in mice (Fig. 2 and Refs. 26, 38, and 39) was blunted in the Dbh(-/-) mice, suggesting that Epi and/or NE only partially mediate the heart rate effect of caloric restriction. Presumably the remainder of the heart rate response is mediated by enhanced parasympathetic nervous system (PNS) activity, but this remains to be tested.

To further analyze the role of Epi and NE in caloric restriction-induced changes, we also calculated the SDIBI. The SDIBI is a measure that describes heart rate variability on a beat-to-beat basis. Others have suggested that SDIBI measurements are a reasonable estimator of the relative contribution of the SNS and PNS in the cardiovascular system, with an increase in SDIBI suggesting an increase in PNS input relative to SNS input (24, 28, 40). Our data from ad libitum-fed Dbh(-/-) mice support this notion. The SDIBI for Dbh(-/-) mice in the dark cycle was more than two times that of Dbh(+/-) mice (Table 1) and 50% greater in the light cycle. The lack of SNS input in cardiovascular control is consistent with the higher SDIBI in Dbh(-/-) mice. In the dark cycle, it is very likely that the increase in SDIBI activity of littermate controls during caloric restriction reflects withdrawal of SNS activity, since this increase in SDIBI was not found during caloric restriction in Dbh(-/-) mice (Table 1). SDIBI did increase in Dbh(-/-) mice in the light cycle during caloric restriction. This provides evidence that PNS activity to the heart likely increased in these mice during the light cycle. Hence, these SDIBI data suggest that both the PNS and SNS are altered in the normal mouse in response to a bout of caloric restriction.

Although stress tests have been used extensively in rodents to assess animal behavior and test anxiolytic drugs, only a few have actually measured cardiovascular parameters in an open-field test (32-34), and none have used mice as subjects. Therefore, we used the mice to 1) characterize the cardiovascular response of the mouse to an open field and 2) to examine the impact on the cardiovascular response in mice missing Epi and NE. Mean blood pressure and heart rate in Dbh(+/-) mice were elevated 29 mmHg (representing a 29% increase over baseline) and 235 beats/min (representing a 43% increase), respectively, within only a few minutes of exposure to the open field. The magnitude of these changes is consistent with the cardiovascular response of the rat (32-34). However, exposure of the Dbh(-/-) mouse to the open field had no effect on heart rate and elevated blood pressure 12 mmHg (representing a 20% increase), also consistent with pharmacological studies within the rat (1, 33). The fact that blood pressure is elevated in Dbh(-/-) mice in the open field is perplexing given the absence of sympathoadrenergic catecholamines and the absence of any tachycardic response. One explanation may be the fourfold elevation in activity observed within the open field (Fig. 4). It is possible that muscle pump action that occurs with activity increased venous pressure, leading to an increase in stroke volume, cardiac output, and blood pressure. However, Janssen and Smits (14) previously reported that stroke volume and cardiac output in mice fall with large movements. Another explanation for the elevated blood pressure is an increase in resistance in the arterial tree. In the absence of Epi and NE, a likely candidate to mediate an increase in resistance is neuropeptide Y (NPY). NPY is released from sympathetic nerve endings upon activation of those nerves and produces potent vasoconstrictor activity (reviewed in Ref. 44). The physiological role of peripheral NPY in these mice, however, remains to be tested. It may be argued that the Dbh(-/-) mice cannot detect the stressful open-field situation, since these mice have ptosis of the eyelids (29). This is unlikely, though, given the large increase in activity observed in these animals when exposed to the open field (Figs. 3 and 4).

In conclusion, we show here the requirement of Epi and/or NE in the adaptive response of the cardiovascular system to caloric restriction. These sympathoadrenergic catecholamines are required for the full 13- to 14-mmHg change in blood pressure and a portion of the bradycardia that occurs in mice during a 7-day bout of caloric restriction at 29°C. Furthermore, data from the Dbh(-/-) mice also implicate a role of the PNS for the cardiovascular response to dieting. These data include 1) the attenuated, but not abolished, bradycardia in the Dbh(-/-) mice; and 2) the rise in SDIBI during caloric restriction in the light cycle in Dbh(-/-) mice. Collectively, caloric restriction of Dbh(-/-) mice suggests a primary role of Epi and NE and a secondary role of the PNS in the cardiovascular response to dieting.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Science Foundation Grant IBN 9984170 to S. J. Swoap and in part by a Howard Hughes Medical Institute grant to Williams College. D. Weinshenker was supported by the Howard Hughes Medical Institute.


   ACKNOWLEDGMENTS
 
We thank Sumitomo Pharmaceuticals (Osaka, Japan) for the generous donation of L-3,4-dihydroxyphenylserine that is used for breeding the Dbh(-/-) mice.


   FOOTNOTES
 

Address for reprint requests and other correspondence: S. J. Swoap, Dept. of Biology, Williams College, Williamstown, MA 01267 (E-mail: sswoap{at}williams.edu).

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. Section 1734 solely to indicate this fact.

Current address for D. Weinshenker: Dept. of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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