Tracer oxygen distribution is barrier-limited in the cerebral microcirculation.

The kinetics of tracer oxygen distribution in the brain microcirculation of the awake dog were investigated with the multiple indicator dilution technique. A bolus containing 51Cr-labeled red blood cells, previously totally desaturated and then resaturated with [18O]2 (oxygen), 125I-albumin, 22Na, and [3H]water, was injected into the carotid artery, and serial anaerobic blood samples were collected from the sagittal sinus over the next 30 seconds. The outflow recovery curves were analyzed with a distributed-in-space two-barrier model for water and a one-barrier model for oxygen. The analysis provided an estimate of flow per gram brain weight as well as estimates for the tracer water and oxygen rate constants for blood-to-brain exchange and tracer oxygen parenchymal sequestration. Flow to tissue was found to vary between different animals, in concert with parallel changes in oxygen consumption. The 18O2 outflow curves showed an early peak, coincident with and more than half the magnitude of its vascular reference curve (labeled red blood cells), whereas the [3H]water curve increased abruptly to a low-in-magnitude curve at low flow values and to a small early peak at high flow values. Analysis indicates that the transfers of both 18O2 and [3H]water indicators from blood to brain are barrier-limited, with the former highly so because of the large red blood cell capacity for oxygen, and that the proportion of the tracer oxygen returning to the circulation from tissue is a small fraction of the total tracer emerging at the outflow.

Liver function improvement following increased portal blood flow in cirrhotic rats.

BACKGROUND/AIMS: Liver microcirculation in cirrhosis is characterized by development of intrahepatic shunts and capillarization of sinusoids secondary to cell necrosis and deposition of new collagen, resulting in both decreased drug elimination and increased vascular resistance with portal hypertension. The aim of this study was to examine the effects of increased portal blood flow on hepatic microcirculation and drug elimination in 13 perfused livers from cirrhotic rats. METHODS: Intrahepatic resistance was assessed under basal conditions (21.2 +/- 0.3 mL/min) and 1 hour after doubling the flow (41.6 +/- 1.0 mL/min). A multiple indicator dilution technique was used at both flow rates to measure sinusoidal volume, albumin and sucrose extravascular volumes, and cellular water volume. Hepatic elimination of labeled taurocholate and propranolol was also measured, and the recovery of 15-microns microspheres was used to evaluate large intrahepatic shunts. RESULTS: After doubling the flow, intrahepatic resistance decreased by 31%. Sinusoidal and extravascular volume increased significantly without a change in microsphere recovery. However, there was a marked increase in taurocholate and propranolol elimination by cirrhotic livers. Moreover, during high flow, significant correlations were found between changes in albumin extravascular volume and taurocholate and propranolol elimination. CONCLUSIONS: Increased portal blood flow in cirrhotic rats induces a decrease in intrahepatic resistance without changes in intrahepatic shunting and improves drug elimination by the liver without deleterious effects on hepatocyte viability.

Hepatic artery and portal vein vascularization of normal and cirrhotic rat liver.

The hepatic artery and portal vein vascularization of seven normal and seven cirrhotic rats was evaluated by means of the multiple-indicator dilution technique using the flow-limited model analysis. Injected 15-micron microspheres were all trapped by the liver in normal and cirrhotic rats after portal vein and hepatic artery injections, ruling out the presence of intrahepatic shunts larger than 15 microns. The albumin curve was linearly displaced relative to the red blood cell curve in both groups of rats, indicating that albumin distribution remained compatible with the flow-limited distribution model. Albumin extravascular space was similar when measured following both routes of injection. Sucrose outflow profile was also compatible with the flow-limited model after portal vein injection in normal rats, but not in severely cirrhotic rats. In contrast, after hepatic artery injection in both normal and cirrhotic rats the sucrose curve was not linearly displaced compared with that of red blood cells; its curve peak was less delayed than its downslope. This finding indicates that, after hepatic artery injection, sucrose distribution was not compatible with the flow-limited model; moreover, its extravascular space was much larger than that after portal vein injection, particularly in cirrhotic rats. This phenomenon is best explained by the peribiliary capillary plexus, lying between terminal arteries and sinusoids, a plexus enlarged in cirrhotic livers. Finally, sinusoidal volume was apparently much larger after hepatic arterial injection compared with that after portal venous injection. This occurrence may well result from an unshared arterial sinusoidal bed or the peribiliary capillary plexus.

