Reduced Cytosolic Ca
            <sup>2+</sup>
            Loading and Improved Cardiac Function After Cardioplegic Cold Storage of Guinea Pig Isolated Hearts

Stowe, David F.; Varadarajan, Srinivasan G.; An, Jianzhong; Smart, Steven C.

doi:10.1161/01.cir.102.10.1172

Cited by 43 publications

(44 citation statements)

References 40 publications

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“…It is well known that the colder the heart during ischemia, the longer ischemia can be tolerated with minimal tissue damage (16,43). However, it is now known that hypothermia, per se, can have a deleterious effect on function with rewarming.…”

Section: Discussionmentioning

confidence: 99%

ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca²⁺ overload, and changes in redox state

Camara¹,

Aldakkak²,

Heisner³

et al. 2007

American Journal of Physiology-Cell Physiology

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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•Ϫ levels and mitochondrial Ca 2ϩ (m[Ca 2ϩ ]) at the left ventricular wall in 120 guinea pig isolated hearts divided into control (Con), MnTBAP (a superoxide dismutase 2 mimetic), MnTBAP (M) ϩ catalase (C) ϩ glutathione (G) (MCG), CϩG (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 2ϩ ], 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 2ϩ ], 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•Ϫ 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. hypothermic ischemia; mitochondrial Ca 2ϩ ; reactive oxygen species HYPOTHERMIA of the arrested, ischemic heart improves its function on reperfusion compared with the normothermic arrested ischemic heart. The strategy behind hypothermic protection against ischemia, i.e., better tissue perfusion, and improved metabolic and mechanical function on reperfusion, is the reduced mitochondrial respiration and oxidative phosphorylation during ischemia that results in better mitochondrial respiration and regeneration of ATP on reperfusion. For example, we demonstrated that NADH, m [Ca 2ϩ ], and reactive O 2 species (ROS) levels were less altered during and after 30 min of ischemia at 17°C vs. 37°C (39). We reported that the more severe the hypothermia, the later is the onset of deleterious changes in mitochondrial function (1,2,16,22,31).Although hypothermia is very protective against ischemia, hypothermic perfusion, e.g., before subsequent cardiac ischemia, may cause injury due to altered cellular ion homeostasis resulting from impaired membrane ion pumps and exchangers and/or to reduced activity of enzymes responsible for mitochondrial respiration, scavenging of ROS, and contractile activity. A well-known effect of hypothermia is hypercontracture with elevated cytosolic [Ca 2ϩ ] (42). Another is a decreasing temperature-depende...

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Section: Discussionmentioning

confidence: 99%

ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca²⁺ overload, and changes in redox state

Camara¹,

Aldakkak²,

Heisner³

et al. 2007

American Journal of Physiology-Cell Physiology

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“…Although both F 385 and F456 decline over time, time control studies showed that the F385-to-F456 ratio (F385/F456) remained stable, indicating that effective measured [Ca 2ϩ ] was unchanged (31). The F385/F456 was converted to [Ca 2ϩ ] after correcting for background autofluorescence and noncytosolic fluorescence (see APPENDIX), as has been described in detail previously (7,10,26,27,30). Developed LVP after indo 1 loading was also not significantly altered over 3 h in the absence of ischemia.…”

Section: Measurement Of Myoplasmic Free Ca 2ϩ In Intact Heartsmentioning

confidence: 96%

Ischemia-reperfusion injury changes the dynamics of Ca²⁺-contraction coupling due to inotropic drugs in isolated hearts

