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S Ji

Publications and source records attributed to S Ji.

At least 19 recordsLinked to original sources
PubMed1991

Effects of charged amphiphiles on cardiac cell contractility are mediated via effects on Ca2+ current.

Exposure of isolated adult rabbit myocytes to the negatively charged amphiphile dodecylsulfate (DDS; 10 microM) increased the contraction amplitude to 185% of control. The positively charged amphiphile dodecyltrimethylammonium (DDTMA; 10 microM) decreased the amplitude to 58%. DDS increased Ca2+ uptake by the same cells, but this uptake was partially prevented by nifedipine. DDTMA had no effect on Ca2+ uptake. Ca2+ binding to isolated sarcolemma of neonatal heart cells was increased by 10 microM DDS and, at higher concentrations, reduced by DDTMA. Single-cell voltage-clamp studies, using isolated rabbit myocytes, showed that DDS enhanced L-type Ca2+ currents (ICa,L), whereas DDTMA depressed ICa,L. DDS shifted current-voltage (I-V) and isochronal inactivation curves of ICa,L in the negative direction, whereas DDTMA shifted them in positive direction. Furthermore, DDS depressed T-type Ca2+ currents (ICa,T), and DDTMA enhanced ICa,T. The inotropic effects of the amphiphiles are therefore mediated to a significant degree by ICa,L. The shifts in the I-V and inactivation curves of ICa,L and the effect on ICa,T can be explained by changes in the actual membrane potential (Em), induced by the insertion of the amphiphiles in the outer monolayer of the sarcolemma. However, the changes in the Em do not explain the effect on the maximal current, indicating effects on the channel per se, possibly by an alteration of the lipid environment.

Action Potentials↗
PubMed1989

Contractile shortening response of ventricular cells to extracellular acidosis. Evidence for two-site control of H+-Ca2+ interaction.

The effect of extracellular acidosis on contraction of single isolated ventricular cells from rabbit was measured in a system in which pHo could be changed in less than 200 msec. The contractile response to acidotic levels was complete within 25 seconds. The response was measured 30 seconds after pHo was decreased to 7.0, 6.5, 6.0, and 5.5 at each of 8 [Ca]o levels (0.125-4.0 mM). Cell shortening versus [Ca]o was plotted to construct a curve for each pHo level, with each point relative to shortening at pH 7.5, [Ca]o = 1 mM (100% value). Calcium current (1 mM [Ca]o) was also measured 30 seconds after pHo was decreased from 7.5 to 6.5 with single-cell patch clamp technique. The contractile response to extracellular acidosis is accurately predicted by assuming two (probably sarcolemmal) sites at which H+ ions affect calcium binding and/or flux: (equation; see text) The first factor represents a set of sites that are proposed to control access, dependent on the degree of their ionization, to sites represented by the second factor. The latter sites are proposed to accept calcium according to mass-action law. The response of calcium channel current to extracellular acidosis was also complete and reversible within 25 seconds. The current response indicates that the two-site model could be predictive for the effect of extracellular acidosis on calcium current in ventricular cells.

Acidosis↗
PubMed1989

Effects of exogenous free radicals on electromechanical function and metabolism in isolated rabbit and guinea pig ventricle. Implications for ischemia and reperfusion injury.

Oxygen-derived free radicals have been implicated in the pathogenesis of cardiac dysfunction during ischemia, postischemic myocardial "stunning," and reperfusion injury. We investigated the effects of oxygen-derived free radicals on cardiac function in intact isolated rabbit hearts and single guinea pig ventricular myocytes. In the intact rabbit ventricle, exposure to free radical-generating systems caused increased cellular K+ efflux, shortening of the action potential duration, changes in tension, and depletion of high energy phosphates similar to ischemia and metabolic inhibition. In patch-clamped single ventricular myocytes, free radical-generating systems activated ATP-sensitive K+ channels, decreased the calcium current, and caused cell shortening by irreversibly inhibiting glycolytic and oxidative metabolism. The results suggest that free radicals generated during ischemia and reperfusion may contribute to electrophysiologic abnormalities and contractile dysfunction by inhibiting glycolysis and oxidative phosphorylation. Inhibition of metabolism by free radicals may be an important factor limiting functional recovery from an ischemic insult after reestablishment of effective blood flow.

Adenosine Triphosphate↗
PubMed1987

A general theory of chemical cytotoxicity based on a molecular model of the living cell, the Bhopalator.

