ubiquinone and oxophenylarsine

This research work is devoted to study of the sensitivity of mitochondrial permeability transition pore (MPTP) opening to its inductors--ions Ca2+ (10(-4) mol/l) and oxidant phenylarsine oxide (10(-4) mol/l) and content of ubiquinone (coenzyme Q, CoQ) and vitamin E in heart mitochondria of adult, old (control) and old rats under administration of precursors an modulator of CoQ biosynthesis--4-hydroxybenzoic acid, methionine and modulator of CoQ biosynthesis, namely vitamin E. The results of our research demonstrate that administration of complex of biologically active substances, which are precursors and modulators of CoQ biosynthesis, leads to decrease in the sensitivity of MPTP opening to its inductors and increase of CoQ and vitamin E content in old rats heart mitochondria. Therefore the results obtained lead to a conclusion that increase of CoQ content due to administration of precursors and modulator of its biosynthesis is an effective way in the inhibition of MPTP opening. This approach as well as application of CoQ-containing medicals may be used for correction of mitochondrial dysfunction under various pathologies of cardiovascular system and in aging.

Topics: Aging; Animals; Arsenicals; Calcium; Male; Methionine; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Mitochondrial Swelling; Myocardium; Parabens; Rats; Rats, Wistar; Ubiquinone; Vitamin E

Protective properties of coenzyme Q10 (CoQ10) on the: (i) Langendorff isolated guinea pig heart's function under ischemia and reperfusion (I/R) and on the isolated mitochondria (ii) the mitochondrial permeability transition pore (MPTP) opening under exposure to calcium as natural MPTP inductor and phenylarsine oxide as oxidant--were studied. Physiological characteristic of contractile function, myocardial oxygen consumption and mitochondrial factor release as index of MPTP opening were compared before and after ischemia of isolated heart in control animals and animals with preliminary administration of CoQ10 per os. It have been shown that I/R disturbances of heart function were decreased and oxygen metabolism was normalised in animals treated with CoQ10 in compare to non-treated control. It was accompanied with substantial stabilization of mitochondrial membrane. Decreased I/R disturbances of isolated heart from CoQ10-treated animals were correlated to amount of mitochondrial factor released to coronary flow. Moreover, preliminary incubation of mitochondria, isolated from rat heart, with CoQ10 (10(-5) mol/l) substantially prevented calcium and phenylarsine-induced, cyclosporine A-sensitive mitochondrial swelling. This protective effect was increased in experiments with deenergizing mitochondria. Results of physiological and biochemical study reveal that one of the mechanisms of CoQ10's cardioprotective effect could be direct inhibition of mitochondrial permeability transition pore opening during ischemia and reperfusion of the heart.

Topics: Animals; Arsenicals; Cardiotonic Agents; Coenzymes; Guinea Pigs; In Vitro Techniques; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Contraction; Myocardial Reperfusion Injury; Oxygen Consumption; Ubiquinone

Coated-platelets are a subset of cells observed during costimulation of platelets with collagen and thrombin. Important characteristics of coated-platelets include retention of multiple alpha-granule proteins and expression of phosphatidylserine on the cell surface. The mitochondrial permeability transition pore (MPTP) is a key step in apoptosis and is suggested to be involved in some forms of platelet activation. The objective of this study was to examine the role of MPTP in the synthesis of coated-platelets.. Flow cytometric analysis of coated-platelet production was used to examine the impact of pharmacological effectors of MPTP formation. Cyclosporin A, coenzyme Q, and bongkrekic acid all inhibit MPTP formation as well as production of coated-platelets. Phenylarsine oxide and diamide, both potentiators of MPTP formation, stimulate coated-platelet synthesis. Atractyloside, another inducer of MPTP formation, does not affect the percentage of coated-platelets synthesized; however, it does increase the level of phosphatidylserine exposed on the surface of coated-platelets.. These findings indicate that MPTP formation is an integral event in the synthesis of coated-platelets. Although the exact function of the MPTP remains to be determined, these data support a growing body of evidence that apoptosis-associated events are vital components of the platelet activation process. Formation of coated-platelets involves a complex set of activation events initiated by dual agonist activation. The mitochondrial permeability transition pore (MPTP) is a key intermediate in apoptosis and has been suggested to impact platelet activation. This report demonstrates that MPTP formation is essential to production of coated-platelets.

Topics: Adult; Apoptosis; Arsenicals; Atractyloside; Benzimidazoles; Blood Platelets; Bongkrekic Acid; Carbocyanines; Collagen; Crotalid Venoms; Cyclosporine; Cytoplasmic Granules; Diamide; Drug Synergism; Flow Cytometry; Fluorescent Dyes; Humans; Ion Channels; Lectins, C-Type; Membrane Lipids; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Phosphatidylserines; Platelet Activation; Thrombin; Thromboplastin; Ubiquinone

We have investigated the regulation of the mitochondrial permeability transition pore (PTP) by ubiquinone analogues. We found that the Ca2+-dependent PTP opening was inhibited by ubiquinone 0 and decylubiquinone, whereas all other tested quinones (ubiquinone 5, 1,4-benzoquinone, 2-methoxy-1,4-benzoquinone, 2,3-dimethoxy-1, 4-benzoquinone, and 2,3-dimethoxy-5,6-dimethyl-1,4-benzoquinone) were ineffective. Pore inhibition was observed irrespective of the method used to induce the permeability transition (addition of Pi or atractylate, membrane depolarization, or dithiol cross-linking). Inhibition of PTP opening by decylubiquinone was comparable with that exerted by cyclosporin A, whereas ubiquinone 0 was more potent. Ubiquinone 5, which did not inhibit the PTP per se, specifically counteracted the inhibitory effect of ubiquinone 0 or decylubiquinone but not that of cyclosporin A. These findings define a ubiquinone-binding site directly involved in PTP regulation and indicate that different quinone structural features are required for binding and for stabilizing the pore in the closed conformation. At variance from all other quinones tested, decylubiquinone did not inhibit respiration. Our results define a new structural class of pore inhibitors and may open new perspectives for the pharmacological modulation of the PTP in vivo.

Topics: Animals; Arsenicals; Atractyloside; Binding Sites; Calcium; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Cyclosporine; Intracellular Membranes; Ion Channels; Mitochondria, Liver; Molecular Structure; Permeability; Porins; Quinones; Rats; Ubiquinone