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J Reichen

Publications and source records attributed to J Reichen.

At least 163 records · Page 9Linked to original sources
PubMed1986

Effects of monensin on vesicular transport pathways in the perfused rat liver.

In the rat hepatocyte, the internalization and degradation of asialoglycoproteins and the secretion of plasma and biliary proteins require specific intracellular sorting of vesicles. To aid in the biochemical characterization of these different vesicular pathways, we examined the effects of the ionophore monensin on the uptake and degradation of 125I-asialoorosomucoid (ASOR) and on the secretion of plasma and biliary proteins by the in situ perfused rat liver. In control livers, 77% of injected 125I-ASOR was extracted on first pass; 93% of the extracted radioactivity was released back into the circulation (totally degraded and some intact ASOR was found); and approximately 2% was recovered in the bile, some of which was intact. Monensin treatment decreased first pass uptake of 125I-ASOR to 57% and abruptly blocked the release of radioactivity into the perfusate and the bile. When hepatic proteins were biosynthetically labeled with 3H-leucine, monensin treatment dramatically reduced and delayed the secretion of newly synthesized proteins into both the perfusate and the bile. In contrast with control livers, in which secretion of protein into the perfusate preceded secretion of protein into the bile, TCA-precipitable 3H-protein appeared in bile about 20 min before TCA-precipitable 3H-protein appeared in the perfusate in monensin-treated livers. Thus, monensin treatment in the perfused liver blocked the degradation of asialoglycoproteins and inhibited the secretion of plasma proteins but had less effect on biliary protein secretion. These data document physiologic effects of monensin in an intact organ and suggest that biochemical distinctions between different vesicular pathways exist in the rat hepatocyte.

Animals↗
PubMed1986

Chronic verapamil administration lowers portal pressure and improves hepatic function in rats with liver cirrhosis.

The effects of verapamil on portal pressure, microsomal liver function and extravascular albumin space were investigated in rats rendered cirrhotic by chronic exposure to phenobarbital and carbon tetrachloride. Verapamil significantly decreased splenic pulp pressure by 28% (P less than 0.05). In cirrhotic animals it improved liver function, measured by the aminopyrine and caffeine breath tests, by 36% (P less than 0.025) and 53% (P less than 0.05), respectively. The extravascular albumin space, an important determinant of drug clearance, was measured by a multiple indicator dilution technique. It was significantly larger in verapamil treated than in untreated cirrhotics (4.41 +/- 1.06 vs 2.73 +/- 0.79 ml/g; P less than 0.01). We conclude that verapamil has significant potential as a portal antihypertensive agent and its value in treating cirrhosis in man should be explored by controlled studies.

Animals↗
PubMed1986

Verapamil favorably influences hepatic microvascular exchange and function in rats with cirrhosis of the liver.

The effect of the calcium channel blocking agent, verapamil, on microcirculatory patterns and hepatic function was investigated in the perfused liver of cirrhotic rats. Compared with controls, cirrhotic livers had higher vascular resistance, increased intrahepatic shunting, and smaller extravascular albumin space and larger extravascular sucrose space, as determined by a multiple-indicator dilution technique. Hepatic function, estimated by determining propranolol and antipyrine extraction, was markedly reduced in cirrhotic livers. Portal pressure was then reduced 25% either pharmacologically by verapamil or hydrodynamically by lowering inflow. Verapamil decreased vascular resistance by 22%. This was associated with a 38% reduction in intrahepatic shunting and a 62% increase in extravascular albumin space. Hydrodynamically lowering pressure had no or adverse effects. The verapamil-induced improvement in microcirculatory characteristics was associated with a significant improvement in oxygen consumption (+21%) and antipyrine clearance (+20%). We conclude that the microvascular distortions of liver cirrhosis in the rat are partially reversible by vasodilators like verapamil.

Animals↗
PubMed1985

[Pharmacological therapy of portal hypertension].

