The angiotensin-(1-7) receptor agonist AVE0991 dominates the circadian rhythm and baroreflex in spontaneously hypertensive rats

Because we previously suggested the endogenous heptapeptide angiotensin (Ang)-(1-7) to be involved in the improvement of baroreflex sensitivity observed in spontaneously hypertensive rats (SHR), we here investigated the role of the heptapeptide in blood pressure control under physiologic conditions in awake SHR using the first nonpeptide, orally applicable Ang-(1-7) receptor agonist AVE0991 by telemetry. Five weeks after the start of treatment the blood pressure signals (500 Hz) were monitored in 10 untreated and 6 age-matched male SHR treated by AVE0991 for 24 hours (every 2 hours for 10 minutes). The autonomous tone was estimated from the heart rate and blood pressure variability (HRV, BPV) and from the spontaneous baroreceptor sensitivity (BRS). AVE0991 treatment blunted the rodent-characterizing nightly increase in blood pressure and led to pronounced changes in the BPV and HRV parameters during the night in comparison to untreated controls (eg, sdNN: AVE0991 = 8.19 versus control = 11.5 mm Hg; P < 0.001). However, even more significant differences were detected for BRS. Whereas the average slope did not alter, the activation of the baroreflexes (P < 10E-6) and the number of baroreflex fluctuations were reduced dramatically by AVE0991 (P < 10E-5). The data obtained pointed to an abating impact of AVE0991 on the baroreceptor in SHR and to its influence on the circadian rhythm, thus implying a direct involvement of Ang-(1-7) in cardiovascular control.