HYPERPOLARIZATION OF THE RAT HEPATOCYTE MEMBRANE BY 2,5-ANHYDRO-D-MANNITOL IN-VIVO

The fructose analogue 2,5-anhydro-D-mannitol (2,5-AM), that inhibits g lucose release and ATP formation in liver cells, seems to stimulate fe eding by acting on the liver, because hepatic portal injection was mor e effective than jugular vein injection and because hepatic branch vag otomy attenuated 2,5-AM's hyperphagic effect. Russek's ''potentiostati c'' hypothesis postulates a role for the hepatic membrane potential in the control of food intake with depolarization of hepatocytes signali ng hunger and hyperpolarization representing a satiety signal. Therefo re, the aim of the present study was to find out, whether 2,5-AM affec ts the hepatic membrane potential under ill vivo conditions. The membr ane potential was measured with microelectrodes in anesthetized rats a fter intraperitoneal (IF) or intraportal (IPV) administration of 2,5-A M or control solution. 2,5-AM significantly hyperpolarized the hepatoc yte membrane 50 min after IP injection (100 mg/kg: 3.6 mV; 300 mg/kg: 9.9 mV). In a second experiment, 2,5-AM (300 mg/kg) elicited a signifi cant hyperpolarization of hepatocytes as soon as 5 - 9 min after IPV i nfusion. These effects occured at doses that have been shown to increa se the afferent discharge rate in the common hepatic vagus branch, and to stimulate food intake, 2,5-AM's hyperphagic effect therefore is as sociated with an increase in the hepatic membrane potential. These fin dings contradict the predictions of the ''potentiostatic'' hypothesis and-are consistent with the notion, that the feeding response to 2,5-A M might be due to ATP depletion in the terminals of vagal afferents.