Tropaphen in experimental drug therapy of cor pulmonale]

The influence of alpha-adrenoblocking drug tropaphen on cardio- and haemodynamics under experimental lung-heart failure was studied in dogs. The findings suggest effectiveness of tropaphen administration in such pathology shown by a decrease of lung hypertension and heart overload, significant increase of the contractile activity and relaxation properties of myocardium of both ventricles and in cardiac pump function optimization.     

Induction of lipid flip-flop by colicin E1 — a hallmark of proteolipidic pore formation in liposome membranes

The addition of the channel-forming domain of colicin E1 to liposomes elicited the transmembrane diffusion (flip-flop) of lipids concomitant to the release of the fluorescent dye from liposomes. Good correlation was found between kinetic and concentration dependences of the two processes. Both the liposome leakage and the lipid flip-flop were stimulated upon alkalinization of the buffer solution after colicin binding at acidic pH. These results in combination with the analysis of the data on colicin binding to liposomes provide evidence in favor of the validity of the toroidal (proteolipidic) pore model as the mechanism of colicin channel formation.     

Prevention of cardiolipin oxidation and fatty acid cycling as two antioxidant mechanisms of cationic derivatives of plastoquinone (SkQs)

The present state of the art in studies on the mechanisms of antioxidant activities of mitochondria-targeted cationic plastoquinone derivatives (SkQs) is reviewed. Our experiments showed that these compounds can operate as antioxidants in two quite different ways, i.e. (i) by preventing peroxidation of cardiolipin [Antonenko et al., Biochemistry (Moscow) 73 (2008) 1273–1287] and (ii) by fatty acid cycling resulting in mild uncoupling that inhibits the formation of reactive oxygen species (ROS) in mitochondrial State 4 [Severin et al. Proc. Natl. Acad. Sci. USA 107 (2009), 663–668]. The quinol and cationic moieties of SkQ are involved in cases (i) and (ii), respectively. In case (i) SkQH₂ interrupts propagation of chain reactions involved in peroxidation of unsaturated fatty acid residues in cardiolipin, the formed SkQ^? being reduced back to SkQH₂ by heme b_H of complex III in an antimycin-sensitive way. Molecular dynamics simulation showed that there are two stable conformations of SkQ1 with the quinol residue localized near peroxyl radicals at C₉ or C₁₃ of the linoleate residue in cardiolipin. In mechanism (ii), fatty acid cycling mediated by the cationic SkQ moiety is involved. It consists of (a) transmembrane movement of the fatty acid anion/SkQ cation pair and (b) back flows of free SkQ cation and protonated fatty acid. The cycling results in a protonophorous effect that was demonstrated in planar phospholipid membranes and liposomes. In mitochondria, the cycling gives rise to mild uncoupling, thereby decreasing membrane potential and ROS generation coupled to reverse electron transport in the respiratory chain. In yeast cells, dodecyltriphenylphosphonium (С₁₂TPP), the cationic part of SkQ1, induces uncoupling that is mitochondria-targeted since С₁₂TPP is specifically accumulated in mitochondria and increases the H⁺ conductance of their inner membrane. The conductance of the outer cell membrane is not affected by С₁₂TPP.     

A new model of weak acid permeation through membranes revisited: does Overton still rule?

According to a recent publication by Thomae, A. V., H. Wunderli-Allenspach, and S. D. Kr?mer (2005. Biophys. J. 89:1802-1811), membrane bilayers are well-permeable to the charged species of aromatic carboxylic acids. At physiological pH, the anions were claimed to be the major diffusing species. In contrast, calculation of the Born energy barrier predicts a 10(5)-fold higher permeability for the uncharged (protonated) form. To test the new model, we now have measured both the current carried by the salicylate anion through solvent-free planar membranes and the amount of protons transported by the neutral species. The corresponding membrane permeabilities of the charged and protonated forms were 4 x 10(-7) cm/s and 1.2 cm/s. These data are in perfect agreement with literature data gathered in the last three decades (compare, e.g., Gutknecht, J., and D. C. Tosteson. 1973. Science. 182:1258-1261). They indicate that the report by Thomae at al. represents an experimental artifact. The well-documented role of neutral species in the permeation process of weak acids and bases across artificial and natural membranes is not in question. Overton still rules.     

