Abstract
Dexmedetomidine (Dex), a highly selective α2-adrenoceptor agonist, attenuates inflammatory responses induced by lipopolysaccharide (LPS) and induces sedative and analgesic effects. Administration of Dex also reduces salivary secretion in human subjects and inhibits osmotic water permeability in rat cortical collecting ducts. However, little is known about the mechanisms underlying the effects of Dex on salivary glands fluid secretion. We demonstrated the α2-adrenoceptor expression in the basolateral membrane of mouse submandibular glands (SMG). To investigate fluid secretion upon treatment with Dex, we studied the effects of Dex on the activity of Na+-K+-2Cl− cotransporter1 (NKCC1) and Cl−/ exchange (CBE), and on downstream pro-inflammatory cytokine expression in isolated primary mouse SMG cells. Dex acutely increased CBE activity and NKCC1-mediated and independent entry in SMG duct cells, and enhanced ductal fluid secretion in a sealed duct system. Dex showed differential effects on cholinergic/adrenergic stimulations and inflammatory mediators, histamine, and LPS, stimulations-induced Ca2+ in mouse SMG cells. Both, histamine- and LPS-induced intracellular Ca2+ increases were inhibited by Dex, whereas carbachol-stimulated Ca2+ signals were not. Long-lasting (2 h) treatment with Dex reduced CBE activity in SMG and in human submandibular glands (HSG) cells. Moreover, when isolated SMG cells were stimulated with Dex for 2 h, phosphodiesterase 4D (PDE4D) expression was enhanced. These results confirm the anti-inflammatory properties of Dex on LPS-mediated signaling. Further, Dex also inhibited mRNA expression of interleukin-6 and NADPH oxidase 4. The present study also showed that α2-adrenoceptor activation by Dex reduces salivary glands fluid secretion by increasing PDE4D expression, and subsequently reducing the concentration of cAMP. These findings reveal an interaction between the α2-adrenoceptor and PDE4D, which should be considered when using α2-adrenoceptor agonists as sedative or analgesics.
Highlights
Dexmedetomidine (Dex) is a selective α2-adrenoceptor agonist with sedative, analgesic, anxiolytic, and hemodynamic stabilizing properties and has protective effects on systemic inflammation by attenuating oxidative stress (Kiliç et al, 2012; Shen et al, 2013)
The major novel finding of the present study was that α2adrenoceptors are expressed in the basolateral membrane of mouse submandibular glands (SMG) cells and that the selective α2-adrenoceptor agonist Dex acutely increased ductal CBE activity and NKCC1independent NH+4 entry, as well as increased fluid secretion in primary isolated SMG acini and ductal cells
Reduced function of transporters caused by the increased expression of PDE4, which may be involved in reduced cAMP level in SMG
Summary
Dexmedetomidine (Dex) is a selective α2-adrenoceptor agonist with sedative, analgesic, anxiolytic, and hemodynamic stabilizing properties and has protective effects on systemic inflammation by attenuating oxidative stress (Kiliç et al, 2012; Shen et al, 2013). Dex exerts its protective effects by inhibiting interleukin (IL)-1β-induced IL-6 synthesis (Tanabe et al, 2014) and by reducing of lipopolysaccharide (LPS)induced production of pro-inflammatory cytokines, such as IL1β and IL-6 (Peng et al, 2013). We demonstrated that Dex attenuated histamine-induced Ca2+ increase and IL6 expression in human salivary glands (HSG) cells (Yang and Hong, 2015). Dex reduces inflammation, there are side effects associated with it, such as reduced salivary secretion (Karhuvaara et al, 1991; Bischoff and Kochs, 1993) and prevented hypersecretion (Marks et al, 2010). Activation of α2-adrenoceptors inhibits adenylate cyclase, thereby reducing cAMP accumulation and cAMP-dependent protein kinase signaling (Rabin et al, 1997)
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