Multiple indicator dilution studies of the hepatic circulation in the dog were carried out using labeled red cells, albumin, inulin, sucrose, sodium, urea, water, and T-1824. The materials were completely recovered in the outflow. Concentrations were expressed as fractions of the injected mass. The outflow pattern of each of the substances was displaced relative to the red cell curve, showing a lower peak concentration and longer transit time. The displacement was largest for water and urea, least for albumin and T-1824, intermediate for inulin, sucrose, and sodium. The results were analyzed using a flow-limited linear two-compartment model system. The analysis yielded estimates of sinusoidal blood volume and of the extravascular volumes of distribution of the diffusible labels. Water and urea volumes agreed with the liver weights and this agreement was taken as validation of the method of analysis. Volumes calculated for the other presumably extracellular substances demonstrated that the rapidly available extracellular space diminishes with increase in the molecular weight of the substance.

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The identified independent clinical predictors of a CBD stone helps select a population of symptomatic gallstone bearers who benefit most from cholangiographic assessment.

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The pulmonary circulation plays an important role in the removal of circulating endothelin-1 (ET-1). Plasma ET-1 levels are increased in pulmonary hypertensive states of various etiologies (e.g., idiopathic, heart failure, and congenital anomalies) in proportion to the severity of pulmonary hypertension. It is possible that reduced pulmonary clearance of this peptide contributes to the hyperendothelinemia of those pathologies. The ETA and ETB receptors are abundant in lung tissues: on the vascular endothelium, the ETB receptor is predominant and may contribute to ET-1 extraction through receptor-mediated endocytosis. We designed experiments to determine and quantify the importance of the ETA and ETB receptors in the pulmonary extraction of circulating ET-1 in anesthetized dogs. The single-pass cumulative tracer ET-1 extraction by the lung was measured with the indicator-dilution technique before and 5 min after intrapulmonary injection of the specific ETA antagonist BQ-123 (n = 5, 120-960 nmol) and the specific ETB antagonist BQ-788 (n = 6, 1,000 nmol). The inhibitors had no significant effect on pulmonary and systemic hemodynamics. Mean cumulative pulmonary ET-1 extraction was not modified by BQ-123 [control (C): 36 +/- 4%, antagonist (A): 34 +/- 6%] but was completely abolished by BQ-788 (C: 34 +/- 6%, A: 0 +/- 2%, P < 0.001). The pulmonary rate constant (K) for ET-1 removal was also unaffected by BQ-123 (C: 0.050 +/- 0.0085 s-1, A: 0.047 +/- 0.012 s-1) but significantly decreased and became close to zero after BQ-788 (C: 0.058 +/- 0.014 s-1, A: 0.009 +/- 0.007 s-1, P < 0.1). We conclude that the ETB receptor is completely and exclusively responsible for pulmonary ET-1 removal in vivo. Future studies are needed to show whether desensitization or downregulation of the ETB receptor may contribute to the increase in circulating ET-1 levels in conditions associated with pulmonary hypertension. This novel pulmonary endothelial cell function may play a protective role by modulating circulating ET-1 levels in the systemic circulation.

A B S T R A C T D-galactose, a monosaccharide rapidly phosphorylated within liver cells, is irreversibly removed from the portal circulation. We have studied the kinetic relations between the hepatic cell entry process and the metabolic sequestration process, by means of the multiple indicator dilution technique. Labeled red blood cells (a vascular indicator), labeled sucrose (an extracellular reference), and labeled galactose were rapidly injected into the portal vein, and from rapidly sampled hepatic venous blood, normalized outflow-time patterns were secured. The labeled red cell curve rises to the highest and earliest peak, and decays rapidly; and that for labeled sucrose rises to a later and lower peak. Its extrapolated recovery is equivalent to that of the labeled red cells. At low blood galactose concentrations, the labeled galactose appears at the outflow with labeled sucrose, but is much reduced in magnitude, and exhibits a long tailing. Its outflow recovery is much reduced. At high blood galactose concentrations, the initial part of the profile increases towards that for labeled sucrose, the tailing becomes much larger in magnitude, and the outflow recovery becomes virtually complete.We have modeled the uptake of labeled galactose, and find two parts to the predicted outflow pattern, corresponding to our experimental observations: throughput material, which sweeps past the cell surface in the extracellular space; and returning material, which has entered the cells but escaped the sequestration process. Analysis of the data by use of this model provides estimates of both transmenmbrane fluxes and rates of sequestration. The capacity of the process subserving cell entry is found to be 40 times that for phosphorylation; and, whereas the Km value for sequestration is less than 15 mg/100 ml, that for entry is approximately 500 mg/100 ml. Both processes are relatively stereoReceived for publicationt 3 February 1971

INDICATOR-DILUTION studies of the coronary circulation will contain information especially concerning the heterogeneity of capillary transit times, information which potentially can be resolved from outflow curves if both a vascular reference substance, one confined to the coronary circulation, and a diffusible substance, one which leaves the vascular space, have been injected simultaneously. One would expect the heterogeneity to change with changes in the vasomotor tone, and this change, in turn, to affect the manner of presentation 'of diffusible substrates to muscle cells, where they are utilized. It therefore seemed important to us to develop a way of characterizing the heterogeneity of capillary transit times in the myocardium and to use this to define the manner in which the heterogeneity alters in response to changes in vasomotor control. The essence of this methodology is to carry out a set of indicator-dilution experiments, to develop a model of events at the level of the capillary net, and, with this, to try to dissect from the data information concerning the heterogeneity of capillary transit times.

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