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Biomedical subjects

A Vrána

Publications and source records attributed to A Vrána.

At least 19 recordsLinked to original sources
PubMed2001

The effect of particle size on bioavailability in cyclosporine preparations based on submicron dispersions.

The effect of particle size on bioavailability of 9 different formulations with cyclosporine A was studied. A common feature of all the formulations was the ability to form submicron dispersions under dilution. The composition of individual formulations was chosen in such a way that they were based on same or similar excipients. For each formulation, pharmacokinetic study was carried out in beagle dogs. On groups of 10 dogs, the average AUC was evaluated. Particle size of formulations under dilution in water was measured by laser scattering method. According to the results of particle size measurement, the formulations were sorted out into groups of similar particle size distribution by use of two methods of multivariate statistical analysis. The average AUC within groups and between-groups was compared, and the effect of particle size on bioavailability was evaluated.

Animals↗
PubMed1998

Thiazolidinediones--tools for the research of metabolic syndrome X.

The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma

Antioxidants↗
PubMed1995

Hereditary hypertriglyceridemic rat: a new animal model of metabolic alterations in hypertension.

Hereditary hypertriglyceridemic rats (hHTg) were developed as a new genetic model for the study of relationships between blood pressure (BP) and metabolic abnormalities. This strain has been produced by selective inbreeding from Wistar rats according to the rise of plasma triglycerides induced by a high-sucrose diet. Though hHTg rats display hypertriglyceridemia, impaired glucose tolerance, hyperinsulinemia, insulin resistance and increased BP even without nutritional stimuli, high sucrose feeding further aggravates these symptoms. High plasma triglycerides levels in hHTg rats seem to be a consequence of their hyperproduction. Impaired insulin action is responsible for the defective glucoregulation in this strain. The loss of insulin responsiveness might be due to a reduction in the number of glucose transporters. Highly significant relationships among plasma triglycerides, ouabain-resistant Na+ transport and BP were demonstrated in the hHTg rats. Segregating populations (F2 hybrids) should be used for genetic analysis of the primary role of lipid and/or ion transport abnormalities in the pathogenesis of this form of genetic hypertension.

Animals↗
PubMed1995

The effect of combination therapy with cyclosporine A and hydrocortisone on glucose metabolism in diabetic rats following pancreatic islet transplantation.

Glucose tolerance, insulin secretion and in vitro insulin action were examined in streptozotocin-induced diabetic rats following pancreatic islet allotransplantation treated with combination of oral cyclosporine A (10 mg/kg) and hydrocortisone (1.5 mg/kg) intramuscularly. 1400 pure islets from multiple donors were implanted either into the portal vein (n = 10) or under the renal capsule (n = 11). Ten sham-operated non-diabetic animals receiving the same immunosuppressive therapy, 8 healthy animals without any treatment and 10 diabetic animals without immunosuppression following islet transplantation were used as controls. In all transplanted animals blood glucose was normalized by day 3 after transplantation with lower levels in those transplanted intraportally (p < 0.05). Non-immunosuppressed animals rejected the graft after 6.5 +/- 1.2 days after transplantation, immunosuppressed animals in both groups remained normoglycaemic till the end of the experiment on day 28. Oral glucose tolerance tests and insulin levels on days 10 and 28 improved dramatically. No differences in glucose and insulin levels between intraportal and subcapsular groups were found. Post-load glucose levels in immunosuppressed non-transplanted animals were higher on day 28 than before treatment and were also higher than in the healthy non-treated group (p < 0.05). In vitro insulin action determined by the incorporation of labelled glucose into adipose tissue was impaired only in animals in which islets were transplanted into the liver (p < 0.05 vs other groups). In conclusion, therapy with cyclosporine A and hydrocortisone prevents allogeneic islet rejection in rats during a short-term experiment. Although glucose tolerance is not completely normalized following transplantation, slight impairment is also demonstrable in healthy animals on the same drug therapy.

