Cardiovascular and autonomic phenotype of db/db diabetic mice

Abstract

The db/db mice serve as a good model for type 2 diabetes characterized by hyperinsulinaemia and progressive hyperglycaemia. There are limited and conflicting data on the cardiovascular changes in this model. The aim of the present study was to characterize the cardiovascular and autonomic phenotype of male db/db mice and evaluate the role of angiotensin II AT(1) receptors. Radiotelemetry was used to monitor 24 h blood pressure (BP) in mice for 8 weeks. Parameters measured were mean arterial pressure (MAP), heart rate (HR) and their variabilities. In 8-week-old db/db mice, the MAP and BP circadian rhythms were not different from age-matched control mice, while HR and locomotor activity were decreased. With ageing, MAP gradually increased in db/db mice, and the 12 h light values did not dip significantly from the 12 h dark periods. In 14-week-old mice, MAP was increased during light (101 +/- 1 versus 117 +/- 2 mmHg, P < 0.01; control versus db/db mice) and dark phases (110 +/- 1.7 versus 121 +/- 3.1 mmHg, P < 0.01; control versus db/db mice). This increase in MAP was associated with a significant increase in plasma angiotensin-converting enzyme activity and angiotensin II levels. Chronic treatment with losartan (10 mg kg(-1) day(-1)) blocked the increase in MAP in db/db mice, with no effect in control animals. Spectral analysis was used to monitor autonomic cardiovascular function. The circadian rhythm observed in systolic arterial pressure variance and its low-frequency component in control mice was absent in db/db mice. There were no changes in HR variability and spontaneous baroreflex sensitivity between control and db/db mice. The results document an age-related increase in MAP in db/db mice, which can be reduced by antagonism of angiotensin II AT(1) receptors, and alterations in autonomic balance and components of the renin-angiotensin system.

Figure 1

Mean arterial pressure (MAP) in db/db diabetic mice and their age matched controls. Blood pressure was recorded continously for 24 hours (500 Hz) once per week, and analyzed during light (□) and dark (■) phases. Three-way ANOVA showed a main effect of group [F (1.176) = 27.26, p < 0.0001] and time [F (1.176) = 29.92, p < 0.0001]. * p < 0.05 light vs. dark. # p < 0.05 control vs. db/db. § p < 0.05 14 vs. 8 wks, n = 8.

Figure 2

24 hours mean arterial pressure (MAP) in db/db diabetic mice and their age matched controls. Blood pressure was recorded continously for 24 hours once per week at 500 Hz and averaged over entire 24 hours period. Two-way ANOVA showed a main effect of group [F (1.88) = 19.29, p < 0.0001]. # p < 0.005 control vs. db/db. p < 0.05 vs. 8 wks, n = 8.

Figure 3

Effect of chronic treatment (8 wks) with losartan (10 mg/kg/day in drinking water) on MAP in control and db/db mice. At 14 wks of age, blood pressure was recorded (500 Hz) continuously for 48 hours and analyzed during light (□) and dark (■) phases. Three-way ANOVA showed a main effect of treatment [F (1.40) = 42.81, p < 0.0001], group [F (1.40) = 7.48, p < 0.01] and time [F (1.40) = 17.89, p < 0.0001]. ANOVA also showed an interaction between treatment and group [F (1.40) = 7.61, p < 0.01]. * p < 0.05 light vs. dark. # p < 0.03 control vs. db/db. † p < 0.03 untreated vs. losartan, n = 8.

Figure 4

Plasma ACE activity (A) and plasma Ang II (B) in young (8 wk) and older (14 wk) db/db diabetic mice and their age matched controls. ACE activity was determined using the synthetic substrate H³ hippuryl glycine glycine purchased from ALPCO Diagnostic. Ang II was determined using RIA kit purchased from ALPCO Diagnostic. For ACE, two-way ANOVA showed a main effect of group [F (1.22) = 7.7, p < 0.03] and age [F (1.22) = 52.1, p < 0.0001] and an interaction between group and age [F (1.22) = 25.3, p < 0.0001]. For Ang II, two-way ANOVA showed a main effect of group [F (1.31) = 46.7, p < 0.0001] and an interaction between group and age [F (1.31) = 7.2, p < 0.01]. # p < 0.005 control vs. db/db. § p < 0.005 14 wks vs. 8 wks, n = 9.