Mitochondrial dysfunction in cardiac ischemia-reperfusion injury: ROS from complex I, without inhibition.

A key pathologic event in cardiac ischemia reperfusion (I-R) injury is mitochondrial energetic dysfunction, and several studies have attributed this to complex I (CxI) inhibition. In isolated perfused rat hearts, following I-R, we found that CxI-linked respiration was inhibited, but isolated CxI enzymatic activity was not. Using the mitochondrial thiol probe iodobutyl-triphenylphosphonium in conjunction with proteomic tools, thiol modifications were identified in several subunits of the matrix-facing 1alpha sub-complex of CxI.

Multiple treatment approach to limit cardiac ischemia-reperfusion injury.

Background: This study evaluates a multiple treatment approach (ie, pharmacologic preconditioning [diazoxide], sodium-proton exchange inhibition [cariporide], and controlled reperfusion) to improve the outcome from severe cardiac ischemia-reperfusion injury that occurs during a cardiac operation.

Methods: Five groups of 10 pigs (group 1: control, group 2: diazoxide, group 3: cariporide, group 4: controlled reperfusion, and group 5: combination of diazoxide and cariporide-controlled reperfusion) underwent 75 minutes of left anterior descending occlusion, 1 hour of cardioplegic arrest, and 2 hours of reperfusion. Prior to occlusion, each group received an infusion of vehicle alone (ie, dimethylsulfoxide for the control and the controlled reperfusion groups) or vehicle with drug (ie, diazoxide or cariporide, or both for all other groups).

Evidence of cardiovascular protection by moderate alcohol: role of nitric oxide.

Epidemiological evidence indicates that moderate alcohol consumption reduces the incidence of heart disease. Endothelial nitric oxide synthase (eNOS) is a key regulator of vascular homeostasis and myocardial functions through the controlled production of nitric oxide (*NO). These studies were conducted to determine if the apparent alcohol-associated cardioprotection is mediated, in part, through modulation of the eNOS protein and activity in the cardiovascular system.

Early reperfusion levels of Na(+) and Ca(2+) are strongly associated with postischemic functional recovery but are disassociated from K(ATP) channel-induced cardioprotection.

We previously demonstrated that pinacidil does not affect Na(+)(i) accumulation, cellular energy depletion, or acidosis during myocardial ischemia, but dramatically improves the cationic/energetic status during reperfusion. We investigated the role of this latter effect in K(ATP) channel-induced cardioprotection. Employing (23)Na and (31)P nuclear magnetic resonance spectroscopy with perfused rat hearts, reperfusion Na(+)(i) was altered with brief infusions of ouabain and/or RbCl to transiently decrease or increase Na(+)/K(+) ATPase activity.

Intra-myocyte ion homeostasis during ischemia-reperfusion injury: effects of pharmacologic preconditioning and controlled reperfusion.

Background: This study determines whether controlled reperfusion or diazoxide improves intramyocyte Na(+) homeostasis using a porcine model of severe ischemia-reperfusion injury.

Methods: Three groups (n = 10 pigs per group) had 75 minutes of left anterior descending artery occlusion during bypass. Group 1 had no treatment (control group), group 2 had controlled reperfusion (500 mL warm cardioplegia) (controlled reperfusion group), and group 3 had diazoxide (50 micromol/L before left anterior descending artery occlusion) (diazoxide group).

Modulation of mitochondrial adenosine triphosphate-sensitive potassium channels and sodium-hydrogen exchange provide additive protection from severe ischemia-reperfusion injury.

Background: Preconditioning and inhibition of sodium-proton exchange attenuate myocardial ischemia-reperfusion injury by means of independent mechanisms that might act additively when used together. The hypothesis of this study is that treatment with a sodium-proton exchange inhibitor and a mitochondrial adenosine triphosphate-sensitive potassium channel opener produces superior functional recovery and a greater decrease in left ventricular infarct size compared with treatment with either drug alone in a model of severe global ischemia.

Methods: Isolated crystalloid-perfused rat hearts (n = 8 hearts per group) were administered vehicle (control, 0.

Mitochondrial function in response to cardiac ischemia-reperfusion after oral treatment with quercetin.

Polyphenolic compounds present in red wines, such as the flavonol quercetin, are thought capable of cardioprotection through mechanisms not yet clearly defined. It has been established that mitochondria play a critical role in myocardial recovery from ischemia-reperfusion (I-R) damage, and in vitro experiments indicate that quercetin can exert a variety of direct effects on mitochondrial function. The effects of quercetin at concentrations typically found in 1-2 glasses of red wine on cardiac I-R and mitochondrial function in vivo are not known.