Animals↗
PubMed1994

Erythrocyte ion transport alterations in hypertriglyceridaemic rats.

1. Hypertension appears to be associated with both abnormalities in ion transport and disturbances in lipid metabolism. The aim of the present study was to search for alterations in erythrocyte ion transport in hereditary hypertriglyceridaemic rats. This strain is characterized by a pronounced elevation of blood pressure which correlates with the plasma triacylglycerol level. 2. Erythrocyte Na+ content was elevated in hypertriglyceridaemic rats due to an increased ouabain-resistant Na+ net uptake. This was caused not only by the acceleration of bumetanide-sensitive Na+ inward co-transport, but also by the augmentation of bumetanide-resistant Na+ inward leak. A moderate enhancement of bumetanide-sensitive Rb+ uptake was seen in hypertriglyceridaemic animals, but there were no changes in bumetanide-resistant Rb+ leak. 3. The plasma triacylglycerol level correlated positively not only with blood pressure (P < 0.001) but also with ouabain-resistant Na+ transport (P < 0.002), bumetanide-sensitive Na+ and K+ (Rb+) co-transport (P < 0.01 and P < 0.001, respectively), bumetanide-resistant Na+ leak (P < 0.02) and erythrocyte Na+ content (P < 0.05). 3. Thus the association of augmented ouabain-resistant Na+ transport with elevated blood pressure in this form of experimental hypertension might be mediated by genetic disorders of lipid metabolism.

Animals↗
PubMed1993

Adrenergic overactivity and insulin resistance in nonobese hereditary hypertriglyceridemic rats.

Nonobese, hereditary hypertriglyceridemic (HTG) rats provide an interesting model of hypertriglyceridemia, glucose intolerance, and hypertension. In age-matched 15 HTG and 16 control Wistar rats fed on a high sucrose diet (70 cal%) for 6 weeks, we measured insulin sensitivity in vivo and some parameters of sympatoadrenal system. Using euglycemic clamps with administration of 2-deoxy[1-3H]glucose, we found whole body insulin resistance and decreased glucose metabolic index Rg' in soleus muscle, epitrochlearis muscle, diaphragm, and white adipose tissue in HTG rats. We found higher levels of plasma epinephrine and higher excretion of vanilmandelic and homovanilic acids in HTG rats. The binding of [3H]-dihydroalprenol to the heart membrane fraction was similar in both groups, but the dissociation constant Kd was increased by 75% in the heart of HTG rats.

Adipose Tissue↗
PubMed1993

Effect of a low salt diet on blood pressure and vasoactive hormones in the hereditary hypertriglyceridemic rat.

In hereditary HTG rats, basal systolic blood pressure using tail-cuff sphygmomanometry was significantly higher (122.1 +/- 2.1 mm Hg; n = 16) than that in NTG animals (107.1 +/- 1.52; n = 16). A low salt diet did not influence blood pressure in NTG rats during the consecutive 4 weekly periods. However, in the second week blood pressure in HTG rats rose significantly in both the control rats on a normal salt diet and those on a low salt diet (132.5 +/- 1.89, n = 8, and 132.6 +/- 1.93, n = 8). No further changes were registered in the third and fourth week in control HTG rats. On the other hand, blood pressure fell significantly in HTG rats on a low salt diet in the third week in comparison with the second week (119.5 +/- 3.2, n = 8), and it increased again in the fourth week (123.0 +/- 2.35, n = 8). Hormones in plasma were determined at the end of the experiment. Plasma levels of norepinephrine were not influenced by differences in salt intake and were significantly higher by about 45% in HTG than in NTG animals. The lowest concentration of corticosterone in plasma was found in control HTG rats (1.2 +/- 0.2 vs 4.6 +/- 0.8 micrograms/100 ml in control NTG rats). Nevertheless, corticosterone concentration increased in HTG rats on a low salt diet at comparable values found in NTG rats on a low salt diet (3.1 +/- 0.8 vs 4.3 +/- 1.5). Plasma renin activity and plasma aldosterone concentrations were not different in the NTG and HTG groups and were uninfluenced by the diets (Table 1). We conclude that the elevated blood pressure in HTG rats and its variations during the experiment may reflect more pronounced sympathetic activity in HTG rats rather than blood pressure dependency on different salt intake.