Bleeding from esophageal varices is a feared complication of liver cirrhosis with high mortality. Pharmacotherapy of the acute bleeding episode with vasopressin has been shown to be effective in controlled studies, but side effects of this therapy are high and therefore replacement of vasopressin with somatostatin is under investigation. Another potential lead is the combination of vasopressin with vasodilators such as nitroglycerin. While acute pharmacotherapy of the patient with esophageal varices is well accepted, chronic or prophylactic pharmacotherapy is still in the investigative stage. Prophylactic therapy with beta-blockers, e.g. propranolol, has been shown to be effective in compensated patients with alcoholic cirrhosis. In patients with more advanced stages of the disease, or with cirrhosis of other etiology, the effectiveness of propranolol has not been proven. The mechanism of propranolol is similar to that of vasopressin, i.e. it lowers portal pressure by reducing portal flow. To maintain function of the affected organ, an alternative approach--namely lowering of portal pressure through reduction of the pathologically elevated resistance--should be actively investigated.

Acute Disease↗
PubMed1985

Taurolithocholate increases heme catabolism and alters the clearance of antipyrine in the rat.

Taurolithocholate has been implicated in human cholestatic syndromes. Its action is believed to be due to an alteration in liver plasma membrane composition. To investigate whether other membranes are similarly affected, we studied the effect of taurolithocholate on hepatic heme turnover by means of a new 14CO breath test. Between 2 and 7 h after taurolithocholate administration, 14CO production was significantly increased, suggesting increased heme catabolism. This was substantiated by the finding of a 47% reduction of microsomal cytochrome P450 content 3 h after taurolithocholate administration. There was a reciprocal increase of 50% in heme oxygenase activity, the key enzyme in heme catabolism. To probe the biological significance of these findings, we measured plasma disappearance of propranolol and antipyrine. Clearance of neither propranolol nor antipyrine was altered by acute taurolithocholate administration. Prolonged administration of taurolithocholate, by contrast, decreased metabolic clearance rate of antipyrine by 48%. This was accompanied by a 25% decrease in microsomal cytochrome P450 content. Our findings suggest that taurolithocholate affects composition and function of the smooth endoplasmic reticulum, and that its action is not limited to the liver plasma membrane.

Animals↗
PubMed1985

Extraction efficiency and biliary excretion of hepatobiliary imaging agents in the rat perfused liver.

A multitude of transitional metal complexes has recently been introduced into clinical practice as hepatobiliary imaging agents; the kinetics of these substances are often poorly understood. To gain better insight into characteristics of these different agents, we measured the extraction efficiency and mean biliary transit time of a variety of iminodiacetate derivatives in the in-situ rat perfused liver. First pass hepatic extraction efficiency averaged 59% for 99mTc N-(p-isopropylacetanilide) iminodiacetate, 73% for 99mTc N-(2,6-diethylacetanilide) iminodiacetate, 74% for 99mTc N-(3-bromo-2,4,6-trimethylacetanilide) iminodiacetate, 90% for 99mTc N-(p-butylacetanilide) iminodiacetate, and 93% for 99mTc N-pyridoxyl-5-methyltryptophan. By comparison, extraction of another organic anionic compound, 131I Rose bengal, was only 12.4%. Mean hepatocyte transit times varied from 2.3 to 7.5 min. Shorter mean transit times were observed for diortho substituted and longer mean transit times for para substituted metal complexes. Radioactivity was quantitatively recovered in bile, and excretion kinetics overall were consistent with data generated in whole animals. These studies demonstrate the value of the in-situ rat perfused liver as a screening tool to characterize hepatobiliary imaging agents.

Animals↗
PubMed1985

Hepatic uptake and disposition of human polymeric IgA1 in perfused rat liver: evidence for incomplete biliary excretion and intrahepatic degradation.

The hepatic uptake of polymeric immunoglobulin A (IgA) is mediated by secretory component; the resulting secretory IgA is excreted intact into bile. To define the hepatic metabolism of polymeric IgA, we quantitated the uptake and transport of human polymeric IgA1 after a single pass through the perfused rat liver. Uptake of polymeric IgA1 was compared with that of asialoorosomucoid, a glycoprotein whose uptake is mediated by the asialoglycoprotein receptor. Single-pass hepatic uptake of 125I-polymeric IgA1 and of 125I-asialoorosomucoid averaged 18.0 +/- 3.1% (SE) and 71.8 +/- 2.8%, respectively. The uptake of 125I-polymeric IgA1 was inhibited by excess unlabeled polymeric IgA1 but not by asialoorosomucoid. Only 13.0 +/- 1.6% of the 125I-polymeric IgA1 extracted by the liver was excreted into bile, whereas three-fourths was released into the hepatic venous effluent in degraded form. Thus, both the uptake and biliary excretion of polymeric IgA1 by the rat liver are inefficient processes. Polymeric IgA1 follows two distinct pathways after uptake by the liver: a small proportion is excreted intact into bile, while the majority is degraded and released back into the circulation.

