The diabetogenic effect of prolactin observed in patients with pathological hyperprolactinaemia was verified in healthy subjects. Plasma prolactin elevation was induced by administration of a dopamine antagonist drug domperidone (Motilium 10 mg orally, 9 subjects) and 2 h later the oral glucose tolerance test was performed. The influence of dopamine receptor stimulation on glucose homeostasis was tested by dopamine infusion (0.3 mg in saline or 20 % glucose, 1 g/min for 60 min, 11 subjects). After the blockade of dopamine receptors, a significant and prolonged increase of prolactin concentration was found. However, the levels of glucose, insulin, and C- peptide either before or after the glucose load were not different from control ones. The decreased number of insulin receptors (1.97±0.41 vs 0.51 ±0.14 pmol per 2.109 red blood cells) was compensated by increased affinity (0.51 ±0.17 vs 1.00±0.22 K* 108 mol.-1 per 1]) of insulin receptors. The stimulation of dopamine receptors showed a negligible effect on glucose regulation. It may be suggested that an endogenous increase of prolactin concentration in the physiological range does not participate in the regulation of glucose homeostasis in healthy subjects.
One explanation of the mechanism of hypoxic pulmonary vasoconstriction (HPV) suggests that hypoxia shifts the redox status of the pulmonary artery smooth muscle cell towards a more reduced state, through changes in the redox couples and the activated oxygen species generation. The outward K+ current is then reduced and the membrane depolarized, leading to Ca++ influx through the voltage dependent Ca++ channels and vasoconstriction. The response of both pulmonary and systemic vessels to hypoxia may depend on the expression of different K+ channels in the two sites. While the oxygen sensor in pulmonary artery smooth muscle cells may be the delayed rectifier K+ channel, in the systemic arteries, hyperpolarization of the smooth muscle cell membrane, leading to vasodilatation, probably represents the effect of hypoxia in opening ATP-sensitive and Ca++-dependent K+ channels. The similarities between oxygen sensing mechanisms in several oxygen sensing cells (pulmonary artery smooth muscle cell, carotid body type 1 cell, neuroepithelial body) are striking. It is very likely that the mechanisms by which hypoxia is sensed at the molecular level are highly conserved and tightly regulated.
Hypoxic vasoconstriction (HPV) has been shown to consist of a biphasic contraction change. The first phase of the hypoxic response peaks at approximately five minutes. The second phase is at about 30 minutes. The force of contraction of both phases of HPV were found to be significantly greater in pulmonary resistance vessels (PRV) than in pulmonary artery (PA) (P<0.01). The endothelium modulates the hypoxic response, especially of the second phase of HPV (68 % reduction in PRV) (P<0.05). In Ca2+-free solution, the first peak and the second peak of HPV were reduced to 11 and 32 % contraction in PRV and to 26 and 21 % contraction in PA. A calcium channel antagonist (amlodipine) caused significant dose-dependent inhibition of the first phase of HPV (P=0.001), with a significantly greater effect on PRV compared to PA (P<0.01). Levcromakalim caused a dose- dependent inhibition of HPV in PRV (58 % at 10 /utA). In contrast, HPV in PA was not significantly inhibited by levcromakalim. In conclusion, this study has confirmed that hypoxia induces a biphasic contractile response in isolated pulmonary arteries requiring extracellular calcium. Both amlodipine and levcromakalim inhibit hypoxic pulmonary vasoconstriction and these agents may be of value in the treatment of pulmonary hypertension.
Acute liver failure (ALF) is a clinical condition with very high mortality rate. Its pathophysiological background is still poorly understood, which necessitates a search for optimal experimental ALF models with features resembling those of the human disorder. Taking into consideration reproducibility of induction of ALF, adequate animal size, cost of animals, the required time gap between insult and death of animals (“therapeutic window”), potential risk to investigator and other aspects, administration of thioacetamide (TAA) in rats is currently most recommended. However, the fundamental details of this ALF model have not yet been evaluated. This prompted us to investigate, first, the course of ALF as induced by intraperitoneal TAA at doses increasing from 175 to 700 mg/kg BW per day. The animals’ survival rate, plasma alanine and aspartate aminotransferase activities, and bilirubin and ammonia levels were determined over the follow-up period. Second, we examined whether Wistar and Lewis rats exhibit any differences in the course of ALF induced by different TAA doses. We found that the optimal dose for ALF induction in rats is 350 mg.kg-1 i.p., given as a single injection. Wistar rats proved more susceptible to the development of TAA-induced ALF compared with Lewis rats. Collectively, our present findings provide a sound methodological background for experimental studies aimed at evaluation of pathophysiology and development of new approaches in the therapy of ALF., E. Koblihová, I. Mrázová, Z. Vernerová, M. Ryska., and Obsahuje bibliografii
„Proteinase-activated“ receptor-2 (PAR-2) is a G protein-coupled transmembrane receptor with seven transmembrane domains activated by trypsin. It has been shown in the pancreatic tissue that PAR-2 is involved in duct/acinary cells secretion, arterial tonus regulation and capillary liquid content turnover under physiological conditions. These above mentioned structures play an important role during the development of acute pancreatitis and are profoundly influenced by a high concentration of trypsin enzyme after its secretion into the interstitial tissue from the basolateral aspect of acinar cells. Among the other factors, it is the increase of interstitial trypsin concentration followed rapidly by PAR-2 action on pancreatic vascular smooth muscle cells that initiates ischemic changes in pancreatic parenchyma and that finally leads to necrosis of the pancreas. Consequent reperfusion perpetuates changes leading to the acute pancreatitis development. On the contrary, PAR-2 action on both exocrine and duct structures seems to play locally a protective role during acute pancreatitis development. Moreover, PAR-2 action is not confined to the pancreas but it contributes to the systemic vascular endothelium and immune cell activation that triggers the systemic inflammatory response syndrome (SIRS) contributing to an early high mortality rate in severe disease.
