Abstract 1625: Central AT1 Receptor Expression and Circadian Rhythms in Mice Post Myocardial Infarction: Effect of Losartan
It is well accepted that various functions of the cardiovascular system change with a 24-hour cycle eg. blood pressure (BP, heart rate (HR), and baroreflex sensitivity (BRS). We have shown a disrupted circadian variability of HR, BP, and BRS in mice with chronic heart failure (CHF) following myocardial infarction (MI) which was associated with an up-regulation of central angiotensin II type 1 receptors (AT1). It was not clear whether these phenomena were related. We hypothesized that blocking AT1 receptors in mice post MI would restore the lost circadian rhythm. No data was available concerning the relationship between peripheral changes in circadian rhythm (HR, BP, & BRS) and “possible” changes occurring in the circadian AT1 expression or oxidative stress in the brain. Hemodynamics was recorded in the conscious unrestrained state in C57BL/6 mice using radiotelemetry. BRS was assessed using the spontaneous sequence technique. Brains were harvested at noon and at mid-night to assess the day-time and night-time AT1 expression. Day-time (lights on 6:00–18:00) and night-time (lights off 18:00 – 6:00) averages were taken over 5-min recordings every hour. Administration of the AT1 receptor blocker, losartan, for 1 week at a rate of 1 μg/g in mice 8 weeks post MI failed to restore the lost circadian variability in HR, BP, & BRS. Losartan infusion enhanced the day-time BRS (1.26 ± 0.2 vs 1.85 ± 0.08 bpm/mmHg, p < 0.05); and the night-time BRS (1.14 ± 0.10 vs 1.69 ± 0.14 bpm/mmHg, p < 0.05). Losartan infusion also reduced AT1 receptor expression in the brainstem during the day-time (1.18 ± 0.11 vs 0.85 ± 0.06, p < 0.05) and during the night-time (1.27 ± 0.11 vs 1.02 ± 0.08, p < 0.05) without restoring the lost circadian rhythm. Measurement of a marker of oxidative stress in the brainstem, the NAD(P)H subunit gp91, showed no remarkable changes following losartan infusion. This study demonstrates a circadian pattern of AT1 receptor expression in the brain that coincides with peripherally recorded hemodynamic changes. Moreover, we showed a lost circadian pattern of AT1 expression in the brain that losartan infusion failed to restore. These data suggest an involvement of central AT1 receptor expression on hemodynamic and baroreflex function but not on circadian variability following CHF.