Central angiotensin type 2 receptor stimulation reduces blood pressure and norepinephrine excretion in conscious normal rats

Abstract

In previous studies, we found a significant down regulation of Angiotensin II Type 2 receptors (AT2R) in the rostral ventrolateral medulla (RVLM) and a critical role of the AT2R in sympatho‐excitation in rats with chronic heart failure. In this experiment, we determined the effects of intracerebroventricular (icv) infusion of Compound 21 (C21), the first selective non‐peptide AT2R agonist, on the mean blood pressure (MAP), heart rate (HR), and norepinephrine (NE) excretion in conscious normal rats. C21 was infused by a Micro‐osmotic pump at a rate of 0.5μg/μl/2hrs for 7 days. On day 7 the rats were euthanized and the RVLM was punched out to measure AT1R and nNOS protein expression by western blot. We found that: (1) C21 treatment significantly decreased MAP (81.5 ± 6.2 vs 93.2 ± 5.9 mmHg, P < 0.05), but did not change HR; (2) both NE concentration in urine (104 ± 12.6 vs 366 ± 9.7 ng/ml, P < 0.05) and NE excretion (1.9 ± 0.3 vs 8.7 ± 1.2 μg/day, P < 0.05) were decreased in the C21 treated rats; (3) C21 down‐regulated AT1R protein expression (0.5 ± 0.1 vs 1.2 ± 0.3 AT1R/GAPDH, P < 0.05) and up‐regulated nNOS (0.7 ± 0.1 vs 0.3 ± 0.1 nNOS/GAPDH, P < 0.05) protein expression in the RVLM. These results suggest that activation of central AT2R evoked hypotension through a sympatho‐inhibitory mechanism, in part, by decreasing AT1R expression and activating nNOS signaling.