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Endocrinology, doi:10.1210/en.2007-1714
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Endocrinology Vol. 149, No. 7 3576-3580
Copyright © 2008 by The Endocrine Society

Diurnal Amplitudes of Arterial Pressure and Heart Rate Are Dampened in Clock Mutant Mice and Adrenalectomized Mice

Hiroyoshi Sei, Katsutaka Oishi, Sachiko Chikahisa, Kazuyoshi Kitaoka, Eiji Takeda and Norio Ishida

Department of Integrative Physiology (H.S., S.C., K.K.), Institute of Health Biosciences, and Department of Clinical Nutrition (E.T.), Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan; and Department of Clock Cell Biology (K.O., N.I.), National Institute of Advanced Industrial Science and Technology, Tsukuba 305-8566, Japan

Address all correspondence and requests for reprints to: Hiroyoshi Sei, M.D., Ph.D., Department of Integrative Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan. E-mail: sei{at}basic.med.tokushima-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Arterial pressure (AP), heart rate (HR), and cardiovascular diseases, including ischemic heart attack and cerebrovascular accident, show diurnal variation. Evidence that circadian-related genes contribute to cardiovascular control has been accumulated. In this study, we measured the AP and HR of Clock mutant mice on the Jcl/ICR background to determine the role of the Clock gene in cardiovascular function. Mice with mutated Clock genes had a dampened diurnal rhythm of AP and HR, compared with wild-type control mice, and this difference disappeared after adrenalectomy. The diurnal acrophase in both mean arterial pressure and HR was delayed significantly in Clock mutant mice, compared with wild-type mice, and this difference remained after adrenalectomy. Clock mutant mice had a lower concentration of plasma aldosterone, compared with wild-type mice. Our data suggest that the adrenal gland is involved in the diurnal amplitude, but not the acrophase, of AP and HR, and that the function of the Clock gene may be related to the nondipping type of AP elevation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CARDIOVASCULAR INDICES, such as arterial pressure (AP) and heart rate (HR), and cardiovascular diseases, such as ischemic heart attack and cerebrovascular accident, show diurnal variation. The importance of the circadian system in cardiovascular control is well established. There is a projection from the suprachiasmatic nucleus (SCN, the master oscillator of circadian rhythm) to the paraventricular nucleus of the hypothalamus that has a crucial influence on the neuroendocrine and autonomic nervous systems (1). Furthermore, a multisynaptic central sympathetic pathway from the SCN to the adrenal gland is critically involved in the light-induced activation of the adrenal cortex (2). Recently the biological clock has been shown to function at the molecular level, and several circadian-related genes have been identified, such as Clock, Per, Bmal1, and Cry (3, 4).

Clock was the first clock gene identified in vertebrates, and it was found by forward mutagenesis with N-ethyl-N-nitrosourea in a behavioral screening experiment (5). The Clock gene encodes a basic helix-loop-helix (bHLH)-Per-Arnt-Sim transcription factor (6). Like other bHLH transcription factors, CLOCK binds DNA and modulates transcription after dimerization with brain and muscle arnt-like factor (BMAL)-1 (a bHLH-Per-Arnt-Sim transcription factor) (6). The CLOCK/BMAL1 heterodimer drives the rhythmic transcription of other clock genes, including period (mPer1, mPer2, and mPer3) and cryptochrome (mCry1 and mCry2), through E-box (CACGTG) elements located in their promoters (6). It should be noted that the CLOCK/BMAL1 heterodimer acts directly on the expression of various circadian output genes, such as vasopressin (7), albumin D-site binding protein (8, 9), plasminogen activator inhibitor-1 (10), prokineticin 2 (11), Wee1 (12), and peroxisome proliferator-activated receptor (13). These observations suggest that CLOCK is involved in a variety of physiological functions in mammals. When Clock is mutated, its target genes, Per1 and Per2, exhibit a dampened rhythm of expression in the SCN (14). Mice on the Jcl/ICR background that are homozygous for a mutation of the Clock gene (Clockj mice) exhibit, in continuous darkness, a lengthened circadian rhythm period of approximately 27 h in body temperature (15) and drinking behavior (14). Under an ordinary light-dark cycle, Clockj mice show a phase delay in body temperature, sleep/wake cycle and spontaneous activity (16). These physiological and behavioral profiles of Clockj mice are quite similar to human evening-type individuals (16).

