Factors determining the maximal rate of organic anion secretion by the liver and further evidence on the hepatic site of action of the hormone secretin

Abstract

SUMMARY1. Bromsulphthalein (BSP) was administered throughout the experiments at a constant rate well in excess of its excretory rate, to anaesthetized dogs in which the common bile duct had been cannulated. The maximal excretory rate of BSP into bile (BSP Tm) obtained in this manner was greatly elevated by choleresis arising from the administration of bile salt (usually taurocholate) at constant rate.2. When bile flow rate was increased in stages by raising the taurocholate administration rate, successive increments in BSP excretion rate were obtained up to a limiting value of about 3 times the original Tm. Beyond this point further increases in taurocholate administration rate caused either no further enhancement of BSP Tm or a decline in the extent of enhancement produced at a previous lower rate of infusion.3. When taurocholate maximal secretion was established first, the subsequent administration of BSP at progressively increasing rates led to reduction in the taurocholate secretion rate.4. Portal infusion of secretin at constant rate (usually 0x2 units/kg body wt. min) which caused substantial increases in bile flow rate, had no effect on BSP Tm. Increases of bile flow rate of the same order following constant taurocholate infusion produced marked elevation of the BSP Tm.5. These findings are discussed and the following conclusions reached: (a) The limiting factor in BSP maximal transfer is the concentration of BSP in bile; increased bile flow rate at the site of BSP excretion (canaliculi) produced by bile salt administration permits an increase in the original Tm to occur without the limiting biliary concentration being exceeded.(b) There is excretory competition between BSP and bile salt but over a certain range of bile salt administration the facilitatory effects of increased bile flow rate outweigh the inhibitory effects due to competition. BILIARY TRANSPORT MAXIMA (c) Since secretin administration had no effect on BSP Tm, it is likely that the hydrocholeresis it produces originates downstream from the canaliculi, i.e. in the bile ductules or ducts; this supports previous evidence obtained in a different manner.

Aspects of bile secretion in the rabbit.

“…The maximum rate at which it is transported into bile may be affected by the excretion of bile salt. It is believed that this is due to the decrease in the biliary concentration of BSP which occurs as bile flow is increased (O'Maille, Richards & Short, 1966). BSP, unlike the bile salts, is a disodium salt, and thus the marked increase in the concentration of sodium in bile, during the excretion of BSP in bile, is not unexpected.…”

Transport of conjugated bilirubin and other organic anions in bile: relation to biliary lipid structures.

“…Physiological studies of bilirubin and other organic anion secretory rates in bile showed a strong correlation with bile acid secretory rates under stimulated conditions but not during fasting (3)(4)(5)(6)(7)(8). This observation led to studies that have concluded that a strong relationship exists between biliary mixed-lipid micelles and bilirubin in addition to a variety of other organic anions, although the precise nature of the putative micellar-organic anion interaction has remained unclear (9)(10)(11)(12)(13)(14)(15).…”

The Biliary Excretion of Sulfbromophthalein in the Pig

“…In the present experiments it was evident that a maximal biliary concentration of BSP was a limiting factor in the biliary excretion and that excretion of BSP above this level was directly proportional to the increase in bile flow. Increased bile flow associated with supramaximal rates of BSP excretion has been reported in the rat (Dhumeaux et al, 1970), the sheep (Gronwall and Cornelius, 1970), and the dog (O'Maillie et al, 1966). It has been suggested that this choleresis is due to an increased excretion of bile acids with a nett increase in bile flow and biliary excretion of BSP.…”

“…There are a variety of factors which might influence the hepatic handling of BSP and these include liver blood flow (Shoemaker et al, 1961), body temperature (Harris, Noble and Munday, 1975), bile flow (Boyer, Scheig and Klatskin, 1970), bile salt concentration and competitive excretion with other organic anions (O'Maillie, Richards and Short, 1966). Care was taken to eliminate the effects of other drugs, particularly anaesthetic agents; experiments were performed in a constant temperature environment and the animals were subjected to minimal stress.…”

“…Three days prior to the experiment an external bile shunt was prepared as previously described (Rose and Ham, 1975). In brief, under halothane anaesthesia a shunt was placed from the common bile duct to the exterior and back to the duodenum.…”