Mechanisms of Ca<sup>2+</sup> Overload in Reperfused Ischemic Myocardium

Tani, Masato

doi:10.1146/annurev.ph.52.030190.002551

Cited by 283 publications

(47 citation statements)

References 37 publications

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“…It has been shown that free radicals can depress the activity of the sarcolemmal Ca 2+ -pump (Kaneko et al 1989), which is involved in the efflux of calcium from the myocyt, and the sarcoplasmic reticular Ca 2+ -pump (Rowe et al 1983), which plays a role in the sequestration of calcium ions into the sarcoplasmic reticulum. In this connection it also has been shown that free radicals may modulate Ca 2+ -(leak) channels (Kaneko et al 1989), as well as the Na + /Ca 2+ exchanger (Tani 1990;Clague et al 1993;Wang et al 1995). The altered response to sodium withdrawal in atria exposed to free radicals in the present study may reflect alterations in the Na + /Ca 2+ exchanger.…”

Section: Discussionmentioning

confidence: 98%

The influence of oxidative stress on various inotropic responses in isolated rat left atria

Peters

Pfaffendorf

Zwieten

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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The effects of free radicals, generated by electrolysis of a physiological salt solution, on various inotropic responses to drugs in isolated rat left atria were studied. Evidence for the generation of hydroxyl radicals was obtained from an appropriate fluorimetric assay. The amount of free radicals produced by electrolysis of the medium proved current-dependent. Exposure of isolated rat left atria to the medium which had been subjected to electrolysis caused a current-dependent decrease in contractile force. Oxidative stress, as a result of the electrolysis of the medium, caused altered inotropic responses to extra cellular Ca2+ (pD2 control group: 2.62 +/- 0.06 vs. 2.44 +/- 0.07 electrolysis group), sodium withdrawal (rise in contractile force control group: 1.73 +/- 0.19 mN vs. 0.48 +/- 0.21 mN electrolysis group) and lowering of stimulation frequency. The response to isoprenaline was diminished in atria subjected to oxidative stress and led to a rightward shift of the concentration response curves (pD2 control group: 7.56 +/- 0.10 vs. 6.77 +/- 0.11 electrolysis group). In addition, the inotropic responses to forskolin (pD2 control group: 6.17 +/- 0.12 vs. < 4.5 electrolysis group) and dibutyryl cAMP (rise in contractile force caused by 1 x 10(-5) M db-cAMP in control group: 2.15 +/- 0.01 mN vs. 1.21 +/- 0.10 mN electrolysis group) proved blunted as well. Measurement of the adenylyl cyclase activity revealed that free radicals attenuated the basal (by 11.1%) and forskolin stimulated (155.0 +/- 5.1 vs. 48.0 +/- 1.8 pmol cAMP/mg prot./min for control and electrolysis group respectively) activity of the adenylyl cyclase. DMSO, a well known hydroxyl radical scavenger, was able to abolish the free radical-induced decrease in the response to isoprenaline. Surprisingly, addition of alpha-adrenoceptor agonists to atria subjected to electrolysis-generated free radicals led to a rapid decrease in contractile force. DMSO was unable to counteract the negative intropic effect of methoxamine in atria subjected to oxidative stress. This negative inotropic response to alpha-adrenoceptor agonists in atria subjected to electrolysed medium is unlikely to be the direct result of phospholipase C or protein kinase C activation. Angiotensin II (which stimulates PLC, as well) did not reduce contractile force and chelerythrine (a PKC inhibitor) was unable to counteract the negative inotropic effect of the adrenoceptor agonists. In addition, the negative inotropic effect of methoxamine proved insensitive to 10(-6) M phentolamine and 10(-5) M doxazosin, which indicates an alpha-adrenoceptor independent mechanism. From this study we conclude that free radicals alter responses to various inotropic stimuli. These alterations may be the result of injured contractile elements, transporter molecules and molecules involved in signal transduction. Addition of alpha-adrenoceptor agonists after oxidative stress leads to a alpha-adrenoceptor. PLC and PKC independent decrease in contractile force.

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Section: Discussionmentioning

confidence: 98%

The influence of oxidative stress on various inotropic responses in isolated rat left atria

Peters

Pfaffendorf

Zwieten

1997

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Thus, in the longer-term ATP production and utilization could control cellular functions via adenosine; adenosine acting to increase respiratory substrate and oxygen supply (by vasodilation) and decrease cellular ATP utilization (by depressing excitability). The ATP/ADP ratio might also conceivably regulate cell functions by ATP dependent 1992 phosphorylation/dephosphorylation of proteins, for example in regulation of ion channels and exchangers (Tani, 1990 (Hansford, 1985;, and only its implications for control of respiration and ATP synthesis will be examined here.…”