In this study, we measured the AP and HR in Clockj mice to determine the role of Clock in cardiovascular function. Preliminarily we obtained data on several physiological indices of the Clockj mice. They had significantly lower water intake and a higher concentration of serum potassium in comparison with wild-type control mice (Fig. 1Go). Together with evidence of the linkage between the SCN and the adrenal gland (2), we hypothesized that, in Clockj mice, the change of water balance might occur as a result of a hormonal dysfunction, such as hyperaldosteronism. We therefore performed adrenalectomy (ADX) experiments to test our hypothesis. We report here that Clockj mice have a dampened rhythm of AP and HR, and the difference in the diurnal amplitude of AP and HR between Clockj and wild-type mice disappears after ADX.


Figure 1
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  		FIG. 1. Diurnal rhythm of the plasma potassium concentration (n = 4/group for each sampling time) and the daily volume of water intake in wild-type (n = 6, open circles) and Clock mutant (n = 6, closed circles) mice. Data are expressed as mean ± SEM. The gray zones indicate the dark periods. *, P < 0.05; **, P < 0.01 between genotypes. ZT, Zeitgeber time.

 

   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and housing
Clock mutant mice were derived from animals supplied by J. S. Takahashi (Northwestern University, Evanston, IL). The animals provided had the Clock allele originally on a BALB/c and C57BL/6J background. A breeding colony was established by further backcrossing to Jcl/ICR mice because the ICR strain has a relatively larger body size, compared with the BALB/c or C57BL/6J strains, which enables implantation of a telemetric device for measuring AP more easily, with less stress. The resulting strain was maintained by interbreeding. Genotypes were determined using the PCR method, as described previously (16). Homozygous wild-type and homozygous Clock mutant mice 10–13 wk old and derived from this colony were used in this study. The animals were housed in a room on a 12-h light, 12-h dark cycle (lights on at 0800 h) under a controlled ambient temperature (23 ± 1 C). All experiments were performed under the same light/dark schedule and temperature condition. Our experiments were approved by the Animal Study Committee of Tokushima University (no. 7068), and were carried out according to the guidelines for the Care and Use of Animals approved by the Council of the Physiological Society of Japan.

Methods
Seven male Clockj (30–40 g) and six wild-type (33–39 g) mice were used for AP recordings under normal conditions. With animals under ketamine and xylazine anesthesia (100 and 25 mg kg–1, respectively), the tip of a catheter of a telemetric device (TA11PA-C20; Data Sciences International, St. Paul, MN) was inserted into the aortic arch via the left carotid artery, with the telemeter body positioned sc on the right flank. After the surgery, the mice were housed individually in square plastic cages (length and width, 30 cm; depth, 35 cm) in a sound-proof recording room. Signals from the transmitter were processed by a computer-assisted data acquisition system (CED 1401 data processor; Cambridge Electronic Design, Cambridge, UK). At least 10 d after the surgery, AP recordings were performed continuously for a 48-h period.

For the other groups of mice [four Clockj (32–38 g) and four wild-type (35–38 g)], in addition to the implantation of an AP transmitter, bilateral ADX was carried out via a dorsal approach under ketamine/xylazine anesthesia. The skin on the back was shaved and disinfected, and an incision of approximately 1 cm was made above and parallel to the spinal cord. Through a small opening in the muscle layer left and right of the spinal cord, the adrenals were removed from the surrounding fat tissue. After ADX, mice were provided with a 0.9% saline solution instead of water to maintain appropriate mineral balance. After a 10-d recovery period from the surgery, 48-h AP recordings were performed.

Offline analysis was carried out on a computer with the Spike 2 program (Cambridge Electronic Design). The mean AP (MAP) was calculated as the average of the digitized AP signal in consecutive 1-sec epochs, and the HR was detected from the AP signal. For observation of the diurnal features of MAP and HR, the MAP and HR were averaged hourly for each animal, and then the amplitude and acrophase were calculated using a least square method. A cosine curve with a fixed period of 24 h was fitted to the data, and the peak position and amplitude of the fitted cosine curve were determined as acrophase and amplitude, respectively.

To determine plasma aldosterone (ALD) levels, we decapitated separate groups of mice and collected trunk blood into heparinized tubes. The samplings were performed every 6 h. Although the mice were kept under the same light/dark condition as in the AP recording experiment, blood was collected under a dim red lamp temporarily during the dark period to avoid any possible influence of light on the ALD profile. Plasma was separated immediately from blood samples by centrifugation at 3000 rpm for 10 min at 4 C and stored at –80 C. Plasma ALD concentrations were determined by an RIA kit [125I] ALD tracer. The standard curve was comparable with the kit standards. Coefficients of inter- and intraassay variation were 7 and 3%, respectively. The minimum detection limit was approximately 10 pg/ml. Duplicates for the standards and samples were nearly identical. The samples were measured in duplicate when sample volume permitted.

