Cyclosporine A, beside its current applications, possesses potential hepatoprotective effects. This study was directed to investigate the effect of Cyclosporine A pretreatment on hepatic injury due to carbon tetrachloride (CCl4) and D-galactosamine. Rats were injected by two successive doses of Cyclosporine A (5 mg kg-1 day-1). Six hours after the second dose, 1 ml kg-1 of CCl4 was administered i.p. Effects associated with Cyclosporine A pretreatment were examined by using isolated hepatocytes and hepatocytes that were immobilized and continuously perfused. D-Galactosamine (5 mM) was added directly to the perfusion medium. After isolation, hepatocytes were examined histologically by light and electron microscopy, immobilized and perfused for further metabolic functional activity evaluation. Cyclosporine A pretreatment in vivo produced hepatoameliorative effects of various degrees which were statistically significant as manifested by: (1) an increased trypan blue exclusion after CCl4; (2) an improved ureagenesis after CCl4; (3) a reduction in the lipid droplets accumulation in the cytoplasm produced by CCl4 administration; (4) well preserved cytoplasmic organelles as mitochondria, endoplasmic reticulum ER, nuclear chromatin structures that were altered by CCl4; and (5) an increased hepatocytes survival in the agarose gel matrix, reduction of LD leakage and improvement of ureagenesis after D-galactosamine addition to the perfusion medium. The beneficial effect of Cyclosporine A pretreatment in modifying hepatotoxicity of chemical insults merits further studies.

Animals↗

PubMedDate not supplied

Heart glycogen content and isoprenaline-induced myocardial lesions.

The role of glycogen content in the heart for the development of isoprenaline-induced myocardial lesions (IML) was studied in Wistar rats and in two inbred rat strains: In IR rats (resistant to the development of IML) and in IS rats (sensitive to IML development). Glycogen content in the heart can be dramatically lowered or increased by various interventions. IML develop during the period of very low heart glycogen content (about 0.6 mg.g-1) induced by isoprenaline administration. In animals with increased resistance to IML, either due to genetic factors or induced by isoprenaline pretreatment a high glycogen content in the heart is found (up to 7.5 mg.g-1). The increase of resistance to IML development and increased glycogen content induced by isoprenaline pretreatment were accompanied by lower basal or ISO-, guanylylimidodiphosphate- (Gpp/NH/p) and forskolin-stimulated activities of adenylyl cyclase. On the other hand, these parameters did not differ between IR and IS rats in spite of the presence of significant differences in the resistance to the development of IML and in heart glycogen content in these two rats strains. These results suggest that genetically determined differences between two inbred rat strains in the resistance of the heart to the development of IML and in the heart glycogen content are caused by factors which are independent of the receptor-adenylyl cyclase complex and are therefore different from those involved in the increase of resistance and glycogen content due to isoprenaline pretreatment.

Adenylyl Cyclases↗

PubMedDate not supplied

Differences in response to activation of adenylyl cyclase by various stimulants in human myocardium.

The response of adenylyl cyclase complex in human atrial tissue removed at corrective surgery of normoxemic and hypoxemic congenital heart defects in children to various stimulants was evaluated and related to the oxygenation state of the myocardium. When comparing response to stimulation in normoxemic and hypoxemic atria a higher basal as well as stimulated adenylyl cyclase activity was found in hypoxemic atria; an insignificant stimulatory effect of isoprenaline in normoxemic hearts became significant in the atria of hypoxemic patients. Hypoxemic samples also showed two times higher activity when the total catalytic activity was evaluated by the stimulation with forskolin. Higher stimulatory effect of Gpp/NH/p was also observed in hypoxemic than in normoxemic state. Increased adenylyl cyclase activity might represent one of adaptive mechanisms to hypoxemia in patients with congenital heart defects.

Adenylyl Cyclases↗

PubMedDate not supplied

The role of myocardial glycogen content for the development of isoprenaline-induced myocardial lesions in different inbred strains of rats.

Two inbred rat strains, differing in their resistance to the induction of myocardial lesions by the administration of isoprenaline (ISO), have been developed. The extent of ISO-induced myocardial lesions (IML) was three to five times lower in the ISO-resistant (IR) strain as compared to that in the ISO-sensitive (IS) strain. The two strains differ also in a number of other genetically determined features, e.g., a higher myocardial glycogen content (MGC) and higher adipose tissue weight in IR rats. Between IML extent and MGC a significant negative correlation has been demonstrated in 2nd filial generation of IR and IS hybrids. By contrast, no correlation has been found between the resistance to the development of IML and the other genetically determined features studied. High resistance to the development of IML and a high MGC were also noted in another inbred strain, the hypertriacylglycerolemic (HTG) rats. Comparison of IML extent in HTG, IR and IS rats has revealed that the extent of IML, while depending on MGC, is independent of triacylglycerolemia. MGC can be raised in IR and IS rats by various interventions (e.g., repeated administration of ISD or fasting). Regardless of the intervention used, it entails a simultaneous increase in resistance to the development of IML. In vivo administration of glucose and insulin, however, exerts only a minimal effect on MGC and on the extent of IML. It may be concluded, therefore, that under our experimental conditions the enhanced resistance to the development of IML, whether genetically determined (IR, HTG rats) or induced by some interventions (fasting, repeated ISO administration), is closely related to an increased MGC.

Adrenergic beta-Agonists↗

PubMedDate not supplied

Possible dual role of nitric oxide in oxidative stress injury: a study in perfused hepatocytes.

Nitric oxide (NO) is a multifunctional messenger in many vertebrates. In the liver, NO was found to play an important but controversial role in injury produced by toxins or sepsis. The purpose of the present investigation was to further characterize the role of NO in hepatocyte oxidative injury. A cellular system formed of immobilized and perfused rat hepatocytes was used to test the ability of the latter to produce endogenous NO after lipopolysaccharide administration in vivo (LPS, 20 mg/kg i.p.) and how hepatocyte functionality competence is modified according to NO level. This cellular system also was used to delineate a relationship between exogenously delivered NO to the perfusion medium as produced by the NO donor, sodium nitroprusside (2.0 and 0.2 mM), and any alteration in the degree of injury as evoked by anoxia/reoxygenation or cumene hydroperoxide (1.0 mM and 0.2 mM). Rat hepatocytes were immobilized in low-gelling agarose and perfused with Williams E medium. Endogenous or exogenous NO was evaluated by measuring the end products of NO (NO2- + NO3-) in the perfusion medium. Functional integrity of hepatocytes was evaluated from lactate dehydrogenase (LD) leakage, urea synthesis in the perfusion medium and lipid peroxides (LP) formation. Normal, anoxia/reoxygenation or cumene hydroperoxide injured hepatocytes did not exhibit measurable NO while LPS-treated hepatocytes produced NO. Apparently, within the present experimental conditions, it seems that there was an inverse relation between the rate of NO produced after LPS administration and the rate of lipid peroxides formed in the hepatocytes. Low concentration of sodium nitroprusside (as NO donor) significantly decreased LD leakage, increased the rate of urea synthesis and increased trypan blue exclusion by hepatocytes in anoxia/reoxygenation or cumene hydroperoxide injured (0.2 mM) cells. Lipid peroxides were decreased by NO in cumene hydroperoxide injured hepatocytes. The present data suggest that NO endogenously produced, or exogenously delivered, has an ameliorative role in mild oxidative liver injury models, but not in severe cases and that inside hepatocytes, there is a very delicate balance between the rate of NO production and its consumption. The disturbance in this balance may be responsible for injury due to the formation of more toxic oxygen species.

Animals↗