Effects of intravenous emulsified perfluorochemicals on hepatic cytochrome P-450.

Intravenous infusion of emulsified perfluorodecalin in rats caused a large increase in hepatic cytochrome P-450 concentration which persisted for many weeks. In contrast, hepatic cytochrome P-450 concentration was not changed significantly after infusion of perfluorotributylamine, but subsequent administration of phenobarbital caused the usual increase of cytochrome P-450. The cytochrome P-450 activity for demethylation of benzphetamine was decreased slightly after perfluorodecalin but was unchanged after perfluorotributylamine. The difference in the effects of these perfluorochemicals on hepatic cytochrome P-450 may be related to the difference in the time these compounds are retained in the liver.

Alteration by perfluorodecalin of hepatic metabolism and excretion of phenobarbital.

The bile duct was cannulated in rats that had been infused intravenously with an emulsion of perfluorodecalin at intervals from 2 to 34 weeks earlier. After injection of [14C]phenobarbital, urine and bile were collected during the next 24 hr and were analyzed for phenobarbital and its metabolites. There was a decrease in the biliary excretion of phenobarbital and its metabolites for several weeks after infusion of perfluorodecalin, but conjugation of the metabolites was not decreased. The reduced excretion returned to normal after about 20 weeks.

Magnetic resonance imaging of fluorine in rats infused with artificial blood.

An MRI pulse sequence has been developed that enables the visualization of a perfluorocarbon (PFC) emulsion in the vascular system of rats. Images were made at 0.12T on a clinical imaging system using a small receiver coil, at intervals of approximately 2 hours, two days, two weeks, and two months after replacement of 50% of total blood volume. The most successful technique produced PA projections of the entire torso for both the fluorine and proton components. Direct comparison allowed identification of PFC in heart, lung, liver, spleen, and large vessels both in vivo and postmortem. Potential clinical applications to vascular imaging are discussed.

Fluorinated blood substitute retention in the rat measured by fluorine-19 magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Emulsions of perfluorocarbons (PFCs) have been tested as blood substitutes. However, evidence exists that there is long-term retention of some PFCs by the organs of the reticuloendothelial system (RES). The authors investigate organ retention of the blood substitute component, perfluorotripropylamine (FTPA), using fluorine-19 (19F) magnetic resonance imaging (MRI). METHODS: Various dosages of an emulsion of FTPA were administered to five rats. At intervals up to 86 weeks after infusion, 19F MRI was used to measure the amount of FTPA in liver and spleen. The data were fit to both linear and exponential elimination models, and organ retention half-lives were calculated. RESULTS: The exponential half-lives for combined liver and spleen FTPA ranged from 110 to 190 days. Linear half-lives ranged from 175 to 300 days. CONCLUSIONS: FTPA retained by the liver and spleen may be quantified by 19F MRI: The half-lives that were measured are longer than those reported previously for FTPA.

In vivo measurements of vascular oxygen tension in tumors using MRI of a fluorinated blood substitute.

The authors measured the level of blood oxygenation in vivo in a series of rats with implanted mammary adenocarcinoma. The technique used was 19F magnetic resonance imaging of a perfluorochemical blood substitute. The method is based on the effect of oxygen on the T1 relaxation time of the fluorochemical and allows the determination of mean vascular PO2 independent of the blood volume in the tissue. The PO2 levels in the liver, lung, and spleen also were determined and were consistent with previously reported results. When the rats breathed air, the tumor PO2 levels were somewhat lower than in the other organs and were in a range typical of venous blood. When the rat was given 100% oxygen to breathe, the tumor PO2 levels increased far less than the PO2 levels of the other organs. This may indicate a greatly diminished blood flow to this particular tumor.

Intestinal ischemia: reduction of mortality utilizing intraluminal perfluorochemical.

This study reports an assessment of a method of intestinal protection by the intraluminal administration of an oxygenated perfluorochemical, perfluorotributylamine, or gaseous oxygen in an attempt to provide oxygen for mucosal cells rendered ischemia. A model of acute arterial or acute arteriovenous ischemia was produced in adult female rats. All control ischemic animals died within 12 hours. To assess intestinal protection, the mortality rates in the experimental groups were compared with the 100 percent control mortality. Gaseous oxygen and oxygenated perfluorochemical administered intraluminally reduced mortality significantly in the acute arterial model but not in rats with arteriovenous occlusion. Electron microscopy demonstrated preservation of villi after 1 and 2 hours of occlusion in the oxygen-treated groups. Light microscopy revealed massive destruction in control animals with preserved architecture in both the gaseous oxygen and oxygenated perfluorochemical groups. These results demonstrate that the intraluminal delivery of oxygen to bowel rendered ischemic by arterial occlusion may significantly decrease anatomic bowel disruption and improve animal survival. Such techniques have a potential clinical application to facilitate salvage of ischemic intestine and to augment intestinal preservation.

