Henry O. Wheeler

Hepatic Uptake and Biliary Excretion of Indocyanine Green in the Dog.

Summary 1. Indocyanine green given intravenously to dogs is distributed in the plasma compartment and rapidly removed by the liver. 2. Biliary excretion of the dye is delayed, but an average of 97.3% of the administered dose is eventually recovered from the bile in apparently unaltered form. Indocyanine green does not appear in the urine. 3. Indocyanine green interferes with hepatic uptake of BSP from the plasma. 4. Absorption of indocyanine green from the bowel is minimal.

Biliary excretion of lecithin and cholesterol in the dog

The biliary excretion rates of bile acid, lecithin, and cholesterol were measured in unanesthetized dogs after interruption of enterohepatic circulation and during infusions of sodium taurocholate, sodium glycocholate, sodium dehydrocholate, SC2644 (a bicyclic organic acid with high choleretic potency), and secretin. Both lecithin output and cholesterol output were directly related to bile acid excretion rate. The curves describing these relationships were concave downward. Molar concentration ratios of lecithin-to-bile acid declined gradually from approximately 0.4 to 0.2 as bile acid output increased from approximately 1 to 70 mumoles/min. Cholesterol-to-lecithin molar ratios were highest (0.05-0.15) at very low rates of bile acid excretion, but descended rapidly to a plateau (0.03-0.04) which was constant over the entire range of bile acid excretion rates from 10 to 70 mumoles/min. Similar lipid excretion patterns were observed during glycocholate infusion, but secretin-induced choleresis and dehydrocholate-induced choleresis were unaccompanied by any increments in lecithin or cholesterol excretion and SC2644 (which caused a marked increase in canalicular bile production as measured by erythritol clearance) caused a depression of lipid excretion. The data are consistent with the view that lecithin moves passively from cell membranes to intracanalicular micelles, that transport of cholesterol is coupled to lecithin transport, and that there is also a small amount of independent passive transport of cholesterol from membranes to micelles. A model developed on these assumptions has been shown to behave in a fashion consistent with the entire range of these observations.

DETERMINANTS OF THE FLOW AND COMPOSITION OF BILE IN THE UNANESTHETIZED DOG DURING CONSTANT INFUSIONS OF SODIUM TAUROCHOLATE

Physiological factors affecting the flow and composition of bile may be divided into two general categories. First, the availability of bile salts (by hepatic synthesis and by reabsorption from the bowel) has a significant influence on the rate of bile production. The choleretic effect of natural bile salts and the phenomenon of enterohepatic circulation of these compounds were first demonstrated by Schiff in 1870 (1). These observations have been confirmed by many workers since that time. It has been estimated that 85 to 90 per cent of the bile salt excreted in the bile is reabsorbed and returned to the liver (2, 3). For this reason the entry of bile itself into the duode-num provides a major stimulus for further bile production. Second, factors independent of the availability of bile salts can affect bile production. This category would include, for example, neural stimuli (4, 5), humoral agents such as secretin (6-8) and changes in vascular perfusion (5). During any investigation of biliary secretion in which bile is removed and not replaced, achievement of a steady state is thwarted by progressive depletion of bile salts which would normally undergo enterohepatic circulation. In the present studies this problem has been circumvented by constant intravenous infusion of sodium tauro-cholate. The results substantiate the important role of active bile salt secretion in the process of bile production and also suggest that the flow and composition of bile are modified by the addition of variable amounts of a solution which is similar in certain respects to pancreatic juice. METHODS All studies were conducted on four trained adult female mongrel dogs (21 to 30 Kg.) which had been pre-* This investigation was supported by a grant from the Department of the Army (Contract DA-49-007-MD-205). t Markle Scholar in Medical Science. t: Rockefeller Traveling Fellow in Medicine. pared several months previously by splenectomy, cho-lecystectomy and installation of a Thomas duodenal fis-tula apparatus (9). Food and water were withheld for 15 hours prior to each study. The fistula was opened and a No. 5 or No. 6 Fr. olive-tipped ureteral catheter inserted into the ampulla of Vater and advanced about 5 cm. into the common bile duct. The animal was then placed upright in a sling. Bile was withdrawn by gentle aspiration using an oiled tuberculin syringe, and collected under mineral oil in graduated tubes. By noting the volume collected, frequent estimations of bile flow were obtained (at …

The relationship between taurocholate secretion rate and bile production in the unanesthetized dog during cholinergic blockade and during secretin administration.

The energy for bile formation must be derived from intrahepatic processes rather than from the hydrostatic pressure of the blood (1). As Sperber has indicated (2), there is a variety of reasons for believing that the secretion of organic anions, and particularly of bile salts, may play a primary role in the production of bile. The bile salts are secreted by active transport (3), they constitute a substantial fraction of the total bile solutes, and are very effective choleretics in most species (4-6). Therefore, one of the objectives of the present studies was the exploration of the relationship between taurocholate secretion and the output of water and inorganic electrolytes in the bile. Previous studies (7) demonstrated the occurrence of marked spontaneous fluctuations in bile flow and composition in unanesthetized dogs even during constant infusions of sodium taurocholate. These fluctuations were thought to represent the addition of variable quantities of an alkaline fluid similar to that which is produced in abundance during secretin stimulation. These findings suggested the existence of transport mechanisms altogether independent of taurocholate secretion. In order to explore this possibility, a detailed examination of the effects of intravenous secretin was also included in the present work. The spontaneous fluctuations in bile flow and composition, although significant in themselves, constituted a technical obstacle to the systematic study of the effects of varying rates of taurocholate secretion. It was therefore desirable to minimize these fluctuations. This was accomplished by ad-

