Does the Operation of Mitochondrial ATP-Dependent Potassium Channels Affect the Structural Component of Mitochondrial and Endothelial Dysfunctions in Experimental Parkinsonism?

We have previously demonstrated that the development of oxidative stress in some pathologies can be prevented by activation of the mitochondrial ATP-dependent potassium channel (mitoK). Here we studied the effect of modulation of mitoK on the development of mitochondrial and endothelial dysfunction in the medulla oblongata and myocardium of rats with experimental parkinsonism. It is known that uridine-5'-diphosphate, activator of mitoK, does not penetrate the plasma membrane, but it can be synthesized in cells from exogenous uridine that is delivered into cells by special transport systems.

Uridine as a protector against hypoxia-induced lung injury.

The effect of the activation of the mitochondrial ATP-dependent potassium channel (mitoK) on the ultrastructure of rat lung in acute hypoxic hypoxia (7% of oxygen in nitrogen, exposure 30 min) was studied. It was shown that uridine, a precursor of the mitoK activator UDP, exerted a protective effect against hypoxic damage to the lung. The administration of uridine to animals prior to hypoxia decreased the number of mitochondria with altered ultrastructure and prevented the hypoxia-induced mitochondrial swelling.

Dynamic Restructuring of the Myocardial Mitochondria in Response to Uridine Modulation of the Activity of Mitochondrial ATP-Dependent Potassium Channel under Conditions of Acute Hypoxic Hypoxia.

We studied the effects of in vivo modulation of activity of mitochondrial ATP-dependent potassium channel (mitoK) by uridine on the morphofunctional state of mitochondria in rat cardiomyocytes under conditions of acute hypoxia. Preinjection of uridine to animals reduced the number of structurally modified mitochondria, but had practically no effect on their morphogenesis after hypoxia. Uridine in vivo stimulated the formation of micromitochondria and their release into the cytoplasm.

Structural and Dynamic Changes in Mitochondria of Rat Myocardium under Acute Hypoxic Hypoxia: Role of Mitochondrial ATP-Dependent Potassium Channel.

The ultrastructure and spatial localization of mitochondria (MC) in the myocardium of rats exposed to a 30-min hypoxic hypoxia were investigated. The mitochondrial structure was found to undergo changes; however, marked necrotic injuries were not observed. Changes occurring in the myocardium are aimed at the intensification of energy processes.

Effect of potential-dependent potassium uptake on calcium accumulation in rat brain mitochondria.

The effect of potential-dependent potassium uptake at 0-120 mM K+ on matrix Ca2+ accumulation in rat brain mitochondria was studied. An increase in oxygen consumption and proton extrusion rates as well as increase in matrix pH with increase in K+ content in the medium was observed due to K+ uptake into the mitochondria. The accumulation of Ca2+ was shown to depend on K+ concentration in the medium.

Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs.

SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days.

Assessment of oral toxicity and safety of 9-cis-UAB30, a potential chemopreventive agent, in rat and dog studies.

9-cis-UAB30 is a potential chemopreventative agent that has been shown to be effective on many different types of tumors. The safety and toxicity of 9-cis-UAB30 had not been previously established. These studies were conducted to evaluate the potential toxicity and pharmacokinetics in a rodent and a nonrodent species for the purpose of investigational new drug submission.

Influence of ATP-dependent K(+)-channel opener on K(+)-cycle and oxygen consumption in rat liver mitochondria.

The influence of the K+(ATP)-channel opener diazoxide on the K+ cycle and oxygen consumption has been studied in rat liver mitochondria. It was found that diazoxide activates the K+(ATP)-channel in the range of nanomolar concentrations (50-300 nM, K(1/2) ~ 140 nM), which results in activation of K+/H+ exchange in mitochondria. The latter, in turn, accelerates mitochondrial respiration in respiratory state 2.

Assessment of oral toxicity and safety of pentamethylchromanol (PMCol), a potential chemopreventative agent, in rats and dogs.

2,2,5,7,8-Pentamethyl-6-chromanol (PMCol) was administered by gavage in rats for 28 days at dose levels of 0, 100, 500, and 2000mg/kg/day. PMCol administration induced decreases in body weight gains and food consumption, hepatotoxicity (increased TBILI, ALB, ALT, TP; increased relative liver weights; increased T4 and TSH), nephrotoxicity (increased BUN and BUN/CREAT, histopathology lesions), effect on lipid metabolism (increased CHOL), anemia, increase in WBC counts (total and differential), coagulation (FBGN upward arrow and PT downward arrow) and hyperkeratosis of the nonglandular stomach in the 2000mg/kg/day dose group (in one or both sexes). In the 500mg/kg/day dose group, toxicity was seen to a lesser extent.

Effect of moderate hypoxia/reoxygenation on mitochondrial adaptation to acute severe hypoxia.

