Restoration of the blood pressure circadian rhythm by direct renin inhibition and blockade of angiotensin II receptors in mRen2.Lewis hypertensive rats

Abstract

Background: Alterations in the circadian arterial pressure rhythm predict cardiovascular mortality. We examined the circadian arterial pressure rhythm and the effect of renin-angiotensin system blockade in congenic mRen2.Lewis hypertensive rats, a renin-dependent model of hypertension derived from the backcross of transgenic hypertensive [mRen-2]27 rats with Lewis normotensive ones.

Methods: Twenty-nine mRen2.Lewis hypertensive rats were randomly assigned to drink tap water (vehicle; n = 9), valsartan (30 mg/kg/day; n = 10), or valsartan (30 mg/kg/day) combined with aliskiren given subcutaneously (50 mg/kg/day; n = 10) for 2 weeks. Arterial pressure, heart rate, and locomotive activity were recorded with chronically implanted radiotelemetry probes. The awake/asleep ratio was calculated as [awake mean arterial pressure (MAP) mean - asleep MAP mean)] / (awake MAP mean) x 100. Plasma renin activity (PRA) and concentration (PRC), and plasma and kidney angiotensin II (Ang II) were measured by radioimmunoassay (RIAs).

Results: Untreated hypertensive rats showed an inverse arterial pressure rhythm, higher at day and lower at night, accompanied by normal rhythms of heart rate and locomotive activity. Treatment with valsartan or aliskiren and valsartan normalized the elevated arterial pressure and the arterial pressure rhythm, with the combination therapy being more effective in reducing MAP and in restoring the awake/asleep ratio. While PRA and PRC increased with the treatments, the addition of aliskiren to valsartan partially reversed the increases in plasma Ang II levels. Valsartan and the aliskiren and valsartan combination markedly reduced the renal cortical content of Ang II.

Conclusion: The altered circadian arterial pressure rhythm in this renin-dependent hypertension model uncovers a significant role of Ang II in the desynchronization of the circadian rhythm of arterial pressure, heart rate, and locomotive activity.

Figure 1

Hourly averages in mean arterial pressure, heart rate, and locomotive activity document a desynchronization of the arterial pressure rhythm - higher in daytime and lower in nighttime- in mRen2.Lewis hypertensive rats at baseline (C3). Heart rate and locomotive activity maintain a normal circadian pattern associated with activities levels (higher in nighttime and lower in daytime).

Figure 2

Changes in mean arterial pressure and heart rate in the three groups. There are no significant differences of mean arterial pressure in three groups at baseline (C1–C3). However, after treatment (T12–T14), mean arterial pressure was reduced by valsartan and further reduced by the addition of aliskiren to the valsartan treatment. There were no significant differences of heart rate in three groups both at baseline (C1–C3) and after treatment (T12–T14). ***: P<0.001 vs. C1 to C3, +++: P<0.001 vs. Vehicle, ###: P<0.001 vs. Valsartan.

Figure 3

Circadian rhythms in three groups after treatment (T14). The circadian rhythm of mean arterial pressure in the vehicle-treated group exhibits an inverse rhythm (panel a) which is essentially normalized in the mRen2.Lewis rats medicated with either valsartan or the combination of valsartan/aliskiren (panel b). The circadian rhythms of heart rate (panel c) and locomotive activity (panel d) are not different from vehicle-treated rats.

Figure 4

Day-night difference of changes in mean arterial pressure and the awake/asleep ratio in three groups. a) There was no significant difference of changes of mean arterial pressure between day and night in vehicle group. However, both valsartan and combination treatments reduced mean blood pressure more in daytime than in nighttime; b) At baseline (C3), awake/asleep ratios in all groups were negative. The ratios in both valsartan and combination groups turned positive at the day T14 although the ratio in vehicle was still negative.

Figure 5

Effects of treatment on plasma and kidney Ang II. a) The addition of aliskiren to rats medicated with valsartan blunted the increases in plasma Ang II levels induced by blockade of AT₁ receptors while both treatments reduce renal Ang II levels. b) Both treatments reduced kidney Ang II levels.

Figure 6

Correlation between kidney or plasma Ang II level and awake/asleep ratio. a) There was negative correlation between awake/asleep ratio and kidney Ang II. b) There was no significant correlation between awake/asleep ratio and plasma Ang II.