Statistical analyses
Statistical analyses for the time course results in MAP and HR were performed using a repeated-measures two-way ANOVA. For ALD, a factorial ANOVA was used because the mice were in separate, independent groups by sampling time. Scheffé’s multiple comparison tests assessed specific differences between genotypes in MAP and HR. The average, amplitude and acrophase in MAP and HR were assessed by two-tailed and unpaired Student’s t tests between the groups. P < 0.05 was considered statistically significant. All values are expressed as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 2Go shows the 48-h profiles of MAP and HR under normal (Fig. 2AGo) and ADX (Fig. 2BGo) conditions. Under normal conditions (Fig. 2AGo), the MAP and HR in Clockj mice showed a dampened diurnal rhythm. During the light period, the MAP of Clockj mice was higher than that of wild-type mice, whereas during the dark period, the MAP was almost the same for both. As summarized in Table 1Go, in Clockj mice, the daily average MAP was significantly higher, whereas that of HR was significantly lower in comparison with the wild-type mice. The diurnal amplitude in both MAP and HR was significantly smaller in Clockj mice than wild-type mice. The diurnal acrophase in both MAP and HR was delayed significantly (for about 3 h) in Clockj mice, compared with wild-type mice. After ADX (Fig. 2BGo), both MAP and HR were almost overlapped in both groups of mice throughout the recording period; the difference between Clockj and wild-type mice seen in the intact condition seemed to disappear. After ADX, the daily average MAP decreased significantly in both Clockj and wild-type mice. In neither MAP nor HR did the diurnal amplitude show a significant difference between genotypes. The disappearance of the difference between genotypes was caused by the decreased amplitude after ADX in wild-type mice. On the other hand, the diurnal acrophase was still significantly different between genotypes in both MAP and HR, regardless of ADX (Table 1Go).


Figure 2
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  		FIG. 2. Diurnal profiles of MAP and HR in wild-type (open circles) and Clock mutant (closed circles) mice under normal conditions (A) and after adrenalectomy (B). Data are expressed as mean ± SEM. The gray zones indicate the dark periods. Horizontal bars on the top of the figure in A indicate the time zone in which the difference between genotypes was significant. There was no significant point in B. The results of ANOVA on MAP and HR were as follows: MAP (normal), group, f = 5.89 P < 0.05, time, f = 9.92, P < 0.001; interaction, f = 2.89, P < 0.001; HR (normal), group, f = 11.33, P < 0.01; time, f = 11.59, P < 0.001, interaction, f = 4.89, P < 0.001; MAP (ADX), group, f < 0.001, P = 0.998; time, f = 3.47, P < 0.001; interaction, f = 1.373, P = 0.063; HR (ADX), group, f = 0.090, P = 0.929; time, f = 5.591, P < 0.001, interaction, f = 1.808, P < 0.01. ZT, Zeitgeber time.

 

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  		TABLE 1. Diurnal average, amplitude, and acrophase of MAP and HR in wild-type and Clock-mutant (Clockj) mice under intact conditions and after ADX

 
The ALD profile is displayed in Fig. 3Go. The level of ALD in Clockj mice was significantly lower than that in wild-type mice during the light period. However, in the wild-type mice, the level of ALD in the light period was higher than that in the dark period (f = 6.16 P < 0.01), whereas the ALD in Clockj did not show a significant light/dark change (f = 1.68 P = 0.224).


Figure 3
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  		FIG. 3. Diurnal rhythm of the plasma aldosterone concentration in wild-type (n = 4 for each time, open circles) and Clock mutant (n = 4 for each time, closed circles) mice. Data are expressed as mean ± SEM. The gray zones indicate the dark periods. **, P < 0.01 between genotypes. ZT2, f = 24.43, P < 0.01; ZT8, f = 18.82, P < 0.01; ZT14, f = 2.26, P = 0.183; ZT20, f = 4.88, P = 0.069. ZT, Zeitgeber time.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we demonstrated three main findings: 1) the diurnal amplitude of MAP and HR in Clockj mice is attenuated; 2) the difference in the diurnal amplitude, but not the acrophase, in AP and HR between genotypes is diminished by ADX; and 3) plasma ALD is lower, with a blunted rhythm in Clockj mice. The change of AP and HR in the Clockj mice coincides with the recent observation in Clock mutant mice on the C57BL/6J background (17). Therefore, the effect of the Clock mutation on cardiovascular function seems to be identical between strains.

