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  • 1
    Online Resource
    Online Resource
    Mitochondrial Ca 2+ -induced K + influx increases respiration and enhances ROS production while maintaining membrane potential
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Cell Physiology Vol. 292, No. 1 ( 2007-01), p. C148-C156
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 292, No. 1 ( 2007-01), p. C148-C156
    Abstract: We recently demonstrated a role for altered mitochondrial bioenergetics and reactive oxygen species (ROS) production in mitochondrial Ca 2+ -sensitive K + (mtK Ca ) channel opening-induced preconditioning in isolated hearts. However, the underlying mitochondrial mechanism by which mtK Ca channel opening causes ROS production to trigger preconditioning is unknown. We hypothesized that submaximal mitochondrial K + influx causes ROS production as a result of enhanced electron flow at a fully charged membrane potential (ΔΨ m ). To test this hypothesis, we measured effects of NS-1619, a putative mtK Ca channel opener, and valinomycin, a K + ionophore, on mitochondrial respiration, ΔΨ m , and ROS generation in guinea pig heart mitochondria. NS-1619 (30 μM) increased state 2 and 4 respiration by 5.2 ± 0.9 and 7.3 ± 0.9 nmol O 2 ·min −1 ·mg protein −1 , respectively, with the NADH-linked substrate pyruvate and by 7.5 ± 1.4 and 11.6 ± 2.9 nmol O 2 ·min −1 ·mg protein −1 , respectively, with the FADH 2 -linked substrate succinate (+ rotenone); these effects were abolished by the mtK Ca channel blocker paxilline. ΔΨ m was not decreased by 10–30 μM NS-1619 with either substrate, but H 2 O 2 release was increased by 44.8% (65.9 ± 2.7% by 30 μM NS-1619 vs. 21.1 ± 3.8% for time controls) with succinate + rotenone. In contrast, NS-1619 did not increase H 2 O 2 release with pyruvate. Similar results were found for lower concentrations of valinomycin. The increase in ROS production in succinate + rotenone-supported mitochondria resulted from a fully maintained ΔΨ m , despite increased respiration, a condition that is capable of allowing increased electron leak. We propose that mild matrix K + influx during states 2 and 4 increases mitochondrial respiration while maintaining ΔΨ m ; this allows singlet electron uptake by O 2 and ROS generation.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00215.2006
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
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    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Cardiac mitochondrial preconditioning by Big Ca 2+ -sensitive K + channel opening requires superoxide radical generation
    American Physiological Society ; 2006
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 290, No. 1 ( 2006-01), p. H434-H440
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 290, No. 1 ( 2006-01), p. H434-H440
    Abstract: ATP-sensitive K + channel opening in inner mitochondrial membranes protects hearts from ischemia-reperfusion (I/R) injury. Opening of the Big conductance Ca 2+ -sensitive K + channel (BK Ca ) is now also known to elicit cardiac preconditioning. We investigated the role of the pharmacological opening of the BK Ca channel on inducing mitochondrial preconditioning during I/R and the role of O 2 -derived free radicals in modulating protection by putative mitochondrial (m)BK Ca channel opening. Left ventricular (LV) pressure (LVP) was measured with a balloon and transducer in guinea pig hearts isolated and perfused at constant pressure. NADH, reactive oxygen species (ROS), principally superoxide (O 2 − ·), and m[Ca 2+ ] were measured spectrophotofluorometrically at the LV free wall using autofluorescence and fluorescent dyes dihydroethidium and indo 1, respectively. BK Ca channel opener 1-(2′-hydroxy-5′-trifluoromethylphenyl)-5-trifluoromethyl-2(3H)benzimid-axolone (NS; NS-1619) was given for 15 min, ending 25 min before 30 min of global I/R. Either Mn(III)tetrakis(4-benzoic acid)porphyrin (TB; MnTBAP), a synthetic dismutator of O 2 − ·, or an antagonist of the BK Ca channel paxilline (PX) was given alone or for 5 min before, during, and 5 min after NS. NS pretreatment resulted in a 2.5-fold increase in developed LVP and a 2.5-fold decrease in infarct size. This was accompanied by less O 2 − · generation, decreased m[Ca 2+ ], and more normalized NADH during early ischemia and throughout reperfusion. Both TB and PX antagonized each preconditioning effect. This indicates that 1) NS induces a mitochondrial-preconditioned state, evident during early ischemia, presumably on mBK Ca channels; 2) NS effects are blocked by BK Ca antagonist PX; and 3) NS-induced preconditioning is dependent on the production of ROS. Thus NS may induce mitochondrial ROS release to initiate preconditioning.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00763.2005
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2006
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    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Differential Increase of Mitochondrial Matrix Volume by Sevoflurane in Isolated Cardiac Mitochondria
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Anesthesia & Analgesia Vol. 106, No. 4 ( 2008-04), p. 1049-1055