To define the molecular processes underlying toxicological manifestations experimentally measured on the cellular level, it is essential to have available a molecular model of the living cell itself. The Bhopalator is a molecular model of the living cell formulated by integrating the three major branches of biology within a coherent theoretical framework - the Watson-Crick molecular genetics, the conformon theory of enzymic catalysis, and the theory of dissipative structures developed by I. Prigogine. According to this model, the living cell is a self-moving, self-thinking and self-reproducing machine (automaton) that receives information and energy from its environment, processes them according to the genetic programs stored in DNA, and generates output signals to environment in order to realize teleonomically designed functions. The Bhopalator suggests a set of general statements useful in toxicological research, and these statements have been utilized to provide possible answers to several fundamental questions raised by recent experimental findings on chemically-induced cell injury and death.

Animals↗
PubMed1986

Potential role of activated macrophages in acetaminophen hepatotoxicity. II. Mechanism of macrophage accumulation and activation.

Treatment of rats with acetaminophen (1.2 g/kg) results in the accumulation of activated macrophages in the centrilobular regions of the liver. To study the mechanism by which these cells accumulate and become activated, we examined the release of chemotactic and activating factors from cultured hepatocytes treated with acetaminophen (10-100 microM). We found a dose- and time-related generation of Kupffer cell and monocyte chemotactic activity by acetaminophen-treated hepatocytes. The maximum response was observed with a 25% dilution of medium collected 24 hr following treatment of hepatocytes with acetaminophen. Using a checkerboard assay, the factor in conditioned medium was determined to induce chemotaxis as well as chemokinesis in both Kupffer cells and monocytes. The hepatocyte-derived chemotactic factor was also found to be stable to freeze-thawing but to lose activity following heat or trypsin treatment. These results, together with our findings that chemotactic activity was eluted in the void volume following Sephadex G-25 size exclusion chromatography, suggested that the chemotactic factor released by hepatocytes is a large molecular weight protein. The release of Kupffer cell activating factors by acetaminophen-treated hepatocytes was also examined. Hepatocyte-conditioned medium was found to stimulate Kupffer cell phagocytosis and superoxide anion release, two characteristics of activated macrophages. These effects were maximal with conditioned medium collected from hepatocytes 24 hr following treatment with 50-100 microM acetaminophen. Acetaminophen alone had no effect on chemotaxis, phagocytosis, or superoxide anion production by Kupffer cells or monocytes. Taken together, these results suggest that macrophage accumulation and activation in the liver following acetaminophen treatment may be mediated, at least in part, by factors released from hepatocytes.

Acetaminophen↗
PubMed1986

Inhibition of para-nitrophenol extraction by stimulation of the hepatic nerves in the perfused rat liver.

The influence of perivascular stimulation of the hepatic nerves on the extraction of para-nitrophenol (pNP) was studied in rat liver perfused in situ without recirculation. Electrical stimulation of the hepatic nerve plexus, which leads to a predominant activation of the sympathetic nerves, caused a decrease in pNP extraction, an increase in glucose output and a reduction in perfusion flow. Sodium nitroprusside (NPN) an inhibitor of vascular smooth muscle contraction, prevented the hemodynamic alterations without affecting the metabolic changes. These results suggest that sympathetic liver nerves regulate conjugation of pNP directly rather than indirectly via hemodynamic alterations.

Animals↗
PubMed1985

The bhopalator: a molecular model of the living cell based on the concepts of conformons and dissipative structures.

A molecular model of the living cell has been formulated based on a new theory of enzymic catalysis which takes into account the complementary roles of free energy and genetic information. The elementary units of free energy and genetic information that are necessary and sufficient for effectuating molecular mechanisms responsible for the life of the cell are called conformons. Conformons are visualized as a collection of a small number of catalytic residues of enzymes or segments of nucleic acids that are arranged in space and time with appropriate force vectors so as to cause chemical transformations or physical changes of a substrate or a bound ligand. So defined, conformons provide a plausible molecular means to link the genetic information stored in DNA and its ultimate expression, namely networks of coupled intracellular biochemical reactions and physical processes maintained by a continuous dissipation of free energy--dissipative structures of Prigogine. The proposed model of the living cell appears to possess the potential for bridging the gap between molecular biology and the biology of multicellular systems.

Binding Sites↗
PubMed1985

Control of oxygen uptake, microcirculation and glucose release by circulating noradrenaline in perfused rat liver.

