HYPERPOLARIZATION OF HEPATOCYTES BY 2,5-AM - IMPLICATIONS FOR HEPATICCONTROL OF FOOD-INTAKE

Because 2,5-anhydro-D-mannitol (2,5-AM) seems to stimulate feeding by acting on the liver and because the hepatic membrane potential has bee n suggested to play an important role in control of feeding (''potenti ostatic'' hypothesis), we investigated the effect of 2,5-AM on the mem brane potential of liver cells with microelectrodes using a superfused liver slice technique. 2,5-AM (2.5 mM), which reduces intracellular A TP in rat liver, hyperpolarized the liver cell membrane in mouse and r at liver slices by 4-7 mV. This hyperpolarization was reversed by quin ine (1 mM), an unspecific blocker of Ca2+-dependent K+ channels, and a bolished by apamin (20 nM), a blocker of Ca2+-activated K+ channels wi th low conductance. Amiloride at 10(-3) M, but not at 10(-6) M, or a l ow-Na medium (26 mM) also eliminated the hyperpolarization. The K+ cha nnel blockers cetiedil (50 mu M), glibenclamide (30 mu M), and Ba2+ (5 mM); flufenamic acid (100 mu M), a blocker of nonselective cation cha nnels; and ouabain (1 mM), an inhibitor of the Na+-K+-adenosinetriphos phatase, did not significantly influence the 2,5-AM-induced hyperpolar ization. It is concluded that 2,5-AM hyperpolarizes the liver cell mem brane by activating Ca2+-dependent K+ channels. This activation seems to be impaired when the Na+/H+ exchanger is inhibited by amiloride or a low-Na+ medium. The findings also imply that the hyperphagic effect of 2,5-AM observed in rats is not associated with a decrease in the he patic membrane potential, as postulated by the potentiostatic hypothes is.