Macrophage depletion lowers blood pressure and restores sympathetic nerve alpha(2)-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats

作者：Thang Loc V; Demel Stacie L; Crawford Robert; Kaminski Norbert E; Swain Greg M; Van Rooijen Nico; Galligan James J^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2015, 309(7): H1186-H1197.

DOI：10.1152/ajpheart.00283.2015

• salt-sensitive hypertension
• immune activation
• sympathetic nervous system
• alpha(2)-adrenergic autoreceptors
• amperometry

We tested the hypothesis that vascular macrophage infiltration and O-2(-) release impairs sympathetic nerve alpha(2)-adrenergic autoreceptor (alpha(2)AR) function in mesenteric arteries (MAs) of DOCA-salt hypertensive rats. Male rats were uninephrectomized or sham operated (sham). DOCA pellets were implanted subcutaneously in uninephrectomized rats who were provided high-salt drinking water or high-salt water with apocynin. Sham rats received tap water. Blood pressure was measured using radiotelemetry. Treatment of sham and DOCA-salt rats with lipo-some- encapsulated clodronate was used to deplete macrophages. After 3-5, 10-13, and 18-21 days of DOCA-salt treatment, MAs and peritoneal fluid were harvested from euthanized rats. Norepinephrine (NE) release from periarterial sympathetic nerves was measured in vitro using amperometry with microelectrodes. Macrophage infiltration into MAs as well as TNF-alpha and p22(phox) were measured using immunohistochemistry. Peritoneal macrophage activation was measured by flow cytometry. O-2(-) was measured using dihydroethidium staining. Hypertension developed over 28 days, and apocynin reduced blood pressure on days 18-21. O-2(-) and macrophage infiltration were greater in DOCA-salt MAs compared with sham MAs after day 10. Peritoneal macrophage activation occurred after day 10 in DOCA-salt rats. Macrophages expressing TNF-alpha and p22(phox) were localized near sympathetic nerves. Impaired alpha(2)AR function and increased NE release from sympathetic nerves occurred in MAs from DOCA-salt rats after day 18. Macrophage depletion reduced blood pressure and vascular O-2(-) while restoring alpha(2)AR function in DOCA-salt rats. Macrophage infiltration into the vascular adventitia contributes to increased blood pressure in DOCA-salt rats by releasing O-2(-), which disrupts alpha(2)AR function, causing enhanced NE release from sympathetic nerves.

• 出版日期2015-10-1