Ischemic preconditioning and Na+/H+ exchange inhibition improve reperfusion ion homeostasis.

Background: Intramyocyte sodium (Na+) increases during ischemia and reperfusion, which causes myocardial calcium (Ca2+) uptake and leads to myocyte injury or death. This study determines if ischemic preconditioning and myocyte sodium-hydrogen ion (Na+-H+) exchange (NHE) inhibition decreases Na+ gain that otherwise occurs with cardioplegic arrest and reperfusion.

Methods: Pigs had 1 hour of cardioplegic arrest followed by reperfusion.

Novel methods to evaluate controlled reperfusion techniques in cardiac surgery.

Background: This manuscript describes two novel techniques that may be useful for comparing methods to reperfuse the heart during cardiac operations. These techniques are based on measurements of intra-myocyte ion content and the analysis of reperfusion arrhythmias.

Methods: Myocyte ion content was measured in normal porcine hearts before and after ischemia (cardioplegic arrest, CP arrest) using atomic absorption spectroscopy.

The effect of K(atp)channel activation on myocardial cationic and energetic status during ischemia and reperfusion: role in cardioprotection.

The role of cation and cellular energy homeostasis in ATP-sensitive K(+)(K(ATP)) channel-induced cardioprotection is poorly understood. To evaluate this, rapidly interleaved(23)Na and(31)P NMR spectra were acquired from isolated rat hearts exposed to direct K(ATP)channel activation from nicorandil or pinacidil. Nicorandil attenuated ATP depletion and intracellular Na(+)(Na(+)(i)) accumulation, delayed the progression of acidosis during zero-flow ischemia and prevented ischemic contracture.

Controlled postcardioplegia reperfusion: mechanism for attenuation of reperfusion injury.

Objective: Controlled reperfusion and secondary cardioplegia are used to minimize reperfusion injury. The mechanisms for their benefit are incompletely defined and may include attenuation of myocyte sodium uptake.

Methods: Pigs had 1 hour of cardioplegic arrest followed by reperfusion with blood (control) or warm cardioplegic solution followed by blood (test).

Peroxynitrite irreversibly decreases diastolic and systolic function in cardiac muscle.

Much of the damaging action of nitric oxide in heart may be due to its diffusion-limited reaction with superoxide to form peroxynitrite. Direct infusion of peroxynitrite into isolated perfused hearts fails to model the effects of in situ formation because the bulk of peroxynitrite decomposes before reaching the myocytes. To examine the direct effects of peroxynitrite on the contractile apparatus of the heart, we exposed intact and skinned rat papillary muscles to a steady state concentration of 4-microM peroxynitrite for 5 min, followed by a 30-min recovery period to monitor irreversible effects.

The Arthus reaction in rodents: species-specific requirement of complement.

We induced reverse passive Arthus (RPA) reactions in the skin of rodents and found that the contribution of complement to immune complex-mediated inflammation is species specific. Complement was found to be necessary in rats and guinea pigs but not in C57BL/6J mice. In rats, within 4 h after initiation of an RPA reaction, serum alternative pathway hemolytic titers decreased significantly below basal levels, whereas classical pathway titers were unchanged.

23Na NMR shift reagents enhance cardiac staircase effect in isolated perfused rat hearts.

The effects of the currently used (23)Na NMR shift reagents, dysprosium bis-triphosphate [Dy(PPP)(2)], dysprosium triethylenetriamine hexaacetate [Dy(TTHA)] and thulium 1,4,7, 10-tetraazacyclododecane-N,N',N",N"'-tetra(methylenephosphonate) [Tm(DOTP)] were studied in the rat heart cardiac staircase model. Rat hearts were perfused with low or normal extracellular free calcium ([Ca(o)](f)). At low [Ca(o)](f) (0.

MDL-28170, a membrane-permeant calpain inhibitor, attenuates stunning and PKC epsilon proteolysis in reperfused ferret hearts.

Objectives: This paper tests the hypothesis that calpains are activated in the ischemic (I)/reperfused (R) heart and contribute to myocardial stunning.

Methods: Isolated ferret hearts were Langendorff perfused isovolumically, and subjected to 20 min of global I followed by 30 min of R in the presence or absence of 0.2 microM MDL-28170, a membrane-permeant calpain inhibitor.

