Circulating Angiotensin II Upregulates Brain Angiotensin Type 1 Receptors in Normal and Heart Failure Rats

Abstract

In heart failure (HF), angiotensin type 1 receptors (AT1-R) are upregulated in multiple brain regions crucial for the regulation of cardiovascular responses and sympathetic drive. The mechanisms responsible for this phenomenon remain unknown. Blood-borne angiotensin II (ANG II) affects the brain by binding to AT1-R in circumventricular organs that lack a blood-brain barrier. In this study, we examined the hypothesis that the increased circulating ANG II in HF upregulates AT1-R in the brain. Male Sprague-Dawley (n=8) rats received a subcutaneous infusion of ANG II (0.25 mg/hr, 4wks) concomitant with an intracerebroventricular (ICV) infusion of the AT1-R antagonist losartan (LOS, 20 mg/hr, 4wks, n=4) or vehicle (VEH, n=4). Control rats received saline (n=4). ANG II increased AT1-R expression (by Western blot, units/μg) from 24.0 ± 3.3 to 40.6 ± 4.9 (saline vs. ANG II, P<0.05) in a section of brain containing paraventricular nucleus of hypothalamus and subfornical organ; LOS completely blocked that response. A second group of rats underwent left coronary ligation to induce HF and were treated with ICV LOS (20 mg/hr, 4wks, n=4) or VEH (n=4). LOS decreased AT1-R expression from 46.8 ± 3.7 to 30.5 ± 5.2 (VEH vs. LOS, P<0.05). These data indicate that increases in circulating ANG II upregulate brain AT1-R, and that upregulation of brain AT1-R in ANG II infused and HF rats can be inhibited by a centrally administered AT1-R antagonist. These results suggest that increased circulating ANG II contributes to upregulation of brain AT1-R in HF rats.