The effect of noradrenaline on oxygen uptake, on periportal and perivenous oxygen tension at surface acini, on microcirculation and on glucose output were studied in isolated rat livers perfused at constant flow with Krebs-Henseleit-hydrogen carbonate buffer containing 5mM glucose and 2mM lactate. Noradrenaline at 1 microM concentration caused a decrease in oxygen uptake, while at 0.1 microM it led to an increase. Both high and low doses of noradrenaline decreased the tissue surface oxygen tension in periportal and - after a transient rise - in perivenous areas. Noradrenaline at an overall constant flow caused an increase of portal pressure and an alteration of the intrahepatic distribution of the perfusate: at the surface of the liver and in cross sections infused trypan blue led to only a slightly heterogeneous staining after a low dose of noradrenaline but to a clearly heterogeneous staining after a high dose. Both high and low doses of noradrenaline stimulated glucose release. All effects could be inhibited by the alpha-blocking agent phentolamine. In conclusion, control of hepatic oxygen consumption by circulating noradrenaline is a complex result of opposing hemodynamic and metabolic components: the microcirculatory changes inhibit oxygen uptake; they dominate after high catecholamine doses. The metabolic effects include a stimulation of oxygen utilization; they prevail at low catecholamine levels. The noradrenergic control of glucose release is also very complex, involving direct, metabolic and indirect, hemodynamic components.

Animals↗
PubMed1984

Regulation of oxygen consumption and microcirculation by alpha-sympathetic nerves in isolated perfused rat liver.

In isolated rat liver perfused at constant flow with erythrocyte-free Krebs-Henseleit bicarbonate buffer containing 5 mM glucose and 2 mM lactate, perivascular stimulation of the hepatic nerves caused a rapid decrease of oxygen uptake, a decrease of the periportal and, after a transient rise, of the perivenous tissue po2 of surface acini, an increase of portal pressure, and an enhancement of glucose output. Furthermore, nerve stimulation changed the intrahepatic distribution of the perfusate drastically. Infusion of trypan blue 20 s after nerve stimulation resulted in a heterogeneous staining of the liver both at the surface and in cross-sections, while it led to a homogeneous distribution in non-stimulated controls. It is concluded that the major component in the mechanism of the nerve-dependent decrease of oxygen uptake is the microcirculatory change rather than a metabolic effect.

Animals↗
PubMed1984

Is hypoxia involved in the mechanism of alcohol-induced liver injury?

Since alcoholism is a major health problem, mechanisms responsible for various forms of alcoholic liver disease (e.g., fatty liver, alcoholic hepatitis, and cirrhosis) require elucidation. Knowledge of these mechanisms is needed to provide a sound framework to treat alcoholic liver disease, to prevent its occurrence and to identify those most susceptible to it. Israel and co-workers proposed that ethanol-induced necrosis results from hypoxia to centrilobular hepatocytes as a consequence of an alcohol-induced increase in hepatic oxygen utilization (Y. Israel, H. Kalant , H. Orrego , J. M. Khanna , L. Videla , and J. M. Phillips, 1975, Proc. Natl. Acad. Sci. USA, 72(3), 1137-1141). We have employed several new techniques to evaluate this hypothesis. Procedures have been developed to make measurements of hepatic metabolism within the hepatic lobule in the isolated, perfused liver using miniature light guides and oxygen electrodes. By comparing these lobular measurements to global metabolism and to hepatic morphology determined by light and electron microscopy, a coherent, quantitative description of lobular oxygen metabolism is emerging. With these techniques, the lobular oxygen gradient was measured directly in isolated, perfused rat livers. This gradient was elevated in livers from ethanol-treated rats, an effect which was blocked by the antithyroid drug, propylthiouracil. Restriction of oxygen delivery to the isolated liver produced stable, circumscribed zones of virtual anoxia localized around the central vein. Anoxic stress led within minutes to centrilobular injury with complete sparing of periportal areas. Cellular injury was characterized by the formation of membranous blebs on the surface of centrilobular hepatocytes. When hypoxic tissue was reoxygenated , blebs were released into the circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Alcohol-induced liver injury. The role of oxygen.

Alcoholism is a major health problem, and one of its primary manifestations is alcoholic liver disease. The mechanisms responsible for the various forms of alcoholic liver disease--fatty liver, alcoholic hepatitis, and cirrhosis--are at present poorly understood. Knowledge of these mechanisms is needed to provide a sound framework for the therapy and prevention of liver disease due to alcohol and for the identification of those individuals most susceptible to develop liver disease from alcohol abuse. These experiments were designed specifically to evaluate the postulate that ethanol-induced pericentral liver damage results from an accentuated gradient of decreasing oxygen tension leading to pericentral hypoxia. Microlight guides were used to detect NADH fluorescence, and miniature oxygen electrodes were employed to measure oxygen tensions from periportal and pericentral regions of the liver lobule from the perfused rat liver. With both techniques, ethanol treatment increased the hepatic oxygen gradient. This increase was blocked by the antithyroid drug propylthiouracil. Thus, these experiments provide evidence in support of the hypothesis that pericentral hypoxia is involved in the mechanism of ethanol-induced liver injury. Furthermore, low-flow hypoxia was shown to cause blebs in the pericentral region of the liver lobule in as little as 15 min. This surface blebbing could represent the mechanism for the well-known release of enzymes by impaired hepatic tissues.