Clearance by the liver in cirrhosis. II. Characterization of propranolol uptake with the multiple-indicator dilution technique.

We studied the steady-state hepatic extraction and single-pass hepatic uptake of propranolol in isolated perfused livers from normal rats and compared these values with those of rats with carbon tetrachloride-induced cirrhosis, rats treated with chlorpromazine (an inhibitor of propranolol metabolism) and rats with acute liver injury. The kinetics of propranolol transport in the liver were characterized by means of the multiple-indicator dilution technique, and estimates of cellular influx, efflux and sequestration rate constants were obtained with a computer fit to the model of Goresky. The outflow pattern of propranolol in the hepatic veins was then resolved into throughput material, which had swept past the hepatocytes along with albumin, and returning material, which had entered the cells but returned in the outflow after escaping metabolic sequestration. The steady-state extraction of propranolol was significantly decreased in the three experimental groups compared with that in controls, but the outflow profile differed within each group. In cirrhotic animals, influx was markedly decreased and the sequestration rate constant remained unchanged; most of the propranolol in the outflow consisted of throughput material. In rats treated with chlorpromazine, the sequestration rate constant was decreased, and propranolol in the outflow was mainly returning material. In rats with acute liver injury, both influx and sequestration rate constants were decreased. Indicator dilution curves for nonsequestered tracers showed a decreased transit time for red blood cells and abnormal diffusion of albumin and sucrose into the space of Disse in cirrhotic rats compared with the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Flow-limited tracer oxygen distribution in the isolated perfused rat liver: effects of temperature and hematocrit.

We used the multiple-indicator dilution technique to examine the kinetics of tracer oxygen distribution and uptake in the rat liver perfused in a nonrecirculating fashion with blood. 51Cr-labeled 18O2-saturated erythrocytes, labeled albumin, sucrose and water (the tracers for oxygen and vascular, interstitial and cellular references) were injected simultaneously into the portal vein. Timed anaerobic samples were collected from the hepatic vein and analyzed by mass spectrometry for relative 18O2 enrichment and radioactivity. In a set of experiments performed at 32 degrees C, oxygen uptake was substantially diminished; tracer oxygen profiles approached those expected for a completely recovered, flow-limited substance. At 37 degrees C, much larger tracer oxygen sequestration occurred. Experiments were carried out at each temperature at higher and lower hematocrit, and oxygen consumption at each temperature was found to be independent of hematocrit. The tissue space of distribution for tracer oxygen relative to the total sinusoidal vascular content was influenced by the hematocrit: it was smaller at higher hematocrit and larger at lower hematocrit, as expected. The derived partition coefficient of oxygen for liver cells relative to plasma (expressed in terms of the liver and plasma water spaces) was, on average, 2.62 ml/ml; it was independent of the hematocrit. Analysis of the indicator dilution experiments indicates that the tracer oxygen is distributed into tissue in a flow-limited rather than a barrier-limited fashion, and that with this, an ongoing concomitant intracellular sequestration of tracer can be seen.

Liver extraction of vitamin D3 is independent of its hepatic venous or arterial route of delivery. Studies in isolated-perfused rat liver preparations.

The hepatic extraction of a naturally occurring secosteroid, vitamin D3 (D3), in relation to its hepatic arterial or portal venous route of delivery has been studied in isolated rat liver preparations perfused at an arterial/venous flow ratio of 1:4. No significant difference in the fractional hepatic extraction of D3 was observed when the vitamin was administered via the portal venous route compared to when it was administered via the hepatic arterial route. Estimation of the uptake and clearance of D3 in relation to its route of delivery revealed, however, that due to the higher perfusion flow through the portal venous than through the arterial route, both the hepatic uptake and clearance of D3 were significantly higher after portal vein than after hepatic artery delivery. Moreover, calculation of the uptake of D3 after delivery through the portal venous route also revealed that it was not significantly different from that of the total hepatic uptake (uptake following portal vein + hepatic artery delivery). The data obtained during the present studies indicate, then, that the fractional hepatic extraction of D3 is not dependent on its route of entry into the liver; it also points out that, in experimental models such as in isolated-perfused liver preparations, the portal vein administration of D3 should represent adequately the total hepatic handling of the secosteroid by the normal rat liver.