Shock Induction by Arterial Hypoperfusion of the Gut Involves Synergistic Interactions between the Peripheral Enkephalin and Nitric Oxide Systems

Abstract

To determine whether critical splanchnic artery hypoperfusion can provoke systemic shock and to identify the roles of the peripheral opioid and nitric oxide (NO) systems in this process, various degrees of superior mesenteric artery hypoperfusion (SMA-H) were produced in anesthetized adult rabbits (n=40), and hemodynamic and metabolic indices were measured. Metabolic acidosis and irreversible hypodynamic shock occurred with SMA-H at levels representing 25-20% of mean baseline SMA blood flow. In 112 other rabbits subjected to SMA-H at 20% (SMA-H20%), we studied plasma NO and enkephalin (ENK) levels, cardiovascular reactivity to selected physiological agonists, effects of ENKs on plasma NO levels, and effects of peripheral opioid receptor blockade and inducible NO synthase (iNOS) inhibition. SMA-H20% progressively increased systemic blood levels of NO and ENKs. Exogenous ENK administration accentuated SMA-H20%-induced increases in plasma NO levels, and their cardiovascular depressing effects were significantly greater when they were administered during SMA-H20% (vs. administration under baseline conditions). Selective blockade of cardiovascular delta-opioid receptors improved hemodynamics, prevented shock irreversibility and reduced plasma NO levels; similar effects were obtained by selective iNOS inhibition. These findings demonstrate that critical arterial hypoperfusion of the gut can induce hypodynamic systemic shock through ENK-induced hyperactivation of cardiovascular delta-opioid receptors, which leads to increased plasma levels of NO related in part to increased iNOS activity. Since pronounced splanchnic artery hypoperfusion occurs in all advanced systemic shock states, selective delta-opioid receptor antagonists and/or iNOS inhibitors may prove to be useful in improving shock hemodynamics and metabolic derangements and/or preventing progression toward irreversibility.

Towards the Resurrection of the Delta-Opioid Receptor Antagonists in Haemodynamic Shock Management?

“…These studies follow what shown by ours in 2005 [3] in rabbits developing hypodynamic systemic shock when the superior mesenteric artery (SMA) was hypoperfused at critical levels representing 25-20% of its mean baseline blood flow. We showed that the selective blockade of cardiovascular δ-opioid receptors by ICI 174864 or naltrindole improved haemodynamics, prevented shock irreversibility and reduced plasma nitric oxide (NO) levels; similar effects were obtained by selective inhibition of inducible NO synthase (iNOS) by AMT ( ± 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine, HCl) but not by blocking opioid receptors other than the δ ones (e.g.…”

“…We showed that the selective blockade of cardiovascular δ-opioid receptors by ICI 174864 or naltrindole improved haemodynamics, prevented shock irreversibility and reduced plasma nitric oxide (NO) levels; similar effects were obtained by selective inhibition of inducible NO synthase (iNOS) by AMT ( ± 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine, HCl) but not by blocking opioid receptors other than the δ ones (e.g. the κ 1 -receptors by nor-binaltorphimine) or by using drugs like fenoprofen and hydrocortisone [3]. Moreover, leu 5 and met 5 -enkephalins (ENK, specific activators of δ-opioid receptors), but not other physiological agonists, impaired haemodynamic function and increased plasma NO levels, when administered intravenously, much more during SMA hypoperfusion (SMAH) than in baseline conditions [3].…”

Inhibitory effect of quercetin on tryptase and interleukin-6 release, and histidine decarboxylase mRNA transcription by human mast cell-1 cell line

“…The activity of the HDC enzyme is altered in various neurological diseases, treated and non-treated with therapeutical compounds. HDC is useful in studies in identification of histaminergic neurons and their function in the brain [34,35].…”

Expression of Co-stimulatory Molecules on Langerhans Cells in Lesional Epidermis of Human Atopic Dermatitis

“…(7)(8)(9) Recently, the expression of the IL-7 related cytokine, thymic stromal lymphopoietin (TSLP), has been shown to provide an AD-like phenotype (eczema and high serum IgE level) in mice expressing the transgene. (10)(11)(12)(13) Moreover, TSLP induces DC activation and maturation, suggesting a pivotal role of this cytokine as initiator of the allergic inflammatory process. (14)(15)(16)(17) TSLP-activated DC then migrates into the draining lymph nodes where they promote the differentiation of allergen-specific naïve CD4+ T lymphocytes to become effector Th2 cells.…”