Abstract 200: Time Course of Macrophages Infiltration and Apha 2 Adrenergic Autoreceptor Impairment in DOCA-salt Hypertensive Rats

Abstract

The development of DOCA-salt hypertension displayed a phasic phenomenon: pre-hypertension, phase 1, phase 2 and established hypertension. We have reported that in established DOCA-salt hypertension rats there were in increased number of pro-inflammatory macrophages (Mϕ) in the mesenteric arteries (MA) adventitia, and the α2-adrenergic autoreceptor (α2AR) regulating norepinephrine (NE) release from sympathetic nerves supplying arteries is impaired. DOCA-salt rats treated with apocynin, an NADPH-oxidase inhibitor, exhibited reduced inflammation and are protected against established hypertension. The proposed studies tested the hypothesis that as blood pressure increased in DOCA-salt rats, Mϕ infiltrated into the adventitia of MA. Mϕ released O2- that disrupted α2AR function causing increased NE release and further increased in blood pressure. Using immunohistochemistry, we detected the number of Mϕ in MA adventitia of phase 1, 2 and established hypertension was 4-5 higher than control (p<0.05). Similarly, the level of O2-, detected with relative ratio of DOCA-Sham mean fluorescence intensity of dihydroethidium, in DOCA-salt (2-2.5) peaked higher than control (1.0) during the same time period (p<0.05). However, using amperometry we found that the normalized NE current in the presence of Idazoxan, an α2AR antagonist, was significantly difference between DOCA and SHAM MA only during Phase 2 and established hypertension (p<0.05). The data suggests in DOCA-salt hypertension development, as the blood pressure increases to Phase 1 hypertension Mϕ is initially recruited to the MA adventitia where they release O2-. Consequently, over a few days period the O2- disrupts the α2AR function causing increased NE release and further increased in blood pressure.