Some Effects of Nitroglycerin upon the Splanchnic, Pulmonary, and Systemic Circulations

Splanchnic, pulmonary, and systemic hemodynamics were studied in 18 patients afterthe sublingual administration of nitroglycerin. The drug, contrary to expectations, produced an over-all vasoconstrictive effect on the splanchnic circulation rather than vasodilatation. There was no evidence of venous pooling in this bed, and indeed the data may indicate a splanchnic supportive role in augmenting venous return to the heart with disengorgement of its own volume. In contrast, there was vasodilatation and pooling of blood in the pulmonary vascular bed. The systemic circulation probably sustains several effects by nitroglycerin, including arterial vasodilatation. A direct change in large artery distensibility probably explains the modest fall in systolic blood pressure seen. Further decline in arterial pressure may depend on venous pooling of a small or large degree. Probably the fall in systemic and specific organ flows is also linked to decreased venous return and the vascular readjustments provoked thereby. Pulsus alternans was produced by nitroglycerin, a previously unreported effect of the drug, but the mechanism by which it arose could not be defined.

HEPATIC STORAGE AND EXCRETION OF SULFOBROMOPHTHALEIN SODIUM IN THE DOG

The use of a halogenated phthalein dye for the investigation of hepatic function was first proposed by Rowntree, Hurwitz and Bloomfield (1) in 1913. Their technique required the measurement of the fecal excretion of phenoltetrachlorphthalein following its parenteral administration. However, it was subsequently shown by Rosenthal and White (2) that intravenously administered phenoltetrabromophthalein disulfonate (BSP) is removed from the blood almost exclusively by the liver and that the function of the liver may therefore be evaluated by measuring the rate of disappearance of this dye from the plasma. Various lines of evidence support the view that the removal of BSP (and presumably many other substances) from the plasma involves two processes: 1) storage of the material in the liver and 2) biliary excretion. Following the intravenous administration of BSP to dogs it was first shown by Wirts and Cantarow (3) that the output of BSP in the bile continues for over three hours after its virtual disappearance from the plasma, indicating that this material is first taken up by the liver and then gradually excreted. This observation was confirmed by Brauer and Pessotti (4), also in dogs. The existence of a similar hepatic BSP storage mechanism in man is evident from the studies of Mendeloff, Kramer, Ingelfinger and Bradley (5) in which a retardation of the BSP disappearance rate from plasma was noted when successive identical intravenous dosts were administered 30 minutes apart. These authors pos-

The Effect of Digoxin in the Splanchnic Circulation in Ventricular Failure

Splanchnic hemodynamics were examined in 22 patients with heart disease, 16 of whom had evidence of ventricular insufficiency at the time of study. The response of the splanchnic vasculature to the exhibition of intravenous digoxin was also studied in nine of these subjects.Ventricular insufficiency was associated with splanchnic vasoconstriction proportional to a generalized increase in peripheral vascularresistance. Splanchnic blood volume was disproportionately increased with respect to total blood volume in patients having visceral congestion with right ventricular failure and combined ventricular failure. A significant relationship between central venous pressure and splanchnic blood volume was demonstrated in these cases. The greater elevation of the former than of the latter suggested the presence of splanchnic venoconstriction.The vascular readjustment to digoxin resulted in a relative intensification of the already existing vasoconstriction of the splanchnic bed as compared to the diffuse systemic vasodilatation which occurred at the same time as the consequence of the inotropic action of the drug: estimated splanchnic blood flow and splanchnic blood volume diminished at a time when systemic flow rose and peripheral vascular resistance decreased. The ultimate distribution of the volume of blood translocated out of the splanchnic bed during this process remains to be determined.

Concentrating function of the gallbladder

Abstract The major effect of the gallbladder on bile composition is the removal of water and inorganic electrolytes, thereby raising the concentrations of all of the larger organic solutes. Some of the mechanisms involved in the absorptive process have been discussed previously. The luminal electronegativity, which is the result of passive ionic diffusion, may effect the distribution of electrolytes and specifically lead to elevated concentrations of potassium and calcium. Finally, the gallbladder is appreciably permeable to lipid-soluble molecules, and this may lead to gradual but significant alteration of bile composition by absorption of biliary lipids and of unconjugated bilirubin (generated, possibly, by bacterial enzymatic breakdown of conjugated bilirubin). Even some of the bile acids, particularly those conjugated with glycine or those which have undergone bacterial deconjugation, may be absorbed. The possible consequences of these gradual changes remain speculative.

Metabolism of Sulfobromophthalein Sodium (BSP) in Dog and Man.

Summary During administration of a constant infusion of BSP in the dog and man, 3 chromatographically distinct metabolites were demonstrated in plasma and bile in addition to BSP itself. Part of the metabolic change involves conjugation of BSP or some BSP derivative with one or more amino acids. Some of the physiologic properties of BSP metabolites are described and discussed, particularly with reference to problems of BSP transport from plasma to bile.

Electrolyte Excretion in Bile

The high concentration of certain test substances in both urine and bile suggests that similarities exist between the biliary and renal tubular functions. Evidence from dogs with permanent duodenal fistulas indicates that the rate of elaboration of bile depends primarily on the rate of secretion of bile salts. The variations in flow and composition of hepatic bile seem to result from the addition of a fluid which is similar in some respects to pancreatic juice.