Aldosterone↗
PubMed1993

Do preoperative branched-chain amino acids have a beneficial effect on the heart after cardiac surgery?

To verify the hypothesis, formulated on the basis of data emerging from animal experiments, that branched-chain amino acids (BCAA) exert a protective effect on the heart during ischaemia, eight patients immediately before aortocoronary reconstruction were provided 400 ml of a 3% BCAA solution. A control group comprised another eight patients. Per- and postoperative myocardial status and myocardial enzyme levels were assessed. Myocardial biopsy was performed during surgery to determine glycogen levels. Creatine kinase (CK) levels were invariably higher in the BCAA group, with statistically significant differences in samples obtained immediately after surgery (10.6 +/- 3.35 mu kat/l vs. 4.07 +/- 0.59, p < 0.0004), in the evening after surgery (14.2 +/- 5.92 vs. 5.91 +/- 2.21, p < 0.06) and in the morning of the first postoperative day (18.0 +/- 10.1 vs. 7.5 +/- 4.76, p < 0.025) when aspartate aminotransferase (AST) levels were likewise higher (1.35 +/- 0.28 vs. 1.00 +/- 0.26, p < 0.035). There were no differences between the groups in the number of defibrillations after ischaemia, myocardial glycogen content, peroperative ischaemia, incidence of arrhythmia and catecholamine support. We conclude that BCAA at the above indicated doses did not raise myocardial glycogen content or improve myocardial status after cardiac surgery. Their administration resulted in a rise in CK and AST in the postoperative period.

Amino Acids, Branched-Chain↗
PubMed1992

The hypertriglyceridemic rat as a genetic model of hypertension and diabetes.

Hypertriglyceridemia was demonstrated in untreated hypertensive patients as well as in animals with genetic and experimental hypertension. The main purpose of the present study was to evaluate the possibility to use the hereditary hypertriglyceridemic (HTG) nonobese rats in hypertensive research. Direct measurement of blood pressure demonstrated significantly higher systolic, diastolic and mean arterial pressures in HTG rats in comparison with control Wistar rats. There was significant positive correlation between blood pressure and plasma triglyceride concentration (r = 0.585, n = 40, p less than 0.001). In addition, there were significantly increased plasma norepinephrine and epinephrine concentrations in HTG rats, suggesting that the stimulation of sympathetic nervous system could be one of the pathogenetic mechanisms involved in the increase of blood pressure of HTG rats.

Animals↗
PubMed1990

Effects of dietary n-3 fatty acids on the composition of cholesteryl esters and triglycerides in plasma and liver perfusate of the rat.

The effects of polyunsaturated fatty acids of the omega-3 family (PUFA n-3), (addition of fish oil), on the molecular composition of cholesteryl esters and triglycerides in plasma and liver perfusate of rats were studied. Rats fed a diet rich in saturated fatty acids (addition of lard) served as controls. Supplemention with PUFA n-3 not only decreases the plasma concentrations of free cholesterol, cholesteryl esters, and triglycerides, it also significantly alters the plasma composition of cholesteryl esters and triglycerides. Analyses of liver perfusate indicate a decrease in triglycerides secretion by in vitro perfused liver and reciprocal changes in relative contents of cholesteryl esters fractions with C(16) and C(20) acyl chains. This finding may be a result of chain-shortening of long-chain fatty acids probably in peroxisomal beta-oxidative system. Alterations in plasma cholesteryl esters and triglycerides composition of the fish oil group could be affected further by additional factors such as increased plasma cholesterol esterification activity and presence of triglyceride species of intestinal origin.

Journal Article↗