The treatment of hypercholesterolemia with bile acid (BA)
sequestrants results in upregulation of BA synthesis through the
classical pathway initiated by cholesterol 7α-hydroxylase (CYP7A1). To characterize the detailed dynamics of serum lipid and BA concentrations and the BA synthesis rate in response to treatment with BA sequestrants and to determine whether the -203A/C promoter polymorphism of the CYP7A1 encoding gene (CYP7A1) affects such a response, this pilot study was carried out in healthy men (8
h omozygous for the -203A allele and 8 homozygous for the -203C allele of CYP7A1). The subjects were treated for 28 days with colesevelam
and blood was drawn for analysis before and on days 1, 3, 7, 14 and 28 of treatment. The response of lipids, BA, fibroblast growth factor-19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) to colesevelam did not differ between carriers of -203A and -203C alleles; their data were then aggregated for further analysis. Colesevelam treatment caused immediate suppression of FGF19 concentration and a fivefold increase in CYP7A1 activity, as assessed from C4 concentration, followed by a 17% decrease in LDL-cholesterol. Although total plasma BA concentrations were not affected, the ratio of cholic acid/total BA rose from 0.25±0.10 to 0.44±0.16 during treatment at the expense of decreases in chenodeoxycholic and deoxycholic acid.
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=ll). 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, lmmunosuppressed 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.
Methylphenidate hydrochloride (MPH/Ritalin) is a stimulant used for off-label management of cancer-related fatigue and sedation; however, its use in pain treatment is still relatively rare. This study 1) compares the antinociceptive effect of MPH and its combination with morphine (MOR) in adult male Wistar rats after a single administration of MPH, MOR or their combination, and 2) compares the analgesic effects of opioids and Ritalin co
mbined therapy with opioid monotherapy in patients with cancer pain. To
objectively assess physical activity during a three-week monitoring period, patients were equipped with Actiwatch Score Actigraph. Patients performed daily evaluations of pain intensity and frequency, and the extent to which pain interfered with their daily life. Our research with rats supports the evidence that MPH in lower doses has the ability to enhance the analgesic properties of morphine when the two drugs are used in combination. Results from the patient arm of our study found that short
-term treatment had no significant effect on intensity or frequency of
pain, however it decreased the overall burden of pain; the combined treatment of opioid and Ritalin also showed anti-sedation effects and resulted in mild improvement in one of our patient’s quality of life.
Factors modulating cardiac susceptibility to ischemia-reperfusion (I/R) are permannetly attracting the attention of experimental cardiology research. We investigated, whether continuous 24 h/day light exposure of rats can modify cardiac response to I/R, NO-synthase (NOS) activity and the level of oxidative load represented by conjugated dienes (CD) concentration. Two groups of male adult Wistar rats were studied: controls exposed to normal light/dark cycle (12 h/day light, 12 h/day dark) and rats exposed to continuous light for 4 weeks. Perfused isolated hearts (Langendorff technique) were exposed to 25 min global ischemia and subsequent 30 min reperfusion. The recovery of functional parameters (coronary flow, left ventricular developed pressure, contractility and relaxation index) during reperfusion as well as the incidence, severity and duration of arrhythmias during first 10 min of reperfusion were determined. The hearts from rats exposed to continuous light showed more rapid recovery of functional parameters but higher incidence, duration and severity of reperfusion arrhythmias compared to controls. In the left ventricle, the NOS activity was attenuated, but the CD concentration was not significantly changed. We conclude that the exposure of rats to continuous light modified cardiac response to I/R. This effect could be at least partially mediated by attenuated NO production., R. Važan, P. Janega, S. Hojná, J. Zicha, F. Šimko, O. Pecháňová, J. Styk, L'. Paulis., and Obsahuje bibliografii
Heartbeat reversal patterns have been monitored in the body of diapausing pupae of M. sexta 2 h before and 3 h after the injections of [Arg7]-corazonin, using noninvasive thermographic and optocardiographic methods. Large dosages (10-6 M final concentrations of corazonin in the body) caused almost immediate, adrenaline-like enhancement of the anterograde heartbeat. During the relatively short, acute phase of the tachycardia induced by corazonin, the systolic anterograde contractions of the heart increased in average from 10.5 to 24 pulses per min, culminating at 2.5 min after the injections. Duration of the acute period of tachycardia was only 7 to 20 min, which was followed by a period of slightly elevated, residual anterograde heartbeat which persisted occasionally for 1 to 3 h. Smaller dosages of corazonin (10-7M concentrations in the body) occasionally also produced a less intensive cardiotropic effect, while the more diluted samples were completely inactive. In pupae of the beetle T. molitor, injections of corazonin (10-6 M in the body) had no effect on the rate of in vivo heartbeat at all. Pharmacological analysis of the effects of corazonin in M. sexta indicated that the cardiostimulating effects of corazonin did not conform with the expected action of a peptidic neurohormone. A possibility that these effects might be artifacts produced by the low molecular breakdown products of corazonin has been discussed.
