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

Abstract

DOCA-salt and obesity-related hypertension are associated with inflammation and sympathetic nervous system hyperactivity. Prejunctional α-adrenergic receptors (αARs) provide negative feedback to norepinephrine release from sympathetic nerves through inhibition of N-type Ca channels. Increased neuronal norepinephrine release in DOCA-salt and obesity-related hypertension occurs through impaired αAR 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 αAR-mediated inhibition of Ca channels in SMCG neurons from DOCA-salt and high-fat diet (HFD)-induced hypertensive rats. Whole cell patch-clamp methods were used to record Ca 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 αAR-mediated inhibition of Ca currents in SMCG neurons. αAR dysfunction did not involve changes in αAR expression, desensitization, or downstream signaling factors. Oxidative stress impaired αAR-mediated inhibition of Ca currents in SMCG neurons and resulted in receptor internalization in human embryonic kidney-293T cells. Systemic clodronate-induced macrophage depletion preserved αAR 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 αAR dysfunction in SMCG neurons. These results suggest that macrophage-mediated αAR dysfunction in the mesenteric circulation may only be relevant to mineralocorticoid-salt excess. NEW & NOTEWORTHY Here, we identify a contribution of macrophages to hypertension development through impaired α-adrenergic receptor (αAR)-mediated inhibition of sympathetic nerve terminal Ca channels in DOCA-salt hypertensive rats. Impaired αAR function may involve oxidative stress-induced receptor internalization. αAR dysfunction may be unique to mineralocorticoid-salt excess, as it does not occur in obesity-related hypertension.

Adventitial macrophage accumulation impairs perivascular nerve function in mesenteric arteries with inflammatory bowel disease

“…Few studies have investigated the macrophage-nerve relationship in the mesenteric vasculature. Studies in a rat model of hypertension found that CD163+ macrophage accumulation in the mesenteric artery adventitia is linked to increased blood pressure through macrophage-derived oxidate stress acting on ganglionic neuronal alpha-2 adrenergic receptors (37). In that study, clodronate-based macrophage depletion acted to lower blood pressure by preserving neuronal alpha-2 receptor function.…”

Potential role of intermittent functioning of baroreflexes in the etiology of hypertension in spontaneously hypertensive rats

“…This could be related to the relative role of the autonomic nervous system in BP regulation in the various models we studied. For example, although baroreflex impairment and neurogenic mechanisms contribute to the BP differences between Dahl SS rats on different salt intakes ( 42 ), autonomic nervous system abnormalities appear to play no role in high-fat diet–induced hypertension in Dahl SS rats ( 43 – 45 ). This is in contrast to the SHR, where autonomic factors clearly are important for the maintenance of hypertension.…”

Differences in the response to periarterial nerve stimulation or exogenous noradrenaline infusion in the mesenteric vascular bed with the intestinal tract harvested from commonly used rat models of hypertension

“…These results suggest that the responsiveness of the postsynaptic α 1 adrenergic receptor is the same in both groups, and sympathetic nervous responsivity to PNS is suppressed in DOCA‐salt rats compared to that in sham rats. According to recent studies, dysfunction of α 2 adrenergic receptors and adenosine A 1 receptors in the superior mesenteric and celiac ganglia of DOCA‐salt rats is related to the augmentation of the sympathetic reaction. Research suggests that the increase in sympathetic nerve excitation and the increased responsiveness of the vascular α 1 adrenergic receptor were associated with vascular constriction in the aorta or veins in DOCA‐salt rats.…”

“…According to recent studies, dysfunction of α 2 adrenergic receptors 23 and adenosine A 1 receptors 24 in the superior mesenteric and celiac ganglia of DOCA-salt rats is related to the augmentation of the sympathetic reaction. Research suggests that the increase in sympathetic nerve excitation and the increased responsiveness of the vascular α 1 adrenergic receptor were associated with vascular constriction in the aorta 25 or veins 26 in DOCA-salt rats.…”