Macrophage (Mϕ) Depletion Reduced Vascular Oxidative Stress, Restored α2 Adrenergic Autoreceptor (α2AR) Function and Attenuated Blood Pressure Development in Deoxycorticosterone Acetate (DOCA)‐salt Hypertensive Rats

Abstract

There is an increase in pro‐inflammatory Mϕ in mesenteric artery (MA) adventitia, and the α2AR regulating norepinephrine (NE) release from perivascular sympathetic nerves is impaired in DOCA‐salt model. The cause of this impairment and the contribution of Mϕ to the pathophysiology of salt‐sensitive hypertension are unknown. We tested the hypothesis that Mϕ release O2−, which disrupts α2AR function causing increased NE release and further increases in blood pressure in DOCA‐salt rats. Liposomal clodronate encapsulate (LEC) was used to deplete adventitial Mϕ in rat MA, (# Mϕ/frame, DOCA PBS: DOCA LEC, 39.96: 4.16, p<0.05). Mϕ depletion reduced vascular O2− (measured using dihydroethidium) (Δσ DOCA PBS‐DOCA LEC: 23.85, p<0.05). α2AR function was also restored in Mϕ depleted animals. To establish this we used focal nerve stimulation and amperometry with microelectrodes to measure NE oxidation currents at the adventitial surface of MA in the presence α2AR agonist, UK 14304, and antagonist, Idazoxan. (Normalized 1μM UK 14304 and Idazoxan NE current % control respectively, DOCA LEC: DOCA PBS, 0.326: 0.611, & 2.74: 2.18, P<0.05). Lastly, using radio telemetry, we found that Mϕ depletion attenuated DOCA‐salt blood pressure development. (MAP on day 25–28,DOCA LEC: DOCA PBS, 154.8mmHg: 197.4mmHg, p<0.05). These data support the hypothesis that Mϕ increased blood pressure in DOCA‐salt rats by releasing O2−, which disrupted α2AR function and enhanced sympathetic nerve activity.