The proportion of proliferating erythroblasts, i.e. proerythroblasts, basophilic erythroblasts and polychromatophilic erythroblasts in blood islands of the chick embryo yolk sac, were counted during embryonic days 2-10. From day 2 when high amounts of erythroblasts signalized the onset of embryonic erythropoiesis, the percentage of less mature erythroid cells gradually decreased. Intraamniotic injection of cyclosporin A in doses 1.5 or 15.0 /rg per embryo on day 5 led to significant changes in the proportion of proliferating erythroblasts in the yolk sac blood islands. We speculate that these changes were caused initially by the release of the more mature cells into the circulation and later by a dose-dependent decrease in the number of stem cells. The estimation of proerythroblast percentage from all proliferating erythroblasts in the yolk sac blood islands may serve as a valuable indication of toxic damage in the late avian embryo.
The aim of our work was to compare the effect of D-galactosamine (GalN) on primary cultures of lean and steatotic rat hepatocytes isolated from intact and fatty liver, respectively. GalN caused more severe injury to steatotic hepatocytes than to lean cells as documented by lactate dehydrogenase leakage. Necrotic mode of cell death strongly prevails over apoptosis since we did not observe any significant increase in activities of caspase 3, 8 and 9 in any group of hepatocytes treated with GalN. Reactive oxygen species (ROS) formation and lipid peroxidation were elevated in a dose-dependent manner by GalN and were significantly more pronounced in fatty hepatocytes. A decrease in the percentage of hepatocytes with energized mitochondria was observed from 30 mM and 10 mM GalN in lean and steatotic hepatocytes, respectively. Our results undoubtedly indicate that steatotic hepatocytes exert higher sensitivity to the toxic effect of GalN. This sensitivity may be caused by more intensive GalN-induced ROS production and lipid peroxidation and by higher susceptibility of mitochondria to loss of mitochondrial membrane potential in steatotic hepatocytes. In our experimental arrangement, apoptosis does not seem to participate considerably on hepatotoxic action of GalN in either group of hepatocytes., O. Kučera, H. Lotková, O. Sobotka Z. Červinková., and Obsahuje bibliografii
Cardiac repolarization is prolonged in diabetes mellitus (DM), however the distribution of repolarization durations in diabetic hearts is unknown. We estimated the ventricular repolarization pattern and its relation to the ECG phenomena in diabetic mice. Potential mapping was performed on the anterior ventricular surface in healthy (n=18) and alloxan-induced diabetic (n=12) mice with the 64-electrode array. Activation times, end of repolarization times, and activation-recovery intervals (ARIs) were recorded along with limb lead ECGs. ARIs were shorter in the left as compared to right ventricular leads (P<0.05). The global dispersion of repolarization, interventricular and apicobasal repolarization gradients were greater in DM than in healthy animals (P<0.03). The increased dispersion of repolarization and apicobasal repolarization gradient in DM correlated with the prolonged QTc and Tpeak-Tend intervals, respectively. The increased ventricular repolarization heterogeneity corresponded to the electrocardiographic markers was demonstrated in DM., M. A. Vaykshnorayte, A. O. Ovechkin, J. E. Azarov., and Obsahuje seznam literatury
The effect of 3 months feeding with diets of different protein and sucrose content (9 % casein -f 70 % sucrose vs. 18 % casein + 61 % sucrose) on the development of diabetic nephropathy and changes in serum lipid spectrum was investigated in rats with insulin-dependent diabetes (streptozotocin 45 mg.kg-1). Metabolism of diabetic animals (before the nutritional regimen) was characterized by hyperglycaemia, moderate hyperlipidaemia, lipid accumulation in the liver and elevated creatinine concentration in the blood. Kidney weight and protein content were not significantly changed. Histological picture of kidneys showed initial changes of glomerular structure. After three months hyperlipoproteinaemia was more accentuated in animals given either of the two diets, the kidneys were hypertrophic with a higher protein content and displayed morphological changes of diabetic nephropathy. Animals given the low-protein diet developed smaller morphological changes both in glomeruli and tubuli. The study indicates that dietary protein and not hyperlipoproteinaemia is the major factor, which may significantly influence the progress of diabetic nephropathy.
The imbalance between nitric oxide (NO) and reactive oxygen species (ROS) production appears to be a common feature of experimental and human hypertension. Previously, different antioxidants and/or scavengers of oxygen free radicals were shown to activate nitric oxide synthase (NO synthase, NOS) and to increase the expression of both endothelial and neuronal NO synthase isoforms leading to blood pressure reduction. On the other hand, various antihypertensive drugs have been documented to possess antioxidant properties, which may contribute to their beneficial effect on blood pressure. This review is focused on the effects of antioxidant treatment in different models of
experimental hypertension with a special attention to the prevention of oxidative damage and the augmentation of NO synthase activity and expression of NOS isoforms.