2,4 Dinitrophenol, Acetazolamide 및 산염기 평형이상이 담즙 및 취액분비에 미치는 영향
Effects of DNP, acetazolamide and acid-base changes on biliary and pancreatic secretion
Both the liver and the pancrease are known to form bicarbonate-rich solutions which are eventually excreted into the gastrointestinal tract. In so doing the two organs show striking similarities. For instance, as the flow increase, the concentration of bicaronate also increase until it reaches a plateau after which it levels off (Birnbaum and Hollander, 1953; Davenport, 1961; Dreiling and Janowitz, 1959; Hart and Thomas, 1945; Wheeler and Ramos, 1960). this fact suggests that the
secretion of bicarbonate plays an important role in determining the flow of the hepatic bile as well as of the pancreatic juice. In further support of this view, the administration of acetazolamide reduces both the pancreatic flow and the bicarbonate output (Birnbaum and Hollander, 1953; Pratt and Aikawa, 1962; Rawls et al., 1963). However, with some unknown reasons, acetazolamide increases the hepatic bile flow while lowering the bicarbonate concentration, thus disrupting the flow
dependence of the bicarbonate concentration (Wheeler and Ramos, 1960). The only common effect of acetazolamide on these organs is to reduce the output of bicarbonate in their products, suggesting that carbonic anhydrase is involved in supplying bicarbonate to these fluids. In addition to this enzyme-catalyzed bicarbonate supply, the exists and uncatalyzed source of bicarbonate in the
pancreas which is related to its concentration in plasma(Rawls et al., 1963).
In the present investigation, the characteristic relationship between the flow and the bicarbonate concentration is first established for both the hepatic bile and the pancreatic juice while administering secretin, pancreozymin or 2,4 dinitrophenol. the last substance was shown earlier to have a remarkable choleretic action (Woo and Hong, 1963), and its effect on the pancreatic secretion was studied. In addition, acetazolamide is administered to normal dogs as well as to acidotic and alkalotic dogs, in order to study the effect of changes in plasma bicarbonate level on the flow and bicarbonate concentration of the hepatic bile and the pancreatic juice. On the basis of experimental results, differences between the liver and the pancreas in forming bicarbonate-rich alkaline solutions are
Experiments were carried out in 24 anesthetized dogs, each weighing approximately 10kg. Having fasted for 12-15 hrs prior to the experiment, the dog was anesthetized with nembutal (27 mg/kg; i.v.) and an endotracheal tube inserted. A femoral artery was cannulated for blood sampling and a femoral vein for infusion. The common bile duct and the pancreatic duct were cannulated while the cystic duct was ligated.
In those experiments dealing with metabolic alterations of acid-base balance, acidosis was induced by intravenous infusion of 0.37 N-HCI at a rate of 7ml/min for 10 min and then 1-2ml/min for the ensuing 3 hrs. Metabolic alkalosis was induced by infusion of 0.5 M-NaHCO^^3 in the same manner as for metabolic acidosis.
From 40 to 50 min after the above surgical procedures, samples of hepatic bile and pancreatic juice were collected under oil along with arterial blood samples. Usually, hepatic bile samples were collected every 10 to 40 min dependent on the flow, pancreatic samples every 10 min and blood samples every 20 min. Before administering any agent, one or two control bile samples were obtained and then two successive doses of secretin (Vitrum) were intravenously administered with a 20 min interval, followed by two successive doses of Pancreozymin (Boots) or Cecekin (Vitrum) which was adinistered in the same manner as secretin. 20 min after the administration of the second dose of pancreozymin, one dose of 2,4 dinitrophenol (DNP) or sodium acetazolamide (American Cyanamid Co.) was intravenously administered and then secretin and pancreozymin were administered as above after a
20 min interval. With the exception of post-acetazolamide period, each dose of secretin or pancreozymin was 10 units. However, following the administration of acetazolamide the dosage of hormone was increased to 20 units. The dosage of acetazolamide was 30 to 65 mg/kg except in the case of acidosis in which 25 mg/kg was given. DNP in a dose of 5 mg/kg was administered only to the dogs in which acid-base balance was not modified.
In 3 dogs, Na-taurocholate was infused at a rate of 7.5 μM/min throughout the entire experimental period, in order to correct for the loss of cholate.
Results and discussion
(1) The administration of secretin or pancreozymin resulted in increases in the flow and the concentration of both bicarbonate and chloride of the hepatic bile. However, when the flow was increased above 0.03ml/kg/min, there was no further increase in the concentration of the above electrolytes.
(2) The administration of secretin or pancreozym in increases in the flow and the concentration of bicarbonate and in a reduction in the conentraton of chloride of the pancreatic juice. However, when the flow was increased above 0.04ml/kg/min, there were no further changes in the electrolyte composition.
(3) The administration of 2,4 dinitrophenol (DNP) resulted in a great increase in the hepatic bile flow while it had no effect on the pancreatic secretion. The observed increase in the hepatic bile flow by DNP was accompanied by concomitant increases in the concentrations of bicarbonate and chloride.
(4) The administration of acetazolamide resulted in an increase in the hepatic bile flow while it reduced the pancreatic flow. However, when a comparison was made for a given flow of both hepatic and pancreatic juice, the concentration of bicarbonate was lowered while the concentration of chloride was elevated after acetazolamide. These results indicate that acetazolamide disrupts the characteristic flow-composition relationship of hepatic bile and the pancreatic juice.
(5) In metabolic alkalosis, the flow of both the hapatic bile and the pancreatic juice increased. Moreover, the concentration of bicarbonate in both fluids also increase. However, in metabolic acidosis, results opposite to alkalosis were observed.
(6) As a whole, the flow and the composition of both the hepatic bile and the pancreatic juice were found to vary as a function of plasma bicarbonate level. However, these correlations were much less obvious after the administration of acetazolamide.
(7) The concentrations of lipase, amylase and trypsin in the pancreatic juice were significantly greater after the administration of pancreozymin than after secretin.
(8) The enzyme output in the pancreatic juice was not altered by either DNP, acetazolamide or acid-base imbalance.
These results indicate that, although there are many similarities between the liver and the pancreas in producing alkaline fluids, there are certain dissimilarities between the two organs. On the basis of these results, the process of formation of hepatic bile and the pancreatic juice were discussed and a new concept was proposed for the formation of the pancreatic juice.