Lipid dependence of the channel properties of a colicin E1-lipid toroidal pore

Colicin E1 belongs to a group of bacteriocins whose cytotoxicity toward Escherichia coli is exerted through formation of ion channels that depolarize the cytoplasmic membrane. The lipid dependence of colicin single-channel conductance demonstrated intimate involvement of lipid in the structure of this channel. The colicin formed "small" conductance 60-picosiemens (pS) channels, with properties similar to those previously characterized, in 1,2-dieicosenoyl-sn-glycero-3-phosphocholine (C20) or thinner membranes, whereas it formed a novel "large" conductance 600-pS state in thicker 1,2-dierucoyl-sn-glycero-3-phosphocholine (C22) bilayers. Both channel states were anion-selective and voltage-gated and displayed a requirement for acidic pH. Lipids having negative spontaneous curvature inhibited the formation of both channels but increased the ratio of open 600 pS to 60 pS conductance states. Different diameters of small and large channels, 12 and 16 A, were determined from the dependence of single-channel conductance on the size of nonelectrolyte solute probes. Colicin-induced lipid "flip-flop" and the decrease in anion selectivity of the channel in the presence of negatively charged lipids implied a significant contribution of lipid to the structure of the channel, most readily described as toroidal organization of lipid and protein to form the channel pore.     

Cyclic nucleotides and lipids in the realization of the radioprotective effect of ceruloplasmin

Ceruloplasmin administered 60 min before irradiation diminished cAMP and cGMP levels, which were increased by irradiation at LD50 and LD100, and normalized cAMP/cGMP ratio in the rat liver during the first 24 h following irradiation with a dose of 6.24 Gy. The content of phospholipids increased and that of cholesterol decreased under the effect of ceruloplasmin leading to normalization of the molar cholesterol/phospholipid ratio in the rat liver on the 7th day of radiation sickness (LD50, 6.24 Gy).     

Effect of phloretin on the carrier-mediated electrically silent ion fluxes through the bilayer lipid membrane: measurements of pH shifts near the membrane by pH microelectrode.

The effect of phloretin on the carrier-mediated electrically silent ion fluxes through the bilayer lipid membrane (BLM) was studied. The measurements were carried out according to our conventional technique, i.e. electrical potential recording in the presence of a protonophore, and by a new method--direct measurements of pH shifts in the unstirred layers of the BLM by pH microelectrode. Both techniques gave similar results. It was shown that the addition of phloretin increased the rate of cation/H+ exchange induced by nigericin and decreased the rate of anion/OH(-)-exchange induced by tributyltin. The effect of phloretin was higher in the presence of cholesterol in the BLM. Cholesterol decreased the nigericin- and tributyltin-induced fluxes under our experimental conditions. The application of an external voltage to the membrane had no effect on the ion fluxes thereby showing that these fluxes were electroneutral. The most probable explanation of these results bases on the effect of the membrane dipole potential on the electroneutral fluxes of ions. The possible mechanism of the dipole potential effect on the carrier-mediated electrically silent ion fluxes was discussed in terms of two competing hypotheses--the translocation through the membrane or the reactions at the membrane surface being the rate-limiting steps of the whole transport process.     

Phospholipids bound with plasma proteins in children with vitamin D-deficient rickets

Composition of phospholipids bound with plasma proteins in the healthy children and in those with vitamin-D-deficient rickets are studied. It is found that the quantitative and qualitative content of phospholipids in the low- and high-density lipoproteins increases considerably with the rickets. At the same time the content of phospholipids which form complexes wit fibrinogen gets two times lower. The character of changes in the phospholipid composition in protein fractions and in the whole plasma in case of rickets is different.     

Clinico-roentgenologic manifestations of intestinal lesions in pseudotuberculosis

The authors presented the results of clinical and x-ray investigation of 102 patients with epidemic pseudotuberculosis (EP). The diagnosis was established on the basis of epidemiological evidence and the results of clinical and serological investigation. The affection of the digestive organs was observed not only in the abdominal type of EP but also in its other types. X-ray examination of the digestive organs revealed terminal ileitis in 56.8% of the patients alongside with functional disorders. X-ray examination plays a certain role in the differential diagnosis of EP from other diseases of the ileocecal region, in particular from acute appendicitis.