Sodium and chloride dependency of dibucaine- and procaine-induced choleresis in isolated perfused rat livers.
The effect of local anesthetics, dibucaine and procaine, on hepatic bile formation was studied in the isolated perfused rat liver. Perfusate Na+ and Cl- were replaced by other ions to define the possible mechanism of action. A single dose (50 mumol) of dibucaine produced an initial cholestasis followed by choleresis. Whereas dibucaine produced only choleresis at a lower dose (10 mumol), only the cholestatic effect was seen at a higher dose (100 mumol). Procaine, on the other hand, produced only choleresis at all doses (1, 10 and 100 mumol); this choleresis was associated with biliary secretion of procaine and its metabolites. Neither dibucaine nor procaine affected the low endogenous bile acid secretion in these studies. The diffusion permeability coefficient of [carboxy-14C]inulin was not altered significantly by dibucaine and procaine, suggesting no significant alteration of biliary permeability. Biliary secretion of Na+ or Cl- declined during cholestasis and increased during choleresis. The initial cholestatic effect of dibucaine was still present when perfusates Na+ and Cl- were replaced by permeable Li+ or NO3-, but declined when Cl- was replaced by relatively impermeable isethionate, suggesting a nonspecific effect. The choleretic effect of both dibucaine and procaine, however, declined significantly when Na+ or Cl- was replaced by Li+, NO3- or isethionate-. These ion-substitutions did not affect significantly the biliary secretion of procaine and its metabolites. The ability to induce biliary secretion of Na+ and Cl- also decreased when Cl- was replaced by NO3- or isethionate and when Na+ was replaced by Li+, respectively. These results suggest that a part of the choleretic effect of both dibucaine and procaine is specifically dependent on Na+ and Cl-. This fraction is thus unlikely to be due to the osmotic effect of the secreted drug. Further studies showed that dibucaine inhibited Na+-dependent hepatic uptake of taurocholate, suggesting possible interference with other Na+-dependent transport processes. It is proposed that although a part of the choleresis is due to the osmotic effect of the secreted drug, the specific dependency of a portion of the choleretic effect on Na+ and Cl- is due to inhibition of Na+-coupled Cl- reabsorption from the canaliculi.
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D003992:Dibucaine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008094:Lithium / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D011343:Procaine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012965:Sodium Chloride / Q000378:metabolism*; D013656:Taurocholic Acid / Q000378:metabolism
D001647:Bile Acids and Salts; D012965:Sodium Chloride; D011343:Procaine; D013656:Taurocholic Acid; D008094:Lithium; D003992:Dibucaine