Rhodes¹,

Ropella²,

Camara³

et al. 2006

Journal of Applied Physiology

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. Ischemia-reperfusion injury changes the dynamics of Ca 2ϩ -contraction coupling due to inotropic drugs in isolated hearts. J Appl Physiol 100: 940 -950, 2006. First published November 10, 2005 doi:10.1152/japplphysiol.00285.2005.-Positive inotropic drugs may attenuate or exacerbate the deleterious effects of ischemia and reperfusion (IR) injury on excitation-contraction coupling in hearts. We 1) quantified the phase-space relationship between simultaneously measured myoplasmic Ca 2ϩ concentration ([Ca 2ϩ ]) and isovolumetric left ventricular pressure (LVP) using indexes of loop area, orientation, and position; and 2) quantified cooperativity by linearly modeling the phase-space relationship between [Ca 2ϩ ] and rate of LVP development in intact hearts during administration of positive inotropic drugs before and after global IR injury. Unpaced, isolated guinea pig hearts were perfused at a constant pressure with Krebs-Ringer solution (37°C, 1.25 mM CaCl 2). [Ca 2ϩ ] was measured ratiometrically by indo 1 fluorescence by using a fiber-optic probe placed at the left ventricular free wall. LVP was measured by using a saline-filled latex balloon and transducer. Drugs were infused for 2 min, 30 min before, and for 2 min, 30 min after 30-min global ischemia. IR injury worsened Ca 2ϩ -contraction coupling, as seen from decreased orientation and repositioning of the loop rightward and downward and reduced cooperativity of contraction and relaxation with or without drugs. Dobutamine (4 M) worsened, whereas dopamine (8 M) improved Ca 2ϩ -contraction coupling before and after IR injury. Dobutamine and dopamine improved cooperativity of contraction and relaxation after IR injury, whereas only dopamine increased cooperativity of relaxation before IR injury. Digoxin (1 M) improved Ca 2ϩ -contraction coupling and cooperativity of contraction after but not before ischemia. Levosimendan (1 M) did not alter Ca 2ϩ -contraction coupling or cooperativity, despite producing concomitant increases in contractility, relaxation, and Ca 2ϩ flux before and after ischemia. Dynamic indexes based on LVP- [Ca 2ϩ ] diagrams (area, shape, position) can be used to identify and measure alterations in Ca 2ϩ -contraction coupling during administration of positive inotropic drugs in isolated hearts before and after IR injury.phase-space diagrams; cooperativity; guinea pigs; linear model POSITIVE INOTROPIC DRUGS ARE frequently administered to patients with left ventricular (LV) dysfunction to improve cardiac output (19). These agents mostly act by increasing myoplasmic Ca 2ϩ concentration ([Ca 2ϩ ]) ("upstream" mechanism) but may also enhance Ca 2ϩ binding to troponin C on the actin (TnCA) myofilament ("central" mechanism) or alter cross-bridge kinetics ("downstream" mechanism). Several classes of inotropic drugs act selectively through these mechanisms to improve Ca 2ϩ -contraction coupling. ␤-adrenergic and dopaminergic agonists (e.g., dobutamine and dopamine) increase myoplasmic cAMP concentrations to promote protein kinase-induced phosph...

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“…It is well known that these solutions are protective against ischemiareperfusion (I/R) dysfunction. This protection is effected by reducing the cardiac total energy consumption (Stowe et al 2000;Wang et al 2003). In previous works, we studied the energetics of a model of beating hearts (rat) perfused with cold cardioplegia (high-K + -low-Ca 2+ crystalloid at 30°C) before subjecting them to I/R.…”

Section: Introductionmentioning

confidence: 99%

Effects of pyruvate on the energetics of rat ventricles stunned by ischemia–reperfusion

Bonazzola

Ragone

Consolini

2014

Can. J. Physiol. Pharmacol.

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Pyruvate (Pyr) was proposed as an additive to cold high-K(+)-low-Ca(2+) cardioplegia (CPG) to protect the heart during surgery. We explored whether Pyr and CPG would work synergistically to protect rat hearts from stunning during ischemia-reperfusion (I/R). We measured the heat release and contractility of perfused ventricles during I/R, and the cytosolic and mitochondrial [Ca(2+)] in cardiomyocytes by confocal microscopy. We found that under cold-CPG (30 °C), 10 mmol·L(-1) Pyr reduced the post-ischemic contractile recovery (PICR) as well as muscle economy, when added either before ischemia or during I/R, which was reversed by blockade of UCam. In noncardioplegic hearts, Pyr was cardioprotective when it was present during I/R, more so at 37 °C than at 30 °C, with improved economy. In cardiomyocytes, the addition of Pyr to CPG slightly increased the mitochondrial [Ca(2+)] but decreased cytosolic [Ca(2+)]. The results suggest that Pyr only protects hearts from stunning when present before ischemia and during reperfusion, and that it dampens the cardioprotective properties of CPG. The mechanisms underlying such different behavior depend on the dynamic balance between Pyr stimulation of the energetic state and mitochondrial Ca(2+) uptake. Our results support the use of Pyr in stunned hearts, but not in cold high-K(+) cardioplegia.

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Reduced Cytosolic Ca ²⁺ Loading and Improved Cardiac Function After Cardioplegic Cold Storage of Guinea Pig Isolated Hearts

Cited by 43 publications

References 40 publications

ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca²⁺ overload, and changes in redox state

ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca²⁺ overload, and changes in redox state

Ischemia-reperfusion injury changes the dynamics of Ca²⁺-contraction coupling due to inotropic drugs in isolated hearts

Effects of pyruvate on the energetics of rat ventricles stunned by ischemia–reperfusion

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Reduced Cytosolic Ca 2+ Loading and Improved Cardiac Function After Cardioplegic Cold Storage of Guinea Pig Isolated Hearts

Cited by 43 publications

References 40 publications

ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca2+ overload, and changes in redox state

ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca2+ overload, and changes in redox state

Ischemia-reperfusion injury changes the dynamics of Ca2+-contraction coupling due to inotropic drugs in isolated hearts

Effects of pyruvate on the energetics of rat ventricles stunned by ischemia–reperfusion

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Reduced Cytosolic Ca ²⁺ Loading and Improved Cardiac Function After Cardioplegic Cold Storage of Guinea Pig Isolated Hearts

ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca²⁺ overload, and changes in redox state

ROS scavenging before 27°C ischemia protects hearts and reduces mitochondrial ROS, Ca²⁺ overload, and changes in redox state

Ischemia-reperfusion injury changes the dynamics of Ca²⁺-contraction coupling due to inotropic drugs in isolated hearts