CARDIOVASCULAR RHYTHMS AND CARDIAC BAROREFLEX SENSITIVITY IN AT(1A) RECEPTOR GAIN-OF-FUNCTION MUTANT MICE

A mutant mouse expressing a gain-of-function of the AT(1A) angiotensin II receptor was engineered to study the consequences of a constitutive activation of this receptor on blood pressure (BP). Cardiovascular rhythms and spontaneous cardiac baroreflex sensitivity (BRS) were evaluated using telemetric BP recordings of five transgenic (AT(1A)MUT) and five wild (AT(1A)WT) mice. The circadian rhythms were described with the Chronos-Fit program. The gain of the transfer function between systolic BP (SBP) and pulse intervals used to estimate the spontaneous BRS (ms/mmHg) was calculated in the low frequency (0.15-0.60 Hz) band. Transgenic AT(1A)MUT exhibited higher BP and heart rate (HR) levels compared to controls (SBP AT(1A)MUT 134.6 +/- 5.9 mmHg vs. AT(1A)WT 110.5 +/- 5.9; p<0.05; HR AT(1A)MUT 531.0 +/- 14.9 vs. AT(1A)WT 454.8 +/- 5.4 beats/min; p = 0.001). Spontaneous BRS was diminished in transgenic mice (AT(1A)MUT 1.23 +/- 0.17 ms/mmHg vs. AT(1A)WT 1.91 +/- 0.18 ms/mmHg; p<0.05). Motor activity did not differ between groups. These variables exhibited circadian changes, and the differences between the strains were maintained throughout the cycle. The highest values for BP, HR, and locomotor activity were observed at night. Spontaneous BRS varied in the opposite direction, with the lowest gain estimated when BP and HR were elevated (i.e., at night, when the animals were active). It is likely the BP elevation of the mutant mice results from the amplification of the effects of AngII at different sites. Future studies are necessary to explore whether AT(1A) receptor activation at the central nervous system level effectively contributed to the observed differences. (Author correspondence: jean-luc.elghozi@nck.aphp.fr)