Macrophage depletion lowers blood pressure and restores sympathetic nerve α₂-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats

Abstract

Thang LV, Demel SL, Crawford R, Kaminski NE, Swain GM, Van Rooijen N, Galligan JJ. Macrophage depletion lowers blood pressure and restores sympathetic nerve ␣ 2-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol 309: H1186 -H1197, 2015. First published August 28, 2015; doi:10.1152/ajpheart.00283.2015.-We tested the hypothesis that vascular macrophage infiltration and O 2 Ϫ release impairs sympathetic nerve ␣ 2-adrenergic autoreceptor (␣2AR) 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 liposome-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-␣ and p22 phox were measured using immunohistochemistry. Peritoneal macrophage activation was measured by flow cytometry. O 2 Ϫ was measured using dihydroethidium staining. Hypertension developed over 28 days, and apocynin reduced blood pressure on days 18 -21. O 2 Ϫ 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-␣ and p22 phox were localized near sympathetic nerves. Impaired ␣2AR 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 Ϫ while restoring ␣2AR function in DOCA-salt rats. Macrophage infiltration into the vascular adventitia contributes to increased blood pressure in DOCA-salt rats by releasing O 2 Ϫ , which disrupts ␣2AR function, causing enhanced NE release from sympathetic nerves.salt-sensitive hypertension; immune activation; sympathetic nervous system; ␣2-adrenergic autoreceptors; amperometry NEW & NOTEWORTHYWe have identified a novel mechanism by which salt-sensitive hypertension disrupts normal function of the sympathetic nervous system. Antioxidants may be helpful in treating some forms of hypertension.INCREASED SYMPATHETIC nerve activity contributes to high blood pressure in some animal models of hypertension, including the DOCA-salt model (10, 57). Hypertension in the DOCA-salt model is driven by reduced renal mass (removal of one kidney), high circulating mineralocorticoid levels, and high salt intake (57). Elevated salt increases central sympathetic drive to the cardiovascular system (17, 48), but there are also alterations in the local mechanisms that modulate sympathetic neurotransmiss...

New actions of an old friend: perivascular adipose tissue's adrenergic mechanisms

“…The finding that macrophages can be active secretors of catecholamines is important as macrophage infiltration of tissues commonly occurs in obesity (Weisberg et al, ). Superoxide generated from infiltrating macrophages disrupts normal pre‐synaptic α 2 ‐adrenoceptor function, increasing the release of NA from the nerves, a mechanism that elevates blood pressure (Thang et al, ). Thus, macrophage infiltration in PVAT may influence NA release and blood pressure in disease.…”

Macrophage-dependent impairment of α2-adrenergic autoreceptor inhibition of Ca2+channels in sympathetic neurons from DOCA-salt but not high-fat diet-induced hypertensive rats

“…In DOCA-salt hypertensive rats, the mineralocorticoid derivative DOCA and salt loading increase splanchnic and renal SNA (4,40,90,91). Several studies have suggested that DOCA-salt hypertension development and sympathetic hyperactivity in these vascular beds involve oxidative stress and immune system activation (4,81,91).…”

“…The prejunctional ␣ 2 -adrenergic receptor (␣ 2 AR) inhibits NE release by coupling via G␣ i/o proteins to inhibit voltage-gated N-type Ca 2ϩ channels that control NE release (35,77). This negative feedback regulates sympathetic tone and prevents sustained increases in blood pressure (55,81). Of the three ␣ 2 ARs, ␣ 2A AR and ␣ 2C AR couple to feedback inhibition of NE release; ␣ 2A AR is predominant at higher levels of SNA (33).…”

“…Of the three ␣ 2 ARs, ␣ 2A AR and ␣ 2C AR couple to feedback inhibition of NE release; ␣ 2A AR is predominant at higher levels of SNA (33). In DOCA-salt hypertension, peripheral mechanisms that enhance neurotransmission include impaired inhibition of NE release caused by prejunctional ␣ 2 AR activation (55), specifically in mesenteric arteries (53,61,81). Mesenteric arteries are major resistance arteries with profound influences on hemodynamics and blood pressure.…”

“…Inflammation and oxidative stress play a role in hypertension development and sympathetic excitation in salt-sensitive (24,25,44,81,91) and obesity-related (57,88) hypertension. NADPH oxidases produce superoxide, the most abundant vascular reactive oxygen species (ROS), and, to a lesser extent, (47,68).…”