Section: Application Of Metabolic Control Theorymentioning

confidence: 99%

Control of respiration and ATP synthesis in mammalian mitochondria and cells

Brown

1992

Biochemical Journal

566

308

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We have seen that there is no simple answer to the question ‘what controls respiration?’ The answer varies with (a) the size of the system examined (mitochondria, cell or organ), (b) the conditions (rate of ATP use, level of hormonal stimulation), and (c) the particular organ examined. Of the various theories of control of respiration outlined in the introduction the ideas of Chance & Williams (1955, 1956) give the basic mechanism of how respiration is regulated. Increased ATP usage can cause increased respiration and ATP synthesis by mass action in all the main tissues. Superimposed on this basic mechanism is calcium control of matrix dehydrogenases (at least in heart and liver), and possibly also of the respiratory chain (at least in liver) and ATP synthase (at least in heart). In many tissues calcium also stimulates ATP usage directly; thus calcium may stimulate energy metabolism at (at least) four possible sites, the importance of each regulation varying with tissue. Regulation of multiple sites may occur (from a teleological point of view) because: (a) energy metabolism is branched and thus proportionate regulation of branches is required in order to maintain constant fluxes to branches (e.g. to proton leak or different ATP uses); and/or (b) control over fluxes is shared by a number of reactions, so that large increases in flux requires stimulation at multiple sites because each site has relatively little control. Control may be distributed throughout energy metabolism, possibly due to the necessity of minimizing cell protein levels (see Brown, 1991). The idea that energy metabolism is regulated by energy charge (as proposed by Atkinson, 1968, 1977) is misleading in mammals. Neither mitochondrial ATP synthesis nor cellular ATP usage is a unique function of energy charge as AMP is not a significant regulator (see for example Erecinska et al., 1977). The near-equilibrium hypothesis of Klingenberg (1961) and Erecinska & Wilson (1982) is partially correct in that oxidative phosphorylation is often close to equilibrium (apart from cytochrome oxidase) and as a consequence respiration and ATP synthesis are mainly regulated by (a) the phosphorylation potential, and (b) the NADH/NAD+ ratio. However, oxidative phosphorylation is not always close to equilibrium, at least in isolated mitochondria, and relative proximity to equilibrium does not prevent the respiratory chain, the proton leak, the ATP synthase and ANC having significant control over the fluxes. Thus in some conditions respiration rate correlates better with [ADP] than with phosphorylation potential, and may be relatively insensitive to mitochondrial NADH/NAD+ ratio.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…This was accompanied by significant inhibition of mitochondrial respiration and a decrease in ATP and ADN contents. It can be hypothesized that these reperfusion conditions had an adverse effect on ischemic myocardium and aggravated cardiomyocyte damage resulting from calcium and oxygen paradoxes [6,12]. The inhibition of mitochondrial respiration and oxidative phosphorylation probably results from the disturbances in electromechanical coupling accompanied by heart contracture due to impaired Ca 2+ homeostasis, exhaustion of cell substrates for the high-energy phosphate synthesis, and disruption of mitochondrial membranes.…”

Section: Resultsmentioning

confidence: 99%

The relationship between mitochondrial respiration and postischemic recovery of isolated heart contractility

Dzhavadov

1998

Bull Exp Biol Med

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Recovery of heart contractility after global normothermic ischemia in New-Zealand rabbits depends on the reperfusion mode and the composition of reperfusion medium and correlates with mitochondrial respiration. Cardiac function can recover also at low ATP concentration (about 1 gmol/g dry tissue). Key Words: rabbit heart; ischemia; reperfusion; mitochondrial respiration; high-energy phosphatesDeep myocardial ischemia reduces tissue content of high-energy phosphates, in particular ATP and creafine phosphate (CP), due to inhibition of oxidative phosphorylation in mitochondria followed by lactate accumulation and enhanced glycogen decomposition. It has been shown that ATP plays an essential role in the development of ischemia-induced myocardial damage [2,4,11]. These studies also demonstrated that myocardial contractility can be restored if the ischemized tissue contains at least 2-3 gmol ATP per gram dry tissue, whereas lower ATP content leads to irreversible changes in cardiomyocytes and loss of contractility [3,7,8]. We assume that under conditions of preserved mitochondrial functions the contractility of myofibrils can be restored even at negligible or zero tissue ATP content. Since tissue ATP content corresponds to the difference between ATP synthesis and degradation, the absence of ATP accumulation during reperfusion may imply its complete utilization. It should be noted that these studies were carried out on the model of regional hypothermic ischelnia with cardioprotection. Mitochondrial respiration was assessed on isolated mitochondria. It is known that considerable proportion of the mitochondria is lost during isolation, particularly from Azerbaijan Medical University, Balm damaged tissues, which masks the real picture and the degree of damage [t0].We investigated the relationship between mechanical function of the myocardium and the rate of mitochondrial respiration and ATP content during reperfusion after normothermic global ischemia. MATERIALS AND METHODSHearts isolated from New Zealand rabbits weighing 1.7-2.0 kg were perfused via the aorta with KrebsHenseleit buffer (Langendorff retrograde perfusion at constant pressure without recirculation) [1]. Before ischemia and during reperfusion the hearts were arrested with St. Thomas's Hospital cardioplegic solution, pH was measured "after carbogen saturation (95% 02, 5% CO2) at 37~ 10 mM CP (disodium salt) and 15 mM glutamaic acid (GA, potassium salt) were added to the cardioplegic solution as cardioprotectors (CP-containing solution with 90 mM NaC1). To model global ischemia the perfusate flow was interrupted; hypothermia (22~ and cardioprotectors were used only during reperfusion with cardioplegic solution.The hearts were perfused before ischemia (group 1), subjected to 80-rain cardioplegic normothernfic ischemia (group 2), and reperfused under different

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Mechanisms of Ca²⁺ Overload in Reperfused Ischemic Myocardium

Cited by 283 publications

References 37 publications

The influence of oxidative stress on various inotropic responses in isolated rat left atria

The influence of oxidative stress on various inotropic responses in isolated rat left atria

Control of respiration and ATP synthesis in mammalian mitochondria and cells

The relationship between mitochondrial respiration and postischemic recovery of isolated heart contractility

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Mechanisms of Ca2+ Overload in Reperfused Ischemic Myocardium

Cited by 283 publications

References 37 publications

The influence of oxidative stress on various inotropic responses in isolated rat left atria

The influence of oxidative stress on various inotropic responses in isolated rat left atria

Control of respiration and ATP synthesis in mammalian mitochondria and cells

The relationship between mitochondrial respiration and postischemic recovery of isolated heart contractility

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Product

Resources

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Mechanisms of Ca²⁺ Overload in Reperfused Ischemic Myocardium