Abstract
Septic shock, the most severe complication associated with sepsis, is manifested by tissue hypoperfusion due, in part, to cardiovascular and autonomic dysfunction. In many cases, the splanchnic circulation becomes vasoplegic. The celiac-superior mesenteric ganglion (CSMG) sympathetic neurons provide the main autonomic input to these vessels. We used the cecal ligation puncture (CLP) model, which closely mimics the hemodynamic and metabolic disturbances observed in septic patients, to examine the properties and modulation of Ca2+ channels by G protein-coupled receptors in acutely dissociated rat CSMG neurons. Voltage-clamp studies 48 hr post-sepsis revealed that the Ca2+ current density in CMSG neurons from septic rats was significantly lower than those isolated from sham control rats. This reduction coincided with a significant increase in membrane surface area and a negligible increase in Ca2+ current amplitude. Possible explanations for these findings include either cell swelling or neurite outgrowth enhancement of CSMG neurons from septic rats. Additionally, a significant rightward shift of the concentration-response relationship for the norepinephrine (NE)-mediated Ca2+ current inhibition was observed in CSMG neurons from septic rats. Testing for the presence of opioid receptor subtypes in CSMG neurons, showed that mu opioid receptors were present in ~70% of CSMG, while NOP opioid receptors were found in all CSMG neurons tested. The pharmacological profile for both opioid receptor subtypes was not significantly affected by sepsis. Further, the Ca2+ current modulation by propionate, an agonist for the free fatty acid receptors GPR41 and GPR43, was not altered by sepsis. Overall, our findings suggest that CSMG function is affected by sepsis via changes in cell size and α2-adrenergic receptor-mediated Ca2+ channel modulation.
Highlights
Sepsis and sepsis-related multi-organ failure remain a major challenge in the care of patients in the intensive care unit (ICU) with the mortality rate in patients with sepsis often being double that of critically ill patients without sepsis [1]
The cecal ligation puncture (CLP) model of peritonitis was employed to determine whether adrenergic, opioid- and SCFAmediated modulation of Ca2+ channels in celiac-superior mesenteric ganglion (CSMG) sympathetic neurons would be altered by sepsis
Previous work indicates that N-type Ca2+ channels contribute approximately 75% of the macroscopic Ca2+ current in CSMG neurons, while the remainder is contributed by L-type channel subtype [11,25,26]
Summary
Sepsis and sepsis-related multi-organ failure remain a major challenge in the care of patients in the intensive care unit (ICU) with the mortality rate in patients with sepsis often being double that of critically ill patients without sepsis [1]. CARS counteracts this inflammatory response by the increased secretion of other cytokines, such as IL-10 and IL-1 receptor antagonist, which limit the overzealous proinflammatory response in an attempt to reestablish homeostasis [2]. An imbalance between these responses can lead to cardiovascular and multi-organ system failure, manifested as septic shock, which is typified by arterial vasodilation and an attenuated pressor response to catecholamines [4]. Administration of lipopolysaccharide (LPS; endotoxin) to healthy volunteers suppressed sympathetic vasomotor tone [9] These findings suggest that the sympathetic nervous system (SNS) plays a dual role in sepsis, which can be either beneficial or harmful depending on the immune system effector
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