Animals↗
PubMed1985

Characterization of calcium deprivation-induced cholestasis in the perfused rat liver.

To elucidate the role of calcium in regulation of canalicular bile flow, we studied biliary sucrose permeability and the transport kinetics of taurocholate in the in situ perfused rat liver. Calcium deprivation did not adversely affect viability or ultrastructural appearances of the liver. Removal of calcium led to initial choleresis followed by cholestasis dependent on external ionized calcium concentration. Biliary recovery of [14C]sucrose relative to that of tritiated water was determined by a biliary multiple-indicator dilution technique. Analysis in terms of irreversible thermodynamics suggested that biliary permeability to sucrose increased due to a change in the sieving coefficient from 0.135 to 0.435. Biliary recovery of taurocholate was significantly (P less than 0.001) reduced in low-calcium medium (from 79.6 +/- 6.5 to 17.6 +/- 11.8%). This was not due to a defect in hepatocellular uptake of taurocholate as determined in the perfused rat liver by a multiple-indicator dilution technique and in isolated hepatocytes. We conclude that calcium deprivation-induced cholestasis is characterized by an increased biliary permeability, a defect in cellular translocation and/or canalicular secretion of bile salts, and a defect in bile salt-independent bile flow.

Animals↗
PubMed1984

Influence of common bile duct cannula size on maximal secretory rate of taurocholate in the rat.

The common bile duct of male Sprague-Dawley rats was cannulated with either PE 10 or PE 50 tubing. Maximal secretory rate of taurocholate averaged 389 +/- 67 (SD) and 657 +/- 115 nmoles X min-1 X g liver-1 in the PE 10 and PE 50 group, respectively (p less than 0.005). Maximal bile secretory pressure was significantly higher in the PE 10 group (240 +/- 28 vs 174 +/- 8 mm H20; p less than 0.005). When the maximal secretory rate was exceeded, bile flow decreased in both groups but this was accompanied with a decrease in maximal bile secretory pressure in the PE 10 group only. Maximal secretory rate of bile salts is markedly influenced by experimental technique. Use of small caliber common bile duct cannulae leads to partial obstruction and decreases the apparent maximal secretory rate for taurocholate.

Animals↗
PubMed1984

Ethynylestradiol impairs bile salt uptake and Na-K pump function of rat hepatocytes.

Ethynylestradiol impairs bile flow and bile salt maximum secretory rate in rats, implying a secretory defect. In addition, Na-K-ATPase activity is decreased in liver surface membranes, suggesting abnormalities at the sinusoidal as well as the canalicular membrane. We investigated whether ethynylestradiol pretreatment affects bile salt uptake and Na-K pump function in isolated rat hepatocytes. Ethynylestradiol-treated cells were functionally intact as assayed with trypan blue exclusion, lactate dehydrogenase release, and oxygen consumption. Initial taurocholate uptake velocity was reduced by 73% in ethynylestradiol-treated hepatocytes [Vmax, 1.0 +/- 0.1 vs. 3.7 +/- 0.2 mumol X min-1 X (10(6) cells)-1; P less than 0.001; Km, 34 +/- 5 vs. 33 +/- 3 microM]. Na-K-ATPase activity in cell homogenates (36 +/- 5 vs. 27 +/- 4 mumol Pi X h-1 X mg prot-1; P less than 0.05), ouabain-suppressible rubidium-86 influx [6.8 +/- 1.1 vs. 4.8 +/- 1.0 nmol K+ X min-1 X (10(6) cells)-1; P less than 0.05], and intracellular potassium concentration (126 +/- 10 vs. 110 +/- 16 mmol/l; P less than 0.05) were reduced after ethynylestradiol. Taurocholate uptake measured at different temperatures between 25 degrees and 37 degrees was linear when plotted according to Arrhenius. The energy of activation was increased by 40% in ethynylestradiol-treated hepatocytes [17 +/- 4 vs. 23 +/- 4 kcal X mol-1 X (10(6) cells)-1; P less than 0.05], consistent with decreased membrane fluidity. These data suggest the possibility that during ethynylestradiol-induced cholestasis a disorder of the sinusoidal domain, caused perhaps by ethynylestradiol-induced alterations in membrane lipid composition, is an important contributing factor.

