Hypertension and disrupted blood pressure circadian rhythm in type 2 diabetic db/db mice

Abstract

Human Type 2 diabetes is associated with increased incidence of hypertension and disrupted blood pressure (BP) circadian rhythm. Db/db mice have been used extensively as a model of Type 2 diabetes, but their BP is not well characterized. In this study, we used radiotelemetry to define BP and the circadian rhythm in db/db mice. We found that the systolic, diastolic, and mean arterial pressures were each significantly increased by 11, 8, and 9 mmHg in db/db mice compared with controls. In contrast, no difference was observed in pulse pressure or heart rate. Interestingly, both the length of time db/db mice were active (locomotor) and the intensity of locomotor activity were significantly decreased in db/db mice. In contrast to controls, the 12-h light period average BP in db/db mice did not dip significantly from the 12-h dark period. A partial Fourier analysis of the continuous 72-h BP data revealed that the power and the amplitude of the 24-h period length rhythm were significantly decreased in db/db mice compared with the controls. The acrophase was centered at 0141 in control mice, but became scattered from 1805 to 0236 in db/db mice. In addition to BP, the circadian rhythms of heart rate and locomotor activity were also disrupted in db/db mice. The mean arterial pressure during the light period correlates with plasma glucose, insulin, and body weight. Moreover, the oscillations of the clock genes DBP and Bmal1 but not Per1 were significantly dampened in db/db mouse aorta compared with controls. In summary, our data show that db/db mice are hypertensive with a disrupted BP, heart rate, and locomotor circadian rhythm. Such changes are associated with dampened oscillations of clock genes DBP and Bmal1 in vasculature.

Figures

Fig. 1.

The 24-h average systolic (A), diastolic (B), and mean arterial blood pressure (C), but not pulse pressure (D) and heart rate (E), were increased in db/db mice. Male 14- to 16-wk-old db/db and age- and gender-matched control mice were chronically instrumented in the left common carotid arteries with telemetry probes. Data of the blood pressure and heart rate were collected continuously and are individual values for each mouse with the average value for each group (horizontal line) over a 24-h period. **P < 0.01; ***P < 0.001.

Fig. 2.

db/db Mice exhibit decreased locomotor activity. Locomotor activity was recorded in 14- to 16-wk-old db/db and control mice. A: time the mice were active over a 24-h period. B: intensity of activity when the mice are active. C: overall activity. Individual values for each mouse are depicted, with the group average (horizontal line). **P < 0.01; ***P < 0.001.

Fig. 3.

Disrupted circadian blood pressure rhythm in db/db mice. A: continuous 48-h mean arterial pressure recording obtained via radiotelemetry in control and db/db mice. B: average mean arterial pressure in the 12-h light and dark period. Data are means ± SE. C: representative mean arterial pressure periodograms from a db/db and a control mouse. **P < 0.01; ***P < 0.001.

Fig. 4.

Disrupted circadian heart rate rhythm in db/db mice. A: continuous 48-h heart rate recording obtained via radiotelemetry in control and db/db mice. B: average heart rate in the 12-h light and dark periods. Data are means ± SE. C: representative heart rate periodograms from a db/db and a control mouse. *P < 0.05; **P < 0.01; ***P < 0.001.

Fig. 5.

Disrupted circadian locomotor activity rhythm in db/db mice. A: 48-h locomotor activity recording obtained via radiotelemetry in control and db/db mice. B: average locomotor activity in the 12-h light and dark period. Data are means ± SE. C: representative locomotor activity periodograms from a db/db and a control mouse. *P < 0.05; **P < 0.01; ***P < 0.001.

Fig. 6.

Blood pressure correlates with plasma glucose, insulin, and body weight. Blood pressures were measured continuously in conscious free-moving normal control and diabetic db/db mice by radiotelemetry. Mouse blood was collected at the end of blood pressure measurement. Plasma glucose and insulin levels were determined as described in the text. The correlation between mean arterial pressure over 24 h (A, D, and G), 12-h light period (B, E, and H), and 12-h dark period (C, F, and I) with plasma glucose, insulin, and body weight were plotted, and statistic significance was tested by Pearson's test. *P < 0.05; **P < 0.01; ***P < 0.001.

Fig. 7.

The oscillations of clock genes DBP and Bmal1 but not Per 1 are suppressed in db/db mice aorta. Male 16-wk-old db/db and control mice were taken down at Zeitgeber time 23 or 11 (ZT 23 or ZT 11, ZT0: light on, ZT 12: light off). Aortas were immediately removed, and mRNA levels of the clock genes DBP (A), Bmal1 (B), and Per1 (C) were determined by real-time PCR. *P < 0.05; **P < 0.01; and ***P < 0.001.