Our results indicate that the Clock gene contributes to both the diurnal amplitude and the acrophase in MAP and HR, whereas the adrenal gland has an important role in the diurnal amplitude, but not the acrophase, of cardiovascular function. Because the difference in the amplitude between Clockj and wild-type mice disappeared after ADX, the effect of the Clock mutation on the amplitude of AP and HR is at least partially linked to the adrenal gland. Corticosterone and ALD, adrenocortical hormones, are largely affected by the mutation of Clock. The corticosterone in Clockj mice was already reported to show a large delay in the acrophase (18), and our data have shown suppressed ALD with a blunted rhythm. It is possible that the Clock gene is related to adrenal function, and changes in adrenal function may affect the circadian profiles in cardiovascular function.

Because the Clockj mice had a lower water intake and an abnormal concentration of serum potassium, we hypothesized that water retention might occur as a result of hyperactivity of ALD. ALD, a mineralocorticoid, has a critical role in water and mineral balance. ALD increases the reuptake of water in the kidney. Activation of ALD is considered to induce an increase in circulating blood volume and subsequently hypertension (19). In fact, the daily average MAP was decreased by ADX in our study (Table 1Go). The intact Clockj mice, however, showed an increased daily average MAP. Therefore, our early hypothesis was wrong, and the change in the diurnal profile of MAP cannot be explained by the change in ALD. As for the daily average of AP and HR, the Clock mutation and ADX have opposite effects. That is, the Clock mutation causes an increase in AP and a decrease in HR, whereas ADX causes a decrease in AP and an increase in HR. Recently it was found that serum adrenaline and noradrenaline are higher in Clockj mice, compared with control mice (20). It is therefore possible that the hyperactivity of the adrenal medulla in Clockj mice is linked to the change in cardiovascular function or the opposing effects of the Clock mutation and ADX. The suppressed ALD may occur secondarily to elevated AP and/or catecholamines. Mutoh et al. (21) indicated the participation of the sympathetic nerves in conveying central clock information to peripheral organs. Our results may be in line with this.

Although the master oscillator is located centrally in the SCN, there are molecular clocks in most peripheral tissues, which are themselves capable of entrained and autonomous functions (22). Cardiomyocyte-specific Clock mutant mice have been developed and exhibit a lowered HR with a dampened diurnal rhythm (23). The decrease in HR is greater during the dark period, quite similar to our results. Therefore, the change in HR observed in our Clockj mice could result in part from the Clock gene in the heart.

Clinically, a nondipping type of AP variation, that is, nocturnal hypertension, was reported to be a marker of a physiological abnormality that causes an increased cardiovascular risk (24, 25). Although the pathogenesis of the nondipping phenomenon is not yet understood completely, there is a possibility that Clockj mice may be a model of human nondippers because Clockj mice have a higher MAP only during the light period, which is a resting period for mice.

Interestingly, the diurnal acrophase is not affected by ADX. Under both intact and ADX conditions, Clockj mice had a delayed acrophase of 2–3 h. As shown in Fig. 2Go, the delay in the rise of MAP and HR at the onset of the dark period can be seen even after ADX. However, there are some differences in the diurnal profile of MAP and HR, such as a second peak around the onset of the light period. It remains possible that the difference in the shape of curve may affect the result of acrophase. The delayed acrophase in body temperature, sleep/wake cycle and spontaneous activity of Clockj mice has already been published (16). The phase delay in MAP and HR coincides with that seen in body temperature, the sleep/wake cycle, and spontaneous activity. It is well documented that AP and HR are strongly affected by the sleep and/or activity of mice (26). Therefore, there is a possibility that not only the acrophase but also the amplitude is determined by the behavior affected by the Clock mutation or ADX, although ADX has been reported repeatedly not to affect the baseline level of spontaneous activity (27, 28). The effect of ADX on behavior should be studied in detail.


   Footnotes
 
This work was supported by the Japan Society for the Promotion of Science Grants-in-Aid (18603005 to H.S.), a grant from the Japan-U.S. Cooperative Science Program, and a Grant-in-Aid for Scientific Research from the 21st Century Centers of Excellence (COE) Program, Human Nutritional Science on Stress Control, Tokushima, Japan.

Disclosure Statement: The authors have nothing to disclose.

First Published Online April 10, 2008

Abbreviations: ADX, Adrenalectomy; ALD, aldosterone; AP, Arterial pressure; bHLH, basic helix-loop-helix; BMAL1, brain and muscle arnt-like factor 1; HR, heart rate; MAP, mean AP; SCN, suprachiasmatic nucleus.

Received December 11, 2007.

Accepted for publication March 28, 2008.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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