Pneumonia was induced in rats by instillation of carrageenin (0.5 ml of 0.7 % solution) into the trachea. Three or four days after instillation, the lungs were isolated, perfused with blood of healthy rat blood donors, and ventilated with air + 5 % C02 or with various hypoxic gas mixtures. Pulmonary vascular reactivity to acute hypoxic challenges was significantly lower in lungs of rats with pneumonia than in lungs of controls. The relationship between 02 concentration in the inspired gas and Po2 in the blood effluent from the preparation was shifted significantly to lower Po2 in lungs with pneumonia compared to control ones. These changes were not present in rats allowed to recover for 2- 3 weeks after carrageenin instillation. We suppose that blunted hypoxic pulmonary vasoconstriction may contribute to hypoxaemia during acute pulmonary inflammation. Decreased Po2 in the blood effluent from the isolated lungs with pneumonia implies significant increase of oxygen consumption by the cells involved in the inflammatory process.
Toxicities expressed as LD50 values of 2-dialkylaminoalkyl-(dialkylamido)-fluorophosphates for rats and mice (i.m. administration) were determined. Rats were more sensitive to these compounds than mice: LD50 values varied from 17 (rats) to 1222 (mice) ^g/kg. LD50 values at different routes of administration (i.v., i.m., s.c., p.o. and p.c.) for one derivative of this group, 2-dimethylaminoethyl-(dimethyIamido)- fluorophosphate, were determined. Depending on the route of administration, LD50 values varied from 11 (i.v.) to 190 (p.o.) pg/V.g for rats and from 27.6 (i.v.) to 222 (p o.)/rg/kg for mice, respectively. Percutaneous toxicity in rats only (LD50 = 1366//g/kg) was determined.
Huntingtonova choroba (HD) je autozomálně dominantní neurodegenerativní onemocnění způsobené zvýšením počtu polyglutaminových repetic (> 35 repetic) v genu pro protein huntingtin. HD je charakteristická pomalými progresivními změnami pohybového aparátu a osobnosti, kdy tyto změny jsou často doprovázeny ztrátou tělesné hmotnosti. Do dnešního dne není znám přesný mechanizmus patofyziologie choroby. Poruchy pohybových funkcí reflektují masivní poškození specifických částí mozku (striatum), které bylo popsáno u pacientů s HD. V roce 2013 Sbodio et al [1] popsali zvýšené množství proteinu Acyl‑CoA binding domain containing 3 (ACBD3) ve striatu HD pacientů. Protein ACBD3 hraje nezastupitelnou roli v mnoha buněčných procesech, a to především díky interakci s různými vazebnými partnery. ACBD3 je esenciální při neuronálním dělení, neurodegeneraci, udržení lipidové homeostáze, stresové odpovědi, virové replikaci, apoptóze, udržení struktury golgiho komplexu. V této práci jsme prokázali nepřítomnost proteinu ACBD3 v mitochondriích v lidských kožních fibroblastech a navíc jsme potvrdili, že změny celkové hladiny proteinu ACBD3 ve fibroblastech HD pacientů nejsou konzistentní., Huntington’s disease (HD) is an autosomal‑dominant neurodegenerative disease caused by the expansion of polyglutamine repeats (> 35 repeats) in the nuclear gene for the huntingtin protein. HD is characterized by slow progressive changes in motor behaviour and personality that are sometimes accompanied by weight loss. To date, the exact mechanisms of HD pathophysiology have not been defined. Impaired motor behaviour reflecting massive and selective destruction of the striatum has been observed in patients with HD. Sbodio et al. [1] reported in 2013 that Acyl‑CoA binding domain containing 3 (ACBD3) protein levels were elevated in the striatum of HD patients and connected with higher neurotoxicity in HD. The ACBD3 protein plays essential roles in many different cellular functions via interactions with a multitude of partners. ACBD3 is involved in neuronal stem cell self‑renewal, neurodegeneration, lipid homeostasis, stress resistance, intracellular vesicle trafficking, organelle maintenance, viral replication and the apoptotic response. Herein, we found that ACBD3 in not present in the mitochondria in skin fibroblasts. Moreover, our findings also revealed that the total cellular level of ACBD3 is not consistent among the fibroblasts of HD patients., and H. Kratochvíľová, M. Rodinova, J. Sladkova, J. Klempir, I. Liskova, J. Motlik, J. Zeman, H. Hansíková, M. Tesarova