Effect of hemoglobin concentration on oxyhemoglobin dissociation during hypothermic blood cardioplegic arrest.

Background: This study compares oxyhemoglobin dissociation during the nonperfused periods of hypothermic cardioplegic arrest in two blood cardioplegic solutions with different hemoglobin concentrations. The hypothesis is that more oxygen will dissociate from hemoglobin in a blood cardioplegic solution with a higher hemoglobin content than from a cardioplegic solution with a lower hemoglobin content. However, the increment in the volume of oxygen that dissociates from hemoglobin will be less than anticipated by a ratio of hemoglobin concentrations in the cardioplegic solution.

Effect of postcardioplegia reperfusion rhythm on myocardial blood flow.

This study compared myocardial blood flow during postcardioplegia reperfusion asystole and ventricular fibrillation. Pigs (n = 20) were placed on cardiopulmonary bypass and blood cardioplegic solution at 38 degrees C was then infused. A preischemia microsphere injection was given in asystolic hearts.

Preischemic glycogen reduction or glycolytic inhibition improves postischemic recovery of hypertrophied rat hearts.

The purpose of this study was to determine whether metabolites produced by glycolysis during ischemia significantly contribute to myocardial injury of hypertrophied hearts. The accumulation of glycolytic metabolites during ischemia was reduced by means of glycogen reduction or by treatment with the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG) before ischemia. Hearts from aortic-banded (Band) and sham-operated (Sham) rats (8 wk postop) were isolated, perfused with Krebs buffer, and had a left ventricular (LV) balloon to measure developed pressure.

The effect of reperfusion pressure on early outcomes after coronary artery bypass grafting. A randomized trial.

Among 60 patients randomly assigned to a reperfusion pressure of 50 mm Hg or one of 75 mm Hg (30 mm Hg during the first 2 minutes in both groups) during initially hyperkalemic, controlled aortic root reperfusion after coronary artery bypass grafting, no in-hospital deaths occurred, no patient received an intraaortic balloon pump, no patient had new Q waves, and creatine kinase MB release was similar in the two groups. Median interval between the beginning of reperfusion and the return of rhythmic cardiac contractions in the 50 mm Hg group was 7 minutes; in the 75 mm Hg group, it was 5 minutes (P = 0.1).

Oxyhemoglobin dissociation during hypothermic blood cardioplegia arrest.

Background: Coronary sinus effluent contains desaturated blood during the first few seconds of hypothermic cardioplegia infusion in humans. This occurs despite the high affinity of hemoglobin for oxygen at a low temperature and alkaline pH. The present study quantitates oxyhemoglobin dissociation during hypothermic cardioplegic arrest.

The response to ischemia in blood perfused vs. crystalloid perfused isolated rat heart preparations.

With a research hypothesis that the behavior of blood perfused hearts was different from that of crystalloid perfused hearts, we tested the null hypothesis that the functional and metabolic status of blood-perfused (paracorporeal oxygenation) and Krebs-Henseleit (bubble oxygenation) perfused Langendorff isolated rat hearts is the same before, during and after global myocardial ischemia. Thirty isolated rat hearts were studied under identical conditions except that in equal numbers they were randomly assigned to either blood or crystalloid perfusion. In the blood perfused and crystalloid perfused hearts subjected to 22 min of normothermic ischemia and 30 min of reperfusion, mean systolic recovery was 72 +/- 3.

Modifying myocardial management in cardiac surgery: a randomized trial.

Among the 160 patients randomly assigned to one of eight protocols of myocardial management, all of which included controlled aortic root reperfusion, no important differences were found between protocols as to the prevalence of death (0 instances), use of an intra-aortic balloon pump (no instances), use of catecholamines, elaboration of CK-MB isoenzymes, new Q-waves, abnormal wall motion scores, or postoperative atrial fibrillation. Ventricular defibrillation was required more often in patients in the protocol with noncardioplegic blood reperfusate. Cardiac index was highest in the operating room in the group receiving hyperkalemic cold cardioplegia and initial hyperkalemic reperfusion.

31P NMR spectroscopy in chronic adriamycin cardiotoxicity.

Abnormal cardiac energy metabolism has been postulated as a mechanism for adriamycin induced cardiotoxicity. This study was designed to determine high energy phosphate stores at rest and with hemodynamic stress in perfused rat hearts after animals had been chronically exposed to adriamycin (2 mg/kg weekly for 14 weeks). Morphologic and hemodynamic changes were mild in this model.