    Details
    In: Anesthesia & Analgesia, Ovid Technologies (Wolters Kluwer Health), Vol. 106, No. 4 ( 2008-04), p. 1049-1055
    Type of Medium: Online Resource
    ISSN: 0003-2999
    URL: Article
    DOI: 10.1213/ane.0b013e318167875e
    RVK:
    XA 22250
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
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  • 4
    Online Resource
    Online Resource
    Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca 2+ -sensitive K + channels
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 293, No. 3 ( 2007-09), p. H1400-H1407
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 293, No. 3 ( 2007-09), p. H1400-H1407
    Abstract: Mitochondria generate reactive oxygen species (ROS) dependent on substrate conditions, O 2 concentration, redox state, and activity of the mitochondrial complexes. It is well known that the FADH 2 -linked substrate succinate induces reverse electron flow to complex I of the electron transport chain and that this process generates superoxide (O 2 •− ); these effects are blocked by the complex I blocker rotenone. We demonstrated recently that succinate + rotenone-dependent H 2 O 2 production in isolated mitochondria increased mildly on activation of the putative big mitochondrial Ca 2+ -sensitive K + channel (mtBK Ca ) by low concentrations of 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2 H-benzimidazol-2-one (NS-1619). In the present study we examined effects of NS-1619 on mitochondrial O 2 consumption, membrane potential (ΔΨ m ), H 2 O 2 release rates, and redox state in isolated guinea pig heart mitochondria respiring on succinate but without rotenone. NS-1619 (30 μM) increased state 2 and state 4 respiration by 26 ± 4% and 14 ± 4%, respectively; this increase was abolished by the BK Ca channel blocker paxilline (5 μM). Paxilline alone had no effect on respiration. NS-1619 did not alter ΔΨ m or redox state but decreased H 2 O 2 production by 73% vs. control; this effect was incompletely inhibited by paxilline. We conclude that under substrate conditions that allow reverse electron flow, matrix K + influx through mtBK Ca channels reduces mitochondrial H 2 O 2 production by accelerating forward electron flow. Our prior study showed that NS-1619 induced an increase in H 2 O 2 production with blocked reverse electron flow. The present results suggest that NS-1619-induced matrix K + influx increases forward electron flow despite the high reverse electron flow, and emphasize the importance of substrate conditions on interpretation of effects on mitochondrial bioenergetics.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00198.2007
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
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    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca 2+ overload, and changes in redox state
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Cell Physiology Vol. 292, No. 6 ( 2007-06), p. C2021-C2031
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 292, No. 6 ( 2007-06), p. C2021-C2031
    Abstract: We have shown that cold perfusion of hearts generates reactive oxygen and nitrogen species (ROS/RNS). In this study, we determined 1) whether ROS scavenging only during cold perfusion before global ischemia improves mitochondrial and myocardial function, and 2) which ROS leads to compromised cardiac function during ischemia and reperfusion (I/R) injury. Using fluorescence spectrophotometry, we monitored redox balance (NADH and FAD), O 2 •− levels and mitochondrial Ca 2+ (m[Ca 2+ ]) at the left ventricular wall in 120 guinea pig isolated hearts divided into control (Con), MnTBAP (a superoxide dismutase 2 mimetic), MnTBAP (M) + catalase (C) + glutathione (G) (MCG), C+G (CG), and N G -nitro-l-arginine methyl ester (l-NAME; a nitric oxide synthase inhibitor) groups. After an initial period of warm perfusion, hearts were treated with drugs before and after at 27°C. Drugs were washed out before 2 h at 27°C ischemia and 2 h at 37°C reperfusion. We found that on reperfusion the MnTBAP group had the worst functional recovery and largest infarction with the highest m[Ca 2+ ], most oxidized redox state and increased ROS levels. The MCG group had the best recovery, the smallest infarction, the lowest ROS level, the lowest m[Ca 2+ ], and the most reduced redox state. CG and l-NAME groups gave results intermediate to those of the MnTBAP and MCG groups. Our results indicate that the scavenging of cold-induced O 2 •− species to less toxic downstream products additionally protects during and after cold I/R by preserving mitochondrial function. Because MnTBAP treatment showed the worst functional return along with poor preservation of mitochondrial bioenergetics, accumulation of H 2 O 2 and/or hydroxyl radicals during cold perfusion may be involved in compromised function during subsequent cold I/R injury.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00231.2006
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477334-X
    detail.hit.zdb_id: 392098-7
    SSG: 12
    Location Call Number Limitation Availability
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