Macrophage‐Dependent Impairment of α2 Autoreceptor Inhibition of Ca2+ Currents in Sympathetic Neurons Contributes to Hypertension in DOCA‐Salt Rats

Abstract

Norepinephrine (NE) release from perivascular sympathetic nerves is regulated by prejunctional alpha‐2 autoreceptors (α2AR), which inhibit nerve terminal N‐type Ca2+ channels. We showed previously that macrophage infiltration and superoxide production in mesenteric arteries (MA) impairs α2AR‐mediated inhibition of NE release. We tested the hypothesis that macrophages disrupt α2AR coupling to N‐type Ca2+ channels in sympathetic neurons.MethodsThe DOCA‐salt rat model of hypertension was used for this study. Immunohistochemistry was used to localize macrophages in MA. Ca2+ current inhibition was evaluated using whole‐cell patch clamp on cultured sympathetic neurons of the celiac ganglion. Liposome‐encapsulated clodronate (LEC) was used to deplete macrophages.ResultsMacrophage infiltration is increased in MA of DOCA‐salt hypertensive rats. The α2AR agonists NE and UK14304 inhibit Ca2+ currents in neurons from normotensive but not hypertensive rats. In all neurons, yohimbine (α2AR antagonist) attenuates the effects of NE and dialysis of GppNHp (non‐hydrolyzable GTP analog) inhibits Ca2+ current equally. In DOCA‐salt rats, LEC treatment prevents macrophage infiltration in MA, reduces blood pressure elevation, and preserves α2AR‐mediated inhibition of Ca2+ current in sympathetic neurons.ConclusionsIn DOCA‐salt hypertensive rats, α2AR dysfunction leads to impaired modulation of Ca2+ current that is independent of factors downstream of receptor activation. Macrophage depletion preserves α2AR function and protects against blood pressure elevation.Support or Funding InformationP01 HL070687