In an experimental model, it was shown that repetitive periods of hypoxia/reoxygenation (H/R) [5 cycles of 5 min hypoxia (12% O(2) in N(2) ) followed by 15 min normoxia, daily for three weeks] attenuated basal and stimulated in vitro lipid peroxidation, as well as H(2)O(2) production in liver and brain mitochondria of rats exposed to acute severe hypoxia. Adaptation to moderate H/R enhanced in mitochondria the production and activity of reactive oxygen species scavengers, such as glutathione, manganese superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase. It was demonstrated that the maintenance of GSH-redox cycle by activation of glutathione reductase and NADP(+) -dependent isocitrate dehydrogenase is an integral part of the biochemical adaptive mechanism of oxidative tolerance to new damaging factor.

Calcium uptake in rat liver mitochondria accompanied by activation of ATP-dependent potassium channel.

The influence of potassium ions on calcium uptake in rat liver mitochondria is studied. It is shown that an increase in K+ and Ca2+ concentrations in the incubation medium leads to a decrease in calcium uptake in mitochondria together with a simultaneous increase in potassium uptake due to the potential-dependent transport of K+ in the mitochondrial matrix. Both effects are more pronounced in the presence of an ATP-dependent K+-channel (K+(ATP)-channel) opener, diazoxide (Dz).

Computer modeling of relationship between critical PvO2, VO2max and blood supply of skeletal muscle at working with a right-shifted blood O2 dissociation curve.

Investigations were performed on a computer model of O2 delivery and O2 consumption in the one working muscle. At working with increasing power and achieving the critical value of VO2 (VO2crit), the muscle VO2 began to lag behind the oxygen demand qO2. The model permits to find critical pO2 in effluent venous blood Pvcrit at VO2crit as well as to calculate VO2max and PvO2 at VO2max under exercise with changing muscle blood flow F and blood pH.

Oxygen transport to skeletal muscle working at VO(2)max in acute hypoxia: theoretical predictions.

The influence of acute hypoxia (30 < or = PaO(2) < or = 100 mmHg) on the values of VO(2)max and parameters of oxygen transport in muscle working at VO(2)max was studied. We investigated muscle working under different values of blood flow F (60 < or = F < or = 120 ml/min per 100 g), blood pH (7.0-7.

Complex analysis of efficiency of transplantation of embryonic nerve tissue to rats with hemiparkinsonism.

Effect of transplantation of embryonic ventral mesencephalon preparation containing dopaminergic neurons on repair of the dopaminergic nigrostriatal system was studied in rats with hemiparkinsonism induced by 6-hydroxydopamine. Transplantation of embryonic ventral mesencephalon into denervated striatum led to a more than 50% decrease in apomorphine-induced rotation, recovery of dopamine and DOPAC levels in the brain, and to an increase in DOPAC excretion and the DOPAC-dopamine ratio in daily urine of rats with hemiparkinsonism. Dopaminergic neurons of the transplant survived, forming a network of tyrosine hydroxylase-positive processes growing beyond the transplant and reinnervating the adjacent compartments of the striatum.

Mechanisms of taurine antihypoxic and antioxidant action.

The study was undertaken to elucidate the effects of taurine on lipid peroxidation (LP) intensity and membrane Na+, K+-ATPase activity in a hypoxic rat model. It was shown that 3 intraperitoneal (i.p.

Catecholamines and their metabolites in the brain and urine of rats with experimental Parkinson's disease.

The content of catecholamines and their metabolites in the brain and the relationship between cerebral catecholamine levels and their urinary excretion were studied in rats with 6-OHDA-induced hemiparkinsonism. 6-OHDA reduced brain concentrations of dopamine, DOPAC, and homovanilic acid and urinary excretion of dopamine, dioxyphenilalanine, and DOPAC by more than 90%. A positive correlation was found between the concentrations of these metabolites in the urine and striatum.

Hypoxic ventilatory responses and gas exchange in patients with Parkinson's disease.

Ventilatory responses to isocapnic, progressive hypoxic rebreathing (HVR), in supine and sitting positions, lung ventilation and gas exchange while breathing air and during 5 min of breathing 11% O2 in N2 were studied in 12 healthy young (20-28 years), 5 old (57-73 years) male subjects, and in 7 male patients with Parkinson's disease (PD) aged 55-67 years. The piecewise linear approximation technique was used for evaluation of the ventilatory response curves, which allowed a separate analysis of slopes during minor and severe hypoxia. It has been shown that body position affected HVR.

[Myoglobin content and distribution in muscle tissues of Black Sea dolphins].

Myoglobin content is found to be higher in skeletal than in cardiac muscle of Tursiops truncatus and Phocaena phocaena and much higher than that in skeletal muscles of terrestrial mammals. According to the myoglobin content muscle fibres are devided into five types: red, white and three intermediate types. Deep muscles contain more red fibres and less intermediate fibres than superficial ones.