Glucose and Glucose Transporters Regulate Lymphatic Pump Activity through Activation of the Mitochondrial ATP-Sensitive K⁺ Channel

Abstract

We investigated the pivotal roles of glucose and its transporter in the regulation of mechanical activity of isolated rat thoracic ducts and then examined whether or not mitochondrial ATP–sensitive K⁺ channels (mitoK_ATP) is involved in those responses. In the absence of extracellular glucose, the thoracic ducts showed pump activity during 120 min. Extracellular glucose caused a dose-dependent increase in the frequency of pump activity and a constriction in the thoracic ducts. Pump activity of the thoracic ducts in 0 mM glucose was completely inhibited in the presence of chlorogenic acid (an inhibitor of glucose-6-phosphatase). Cytochalasin B, an inhibitor of facilitative glucose transporter (GLUT), or phlorizin, an inhibitor of sodium-dependent glucose cotransporter (SGLT), significantly reduced the frequency of pump activity and dilated the thoracic ducts. 5-hydroxydecanoate (5-HD, a selective blocker of mitoK_ATP)–induced decrease in the frequency of pump activity was completely reversed by ruthenium red (an inhibitor of Ca²⁺ uniporter in mitochondria). Diazoxide (a selective opener of mitoK_ATP) significantly increased the frequency of pump activity. Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP, a protonophore of mitochondrial proton pump action) significantly reduced the frequency of pump activity and dilated the thoracic ducts. Collectively, these findings suggest that glucose derived from intracellular glycogen and/or through GLUT/SGLT in lymphatic smooth muscles contributes to the regulation of pump activity of isolated rat thoracic ducts, and that mitoK_ATP in the cells may partially serve as a modulator of the mechanical functions associated with mitochondrial Ca²⁺ uptake.