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.

DOCA-salt and obesity-related hypertension are associated with inflammation and sympathetic nervous system hyperactivity. Prejunctional α2-adrenergic receptors (α2ARs) provide negative feedback to norepinephrine release from sympathetic nerves through inhibition of N-type Ca2+ channels. Increased neuronal norepinephrine release in DOCA-salt and obesityrelated hypertension occurs through impaired α2AR signaling; however, the mechanisms involved are unclear. Mesenteric arteries are resistance arteries that receive sympathetic innervation from the superior mesenteric and celiac ganglia (SMCG). We tested the hypothesis that macrophages impair α2AR-mediated inhibition of Ca2+ channels in SMCG neurons from DOCA-salt and high-fat diet (HFD)- induced hypertensive rats. Whole cell patch-clamp methods were used to record Ca2+ currents from SMCG neurons maintained in primary culture. We found that DOCA-salt, but not HFD-induced, hypertension caused macrophage accumulation in mesenteric arteries, increased SMCG mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-α, and impaired α2AR-mediated inhibition of Ca2+ currents in SMCG neurons. α2AR dysfunction did not involve changes in α2AR expression, desensitization, or downstream signaling factors. Oxidative stress impaired α2AR-mediated inhibition of Ca2+ currents in SMCG neurons and resulted in receptor internalization in human embryonic kidney-293T cells. Systemic clodronateinduced macrophage depletion preserved α2AR function and lowered blood pressure in DOCA-salt rats. HFD caused hypertension without obesity in Sprague-Dawley rats and hypertension with obesity in Dahl salt-sensitive rats. HFD-induced hypertension was not associated with inflammation in SMCG and mesenteric arteries or α2AR dysfunction in SMCG neurons. These results suggest that macrophage-mediated α2AR dysfunction in the mesenteric circulation may only be relevant to mineralocorticoid-salt excess. [ABSTRACT FROM AUTHOR]