Macrophage Depletion by Intracerebroventricular Administration of Clodronate-Liposome Attenuates the Development of Angiotensin II-Salt-Induced Neurogenic Hypertension in Rats.

INTRODUCTION: The increase in peripheral angiotensin II level results in neurogenic hypertension with brain inflammation. Macrophages in the cerebrospinal fluid (CSF) influence neuroinflammation through communication between the peripheral and central nervous systems. However, the role of macrophages in neurogenic hypertension development remains unclear. We hypothesized that macrophages in the CSF have a role in the development of angiotensin II-initiated neurogenic hypertension. METHODS: Sprague-Dawley rats with radio-telemetry pressure transducers underwent surgery for the subcutaneous implantation of either saline- or angiotensin II-filled osmotic minipump. They received an intracerebroventricular injection of either phosphate-buffered saline-liposome as a control or clodronate-liposome to deplete macrophages. Postoperatively, rats received 2% salt diet for 14 days. Different groups of rats underwent a hexamethonium challenge test at 7-9 days after treatment initiation to evaluate their sympathetic tone. RESULTS: Rats with angiotensin II-salt treatment demonstrated a time-dependent arterial pressure increase. Rats receiving angiotensin II-salt treatment with clodronate-liposome had delayed arterial pressure increases and lower mean arterial pressure (91 ± 4 mmHg) than rats receiving control-liposome (111 ± 4 mmHg) on day 8. The angiotensin II-salt treatment increased the peak depressor response to intravenous hexamethonium injection, messenger RNA expression of interleukin-6 and transforming growth factor-ß, and number of Iba1-positive cells in the brainstem. Intracerebroventricular injection of clodronate-liposome attenuated the angiotensin II-salt-induced increases in the depressor response, gene expressions, and cell number. CONCLUSIONS: Our data suggest that macrophages in the CSF are involved in the development of angiotensin II-salt-induced neurogenic hypertension by modulating brain inflammation.