Endotoxemia Enhances Catecholamine Secretion From Male Mouse Adrenal Chromaffin Cells Through an Increase In Ca2+ Release From the Endoplasmic Reticulum

Abstract

Enhanced epinephrine secretion from adrenal chromaffin cells (ACCs) is an important homeostatic response to severe systemic inflammation during sepsis. Evidence suggests that increased activation of ACCs by preganglionic sympathetic neurons and direct alterations in ACC function contribute to this response. However, the direct effects of sepsis on ACC function have yet to be characterized. We hypothesized that sepsis enhances epinephrine secretion from ACCs by increasing intracellular Ca(2+) signaling. Plasma epinephrine concentration was increased 5-fold in the lipopolysaccharide-induced endotoxemia model of sepsis compared with saline-treated control mice. Endotoxemia significantly enhanced stimulus-evoked epinephrine secretion from isolated ACCs in vitro. Carbon fiber amperometry revealed an increase in the number of secretory events during endotoxemia, without significant changes in spike amplitude, half-width, or quantal content. ACCs isolated up to 12 hours after the induction of endotoxemia exhibited larger stimulus-evoked Ca(2+) transients compared with controls. Similarly, ACCs from cecal ligation and puncture mice also exhibited enhanced Ca(2+) signaling. Although sepsis did not significantly affect ACC excitability or voltage-gated Ca(2+) currents, a 2-fold increase in caffeine (10 mM)-stimulated Ca(2+) transients was observed during endotoxemia. Depletion of endoplasmic reticulum Ca(2+) stores using cyclopiazonic acid (10 μM) abolished the effects of endotoxemia on catecholamine secretion from ACCs. These findings suggest that sepsis directly enhances catecholamine secretion from ACCs through an increase in Ca(2+) release from the endoplasmic reticulum. These alterations in ACC function are likely to amplify the effects of increased preganglionic sympathetic neuron activity to further enhance epinephrine levels during sepsis.

Glibenclamide attenuates myocardial injury by lipopolysaccharides in streptozotocin-induced diabetic mice

“…It is well known that acute infections lead to difficulty in controlling blood glucose and that infection is the most frequently documented cause of ketoacidosis during diabetes mellitus [35]. In this study, the endotoxemic mice displayed hypotension, decreased heart rate, and elevated serum epinephrine level after LPS stimulation, which was consistent with previous reports [24,36,37]. Prevention or management of sepsis remains a barrier to the successful care of many surgical and traumatic patients with diabetes, needing novel therapies urgently [38].…”

Divergent neuroendocrine responses to localized and systemic inflammation

“…Sepsis also directly enhances the secretory capacity of ACCs through an increase in ER Ca 2+ release [110]. A similar increase in Ca 2+ signaling was observed in postganglionic sympathetic neurons and likely results in enhanced norepinephrine release within peripheral tissues during sepsis (Lukewich & Lomas, unpublished observations).…”

“…Similar alterations in ACC Ca 2+ signaling are produced by the cecal ligation and puncture model of sepsis. Furthermore, incubation of ACCs in sera from septic mice enhances intracellular Ca 2+ signaling, suggesting that circulating factors play an important role in this response [110]. Whether sepsis leads to similar effects on Ca 2+ handling and transmitter release from postganglionic neurons remains to be determined.…”

“…The adrenal medullae and sympathetic ganglia possess fenestrated capillaries that may allow circulating inflammatory mediators to interact with ACCs and postganglionic sympathetic neurons during sepsis and IBD to alter their function. Indeed, sera from septic mice enhance ACC Ca 2+ signaling [110] and incubation of postganglionic sympathetic neurons in nanomolar concentrations of TNF-α inhibits I Ca similar to colitis [57]. Animal models of sepsis are associated with much larger elevations in circulating cytokine levels than animal models of IBD [111;112].…”

Adrenal Gland Microenvironment and Its Involvement in the Regulation of Stress-Induced Hormone Secretion during Sepsis

“…During sepsis, an enhanced production of epinephrine and norepinephrine (42–44) and increased secretory capacity of adrenal chromaffin cells were reported (45). Unlike expression of tyrosine hydroxylase, which enzyme is involved in first step of CA biosynthesis, upregulation of PNMT gene expression in adrenal medulla was found to be regulated independently of splanchnic nerve stimulation (28).…”