diacetylmonoxime and Myocardial-Infarction

Fibrinolytic therapy is aimed at dissolving the fibrin clot. Its use now represents the optimal therapy for an acute evolving myocardial infarction. Although improved fibrinolytic agents are now being developed, the next frontier appears to be thrombolytic therapy which will combine fibrinolysis to platelet active drugs and specific inhibitors of blood coagulation, targetting the blood clot formation process itself. The most promising agents in this regard are inhibitors of the platelet glycoprotein IIb-IIIa receptors and specific thrombin inhibitors active on clot bound thrombin. This should result in more complete control of the thrombogenicity of the culprit coronary artery lesion. The comprehensive approach for the management of acute myocardial infarction should however ultimately be reperfusion therapy combining to thrombolytic therapy measures that will preserve the acutely ischemic myocardium and prevent the long-term deleterious effect of infarct expansion and left ventricular remodelling.

Topics: Aspirin; Blood Coagulation Factors; Cholinesterase Reactivators; Chromogenic Compounds; Clinical Trials as Topic; Diacetyl; Drug Therapy, Combination; Hirudins; Humans; Infusions, Parenteral; Myocardial Infarction; Myocardial Reperfusion; Platelet Membrane Glycoproteins; Thrombin; Thrombolytic Therapy

Although ischemic postconditioning (IPost) confers cardioprotection by protecting the mitochondria though the activation of phosphatidylinositol 3-kinase (PI3K), a potential drawback of IPost is impairment of aerobic ATP generation during reperfusion by repeated ischemia. This decrease in ATP might inhibit the restoration of sarcolemmal dystrophin, which is translocated during ischemia, and render cardiomyocytes susceptible to contraction-induced oncosis.. Isolated rat hearts were subjected to 30 min ischemia and 120 min reperfusion. IPost induced by 20 cycles of 10-s reperfusion and 10-s ischemia enhanced the activation of PI3K as evidenced by the increased phosphorylation of Akt, but had no effect on myocardial ATP, restoration of sarcolemmal dystrophin, or cardiomyocyte oncosis during IPost. Administration of the contractile blocker, 2,3-butanedione monoxim (BDM), during IPost increased myocardial ATP and facilitated the redistribution of dystrophin to the sarcolemma. This led to reduced cardiomyocyte oncosis and infarct size, and improved the left ventricular function. The anti-oncotic effect of BDM occurred without changing the anti-apoptotic effect of IPost. The PI3K inhibitor, LY294002, prevented the phosphorylation of Akt, decreased the recovery of ATP and restoration of sarcolemmal dystrophin, and blocked the anti-oncotic and anti-apoptotic effects of IPost.. These results suggest that the inhibition of contractile activity during IPost prevents cardiomyocyte oncosis and enhances cardioprotection through PI3K-dependent restoration of sarcolemmal dystrophin.

Topics: Adenosine Triphosphate; Animals; Apoptosis; Chromones; Cytoprotection; Diacetyl; Dystrophin; Enzyme Activation; In Vitro Techniques; Ischemic Postconditioning; Male; Morpholines; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Perfusion; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Protein Transport; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Sarcolemma; Signal Transduction; Time Factors; Ventricular Function, Left

Topics: Adenosine Triphosphate; Animals; Apoptosis; Cytoprotection; Diacetyl; Dystrophin; Enzyme Activation; Humans; Ischemic Postconditioning; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphatidylinositol 3-Kinases; Protein Transport; Sarcolemma; Signal Transduction; Time Factors; Ventricular Function, Left

Actomyosin ATPase is one of the major ATP consuming enzymes in the myocardium. We tested whether 2,3-butanedione monoxime (BDM), a reversible inhibitor of actomyosin ATPase, given before coronary occlusion, limits infarct size in anesthetized open-chest dogs.. After circumflex artery catheterization using fluoroscopic guidance, BDM (125 mM) or buffer vehicle was infused (12.0 ml/min) for 20 min (BDM-20, n = 5 and Buffer-20, n = 6) or for 5 min (BDM-5, n = 6 and Buffer-5, n = 6) prior to 60 min of ischemia and 3 h of reperfusion. BDM administration increased subendocardial blood flow 271% above baseline flow (radioactive microspheres), and systolic wall thickening was converted to wall bulging (wall thickening by sonomicrometry was -27 +/- 29% and -22 +/- 13% of baseline in BDM-20 and BDM-5, respectively). Adjusted mean infarct size (% area-at-risk) was 11.0 +/- 2.8% and 11.9 +/- 2.6% in BDM-20 and BDM-5 vs. 20.2 +/- 2.5% and 20.5 +/- 2.5% in Buffer-20 and Buffer-5 (ancova, P < 0.05 for each BDM vs. Buffer group). Measurement of glycolytic metabolites and the adenine nucleotide pool of myocardium paced electronically at 150 beats per minute during total ischemia at 37 degrees C following BDM showed a metabolic response similar to that seen in ischemic preconditioning. ATP depletion, nucleoside production, and lactate accumulation were slowed in ischemic tissue treated with BDM.. BDM given before the onset of ischemia markedly limited infarct size and reduced energy demand after the onset of ischemia. The explanation for the reduced infarct size induced by BDM treatment is hypothesized to be the persistent reduction in energy demand found in ischemic BDM treated myocardium.