Acetaldehyde↗
PubMed1983

Stimulation of mixed-function oxidation of 7-ethoxycoumarin in periportal and pericentral regions of the perfused rat liver by xylitol.

Rates of O-deethylation of 7-ethoxycoumarin by perfused livers from fasted, phenobarbital-treated rats were 3.7 mumol X g-1 X h-1. Approximately 50% of the product was conjugated. When rates of 7-ethoxycoumarin O-deethylation were varied by infusing different concentrations of substrate, a good correlation (r = 0.91) was found between rates of O-deethylation of 7-ethoxycoumarin and fluorescence of 7-hydroxycoumarin detected from the liver surface. Micro-light guides (tip diameter 170 microns) placed on periportal and pericentral regions on the liver surface were used to monitor the conversion of nonfluorescent 7-ethoxycoumarin to fluorescent 7-hydroxycoumarin. The O-deethylation of 7-ethoxycoumarin to 7-hydroxycoumarin increased fluorescence 64% and 28% in pericentral and periportal regions of the liver lobule, respectively. Rates of 7-ethoxycoumarin O-deethylation estimated from these increases in fluorescence were 5.2 mumol X g-1 X h-1 in pericentral and 2.2 mumol X g-1 X h-1 in periportal regions of the liver. During mixed-function oxidation of 7-ethoxycoumarin, the oxidation:reduction state of NADP(H) was similar in both regions of the liver lobule. Xylitol (2 mM) decreased the NADP+/NADPH ratio and stimulated rates of drug metabolism in both regions of the liver lobule. This indicates that conditions exist where the supply of NADPH is an important rate-determining factor for 7-ethoxycoumarin metabolism in both periportal and pericentral regions of the liver lobule.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1983

Metabolic heterogeneity in the perfused rat liver.

New methods have been developed to monitor metabolic events non-invasively within periportal and pericentral regions of perfused rat livers. These techniques utilize two-fiber micro-light guides and miniature oxygen electrodes positioned on identified lobular regions of the perfused liver based on differential pigmentation of periportal and pericentral areas. Two-fiber micro-light guides detect the fluorescence of native and introduced fluors and are used to monitor redox changes of endogenous pyridine nucleotides and the generation of fluorescent products (e.g., 7-hydroxycoumarin) from exogenous substrates. Changes in fluorescence detected with two-fiber micro-light guides are correlated with changes measured with large, multi-fiber light guides and with whole organ rates of metabolism. Subsequently, local rates are estimated. With these techniques, we show that (a) rates of ethanol and acetaldehyde metabolism are similar in periportal and pericentral regions of the liver lobule; (b) mixed-function oxidation predominantes in pericentral regions in livers from phenobarbital-treated rats; (c) rates of sulfation of 7-hydroxycoumarin are greater in periportal than in pericentral hepatocytes; and (d) oxygen uptake is approximately 3-fold greater in periportal than in pericentral areas of the liver lobule.

Acetaldehyde↗
PubMed1983

Selective increase in pericentral oxygen gradient in perfused rat liver following ethanol treatment.

The oxygen gradient across the liver lobule was measured in isolated, hemoglobin-free perfused livers from control and ethanol-treated rats using micro-light guides and miniature oxygen electrodes. Both techniques yielded similar values for the lobular, periportal and pericentral oxygen gradients. Oxygen uptake increased 33% in livers from rats treated with ethanol for 4 to 6 weeks. In addition, the pericentral oxygen gradient increased by 100%, but the periportal gradient was unchanged. These observations suggest that chronic ethanol treatment may increase the rate of cellular respiration in pericentral regions of the liver lobule selectively. One possible explanation for a region-specific effect of ethanol may be ethanol-induced inhibition of glycolysis which predominates in pericentral hepatocytes.

Alcoholism↗
PubMed1983

Hypoxic hepatocellular injury.

Low flow hypoxia to the isolated, perfused rat liver produced stable, circumscribed zones of virtual anoxia which were confined to centrilobular regions of the liver lobule. As a result, centrilobular hepatocytes were injured while periportal tissue was spared. In hypoxic areas, blebs of hepatocyte plasma membrane cytoplasm protruded into sinusoids through fenestrations of the endothelium, evidently as a result of disruption of the cytoskeleton. Upon resumption of normal flow rates (reoxygenation), blebs disappeared and hepatocytes decreased markedly in volume. Concomitantly, sinusoids widened, endothelial fenestrations dilated, and lactate dehydrogenase activity appeared in the effluent. Filtration of perfusates following resumption of flow yielded cytoplasmic fragments, and it was concluded that blebs were released into the circulation. This shedding of cytoplasmic fragments may represent the cellular basis for the appearance of hepatic enzymes in the sera of patients with liver disease.

Animals↗