Animals↗
PubMed1984

Aphthous ulceration in diversion colitis. Clinical implications.

Two cases of aphthous ulceration apparently due to diversion colitis are described. There was no evidence of Crohn's disease initially or at follow-up. Aphthous ulceration of the colon and diversion colitis are reviewed, and the nonspecificity of aphthae for Crohn's disease is stressed. The presence of aphthous ulcers in a diverted colon should not preclude colostomy closure.

Adult↗
PubMed1983

Familial unconjugated hyperbilirubinemia syndromes.

Our understanding of the biochemical defects underlying the hepatic forms of congenital, unconjugated hyperbilirubinemias has been greatly enhanced over the past decade. This is mostly due to the availability of pure, labeled bilirubin, the appropriate kinetic analyses, and a better understanding of the mechanisms underlying bilirubin conjugation. Although it is quite obvious that the defect underlying Gilbert's and Crigler-Najjar syndromes is deficient glucuronidation, the molecular explanation may eventually be found in altered composition of the microsomal lipids rather than in a protein defect of glucuronyl transferase. The recognition that Gilbert's syndrome is a quite heterogeneous entity will allow a better understanding of the mode of inheritance of this disorder; its relationship to Crigler-Najjar type II disease also awaits further definition. It is hoped that definition of the molecular defect in Crigler-Najjar type I will lead to better therapeutic modalities, but this remains to be seen.

Animals↗
PubMed1983

A novel method for continuous monitoring of bilirubin production in unstressed rats.

We describe a device for continuous infusion and monitoring of exhaled 14CO as a test of hepatic bilirubin production in rats. A Silastic catheter, implanted into a jugular vein under light ether anesthesia, was protected with a spring shield and a cannula swivel. The animals were kept in a modified Bollman cage. delta-[5-14C]aminolevulinic acid, a heme precursor yielding 14CO upon breakdown of heme to bilirubin, was infused at a constant rate. Exhaled 14CO was oxidized to 14CO2 and collected in ethanolamine. The efficiency of the system averaged 97.8%. In untreated animals 14CO production reached a plateau within 12 h; thereafter, it increased by 2.8% per day. The responsiveness of the system was tested by fasting the animals, which stimulated hepatic bilirubin production. Fasting increased 14CO production by 32.8 +/- 8% (mean +/- SD, P less than 0.005) after 72 h. This was associated with an increase in hepatic heme oxygenase activity (+48%, P less than 0.05) and a decrease in microsomal cytochrome P-450 content (-45%, P less than 0.05). Thus, our approach permits continuous monitoring of hepatic bilirubin production without subjecting the animals to the stress of handling, restraint, or anesthesia. The method can easily be applied to other breath tests involving formation of 14CO2.

Aminolevulinic Acid↗
PubMed1983

Taurocholate, but not taurodehydrocholate, increases biliary permeability to sucrose.

To determine whether bile salts alter the permeability of the biliary tree to inert solutes, we investigated the effects of taurocholate and taurodehydrocholate on [14C]sucrose bile-to-plasma ratio in the situ perfused rat liver. Sucrose bile-to-plasma ratio remained virtually constant over a 3-h period in untreated rats. Infusing increasing amounts of taurocholate produced the anticipated dose-dependent increase in bile flow and bile salt secretion up to a maximal secretory rate of 278 nmol X min-1 X g liver-1. When the secretory rate was exceeded, bile flow decreased by 22%. Even at doses below the maximal secretory rate, sucrose bile-to-plasma ratio increased in a dose-dependent fashion. To determine whether this was due to recruitment of more permeable centrizonal hepatocytes, the effect of equimolar amounts of taurodehydrocholate was determined. This nonmicelle-forming bile salt led to more marked choleresis than taurocholate but did not affect sucrose bile-to-plasma ratio. We conclude that taurocholate, but not taurodehydrocholate, leads to a dose-dependent increase in biliary permeability.

Animals↗