Oxygen-sensitive 19F NMR imaging of the vascular system in vivo.

The fluorine nuclear magnetic resonance spin-lattice relaxation rate (1/T1) of the perfluorochemical blood substitute perfluorotripropylamine (FTPA) is very sensitive to oxygen tension. This presents the possibility of measuring blood oxygen tension by 19F MR imaging. We obtained oxygen-sensitive 19F NMR images of the circulatory system of rats infused with emulsified FTPA. Blood oxygenation was assessed under conditions of both air- and 100% O2-breathing. T1 relaxation times were derived from MR images using a partial saturation pulse sequence. The T1 times were compared with a phantom calibration curve to calculate average blood pO2 values in the lung, liver, and spleen. The results showed marked, organ-specific increases in blood oxygen tension when the rat breathed 100% O2 instead of air.

Intestinal ischemia: treatment by peritoneal lavage with oxygenated perfluorochemical.

Though the delivery of elemental oxygen to tissues ravaged by anaerobic infection may be useful, little data exists that suggests that such therapy may benefit ischemic tissue. We report the development of a model to test the question that peritoneal lavage with an oxygen containing solution may favorably influence occlusive intestinal ischemia. Adult Sprague-Dawley rats with Nembutal (sodium pentobarbital) anesthesia underwent midline laparotomy; a microvascular clamp was applied to the superior mesenteric artery (SMA); and an inflow and outflow lavage catheter was placed. Treatment groups included control rats undergoing SMA occlusion only without lavage, rats lavaged with albumin during SMA occlusion (medium control), and rats lavaged during SMA occlusion with oxygenated perfluorochemical FC-47 emulsified in albumin (O2-FC-47). The increase in serum L-lactate following occlusion was used as an index of intestinal injury whether the perfusate was maintained at room temperature (28 degrees C) or body temperature (37 degrees C). Beginning with time O, which corresponded to the time of unclamping, subsequent samples were collected at 15, 30, and 60 minutes after a 30-minute SMA occlusion. Sequential lactates in 13 control rats were 4.18, 4.10, 3.88, and 4.52 mmol/L. Albumin lavaged animals had values at 28 degrees C of 2.23, 1.35, 1.8, and 2.44 mmol/L and values at 37 degrees C of 2.22, 1.40, 2.07, and 3.21 mmol/L, respectively. With O2-FC-47 lavage the respective lactates were 1.89, 1.09, 1.32, and 1.44 mmol/L at 28 degrees C and 2.14, 2.19, 2.50, and 2.1 mmol/L at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Perfluoro compounds as artificial erythrocytes.

Some liquid perfluoro compounds dissolve relatively large amounts of oxygen and can be used in dispersed form as substitutes for erythrocytes. The commonly used perfluoro compounds contain about the same amount of oxygen as do equal volumes of erythrocytes when equilibrated with 100% oxygen. However, when equilibrated with alveolar air, the perfluoro compounds contain much less oxygen than erythrocytes. The dispersed fluorochemicals are adequate substitutes for perfusion of isolated preparations of mammalian brain, heart kidney, lung and liver. However, when put into the circulation of the intact animal, the dispersed fluorochemicals tends to produce lesions of the lungs, dilation of the right heart, and ultimately fatal hypoxia. It is suggested that the course of events following intravenous injection of dispersed fluorochemical is initiated by an interaction of the perfluoro particles with blood platelets or blood clotting factors. The ensuing intravascular clotting could then cause the changes in the lungs which lead to a marked increase in pulmonary artery pressure and dilation of the right heart. These events would terminate in fatal hypoxia due to pulmonary pathology and heart failure.

Metabolic studies with an isolated, perfused rat brain preparation.

An unanesthetized, isolated, perfused rat brain, consisting of the skull and its contents with nearly all other tissues removed, has metabolic and electrical activity similar to that of the brain of the intact rat with its blood-brain barrier intact. Its use yielded results that are difficult or impossible to obtain from in vitro preparations or in vivo. With the perfused brain it was shown that mannose can completely replace glucose as metabolic substrate, that insulin has no direct effect on the brain, that in the absence of added substrate glutamate is metabolized to aspartate, that the brain does not metabolize ethanol, and that morphine probably inhibits mitochondrial oxidative activity.