Topics: Adenosine Triphosphate; Animals; Coronary Circulation; Diacetyl; Dogs; Enzyme Inhibitors; Female; Heart; Hemodynamics; Infusions, Intra-Arterial; Lactic Acid; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Myosins

An important mechanism of lethal myocardial reperfusion injury is the development of cellular hypercontracture at the onset of reperfusion. Hypercontracture can lead to cytolysis by mutual mechanical disruption of myocardial cells. 2,3-Butanedione monoxime (BDM) inhibits myofibrillar cross-bridge cycling and may therefore reduce infarct size in ischaemic reperfused myocardium. This study investigated whether a temporary presence of BDM protects against myocardial reperfusion injury in an intact-animal preparation. Anaesthetized open-chest dogs (n = 10) underwent 1 h of left anterior descendent artery (LAD) occlusion and received intracoronary BDM (25 mM, n = 5) or vehicle (n = 5) for 65 min starting with an anoxic local infusion 5 min before reperfusion. Infarct size was assessed by triphenyltetrazolium staining after 6 h reperfusion. The infusion of BDM was accompanied by a transient reduction of left ventricular systolic pressure from 84.3 +/- 11.2 mm Hg during occlusion to 66.4 +/- 9.9 mm Hg at 30 min reperfusion (mean +/- SD, P < 0.01 vs. control). LAD-flow and regional wall motion in the area at risk showed no difference between groups. Infarct size (% of area at risk) was reduced from 24.4 +/- 8.7 (control) to 6.6 +/- 2.0% (BDM) (P < 0.01). The results demonstrate that development of necrosis in reperfused myocardium can be greatly reduced by temporary presence of the contractile inhibitor BDM at the onset of reperfusion.

Topics: Animals; Coronary Circulation; Diacetyl; Disease Models, Animal; Dogs; Female; Heart Rate; Infusions, Intra-Arterial; Male; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Ventricular Pressure

Myocardial reperfusion is associated with calcium overload and cell contracture, mechanisms that may precipitate cell death. In this study, we tested the hypothesis that in vivo inhibition of this contracture could lead to cell preservation in an open-chest large animal model.. Regional myocardium function was measured during a selective intracoronary infusion of 2,3-butanedione monoxime (BDM), a specific inhibitor of actin-myosin coupling, in the control state (10 pigs) and in a protocol of a 51-minute coronary occlusion followed by reperfusion (40 pigs). The effects on coronary artery blood flow in the basal state were also studied (seven pigs). Intramyocardial distribution of the infusate during coronary occlusion, myocardial water content after 30 minutes of reperfusion and area at risk, infarct size, type of histological necrosis, and infarct geometry after 24 hours of reperfusion were assessed. Methods used included electromagnetic flowmeter, radiolabeled microspheres, subendocardial sonomicrometers, fluorescein, triphenyl tetrazolium chloride and Masson's trichrome staining, and computer quantification of infarct edges. In the absence of ischemia, BDM infusion inhibited regional shortening in a dose-dependent manner up to full systolic bulging while producing marked regional increase in coronary blood flow. During early reperfusion, BDM reduced end-diastolic length 76% more than the control infusion (p less than 0.05) and increased systolic bulging by 420% compared with no change in control animals. The ratio of infarct size/area at risk was reduced by 31% with BDM (p less than 0.05), with striking modifications of infarct histology and infarct geometry; specifically, the extent of contraction band necrosis was reduced by 63% from 105.5 +/- 18.2 to 39.2 +/- 13.6 mm2 (p less than 0.02), and more patches of necrosis (6.5 +/- 2.1 versus 1.6 +/- 0.4, p less than 0.05) and higher contour (7.7 +/- 1.2 versus 5.03 +/- 0.2, p less than 0.05) and fractal (12.1 +/- 1.3 versus 7.8 +/- 0.2, p less than 0.05) indexes were found.. Selective intracoronary infusion of BDM at doses inhibiting regional wall motion decreased infarct size after reperfusion. The effects of BDM on regional function, the reduction in contraction band necrosis at histology, and the peculiar configuration of these infarcts all suggest that inhibition of contracture can interfere with cell-to-cell progression of myocardial necrosis, supporting a role for contracture in reperfusion-induced cell death.

Topics: Actins; Animals; Calcium; Chromogenic Compounds; Coronary Circulation; Diacetyl; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Myosins; Swine