pyrimidinones and Myocardial-Infarction

Acute coronary syndrome causes several types of arrhythmia because of its electrical instability and ischemia. The most important arrhythmia is ventricular tachycardia which degenerates to ventricular fibrillation. Prompt direct current cardioversion will be needed and prevention of ventricular tachyarrhythmia by potassium channel blocker became more popular in Japan. Nifekalant or amiodarone should be selected. Atrial fibrillation also occurred in the patients with acute coronary syndrome, and it may deteriorate hemodynamics condition. Therefore, termination and prevention of atrial fibrillation is another important issue in acute coronary syndrome. Aprindine, amiodarone, or bepridil will be the choice to prevent recurrent atrial fibrillation after direct current cardioversion.

Topics: Amiodarone; Angina, Unstable; Anti-Asthmatic Agents; Aprindine; Atrial Fibrillation; Bepridil; Electric Countershock; Humans; Myocardial Infarction; Potassium Channel Blockers; Pyrimidinones; Recurrence; Syndrome; Tachycardia, Ventricular; Ventricular Fibrillation

In recent clinical trials, class III anti-arrhythmic drugs were found to reduce arrhythmic deaths in patients after myocardial infarction. The purpose of this study was to assess the electrophysiologic properties and anti-arrhythmic efficacy for inducible sustained ventricular tachycardias (VTs) of the pure class III agent nifekalant hydrochloride (MS-551) in comparison with those of procainamide. Programmed ventricular stimulation of up to three extra stimuli was performed for induction of VTs. Effective refractory period (ERP) of the ischemic zone and normal zone was also measured before and after nifekalant. Nifekalant and procainamide suppressed sustained VT induction in four of 15 patients and in six of 15 patients, respectively (p = NS). Sinus cycle length, PR interval, and QRS duration were not changed, but QT and QTc intervals were significantly increased with nifekalant (p < 0.01). Ventricular ERP also increased, whereas there were no significant differences in the increase of ERP between the ischemic and normal zones. The suppression of VT induction did not correlate with the changes in QT, QTc, and ERP after nifekalant administration. There were no significant differences in induced VT cycle length at baseline study between responders and nonresponders to nifekalant. Reverse use dependence was not apparent on review of electrophysiologic parameters. Neither proarrhythmic events nor hemodynamic disturbances occurred after nifekalant administration. It was concluded that nifekalant could be used safely and showed comparable effectiveness to procainamide for the suppression of VT induction.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Electrocardiography; Electrophysiology; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Procainamide; Pyrimidinones; Tachycardia, Ventricular

To explore the influence of micro ribonucleic acid (miR)-154 on myocardial apoptosis in rats with acute myocardial infarction (AMI), and to analyze whether Wnt/β-catenin signaling pathway was involved in the regulation.. The Sprague-Dawley (SD) rat model of AMI was established via ligation of left anterior descending artery. Rats were randomly divided into model group (M group, n=12) and ICG-001 intervention group (I group, n=12). At the same time, sham operation group (S group, n=12) was established. In I group, ICG-001 (5 mg/kg) was intraperitoneally injected every day after operation. Meanwhile, an equal amount of normal saline was injected in rats of S group and M group. 21 d after operation, the cardiac function of rats in each group was detected via echocardiography. After that, the rats were immediately executed. MI area in each group was detected via 2,3,5-triphenyltetrazolium chloride (TTC) staining. Myocardial apoptosis level in each group was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Moreover, the changes of apoptotic proteins in rat myocardial cells were detected via Western blotting. Moreover, the expression level of miR-154 in myocardial cells of rats was detected via quantitative polymerase chain reaction (qPCR). Furthermore, the influence of miR-154 on Wnt/β-catenin signaling pathway was detected via Western blotting.. Compared with S group, left ventricular ejection fraction (LVEF, %) and left ventricular fractional shortening (LVFS, %) were significantly decreased in M group (p<0.01). However, left ventricular internal diameter at end-diastole (LVIDd) and left ventricular internal diameter at end-systole (LVIDs) were significantly increased (p<0.01). In I group, LVEF (%) and LVFS (%) were significantly higher than those of M group (p<0.05), whereas LVIDs and LVIDd were significantly lower (p<0.05). MI area in M group was remarkably larger than that of S group (p<0.01). Meanwhile, MI area in I group was significantly smaller than that of M group (p<0.01). Compared with S group, the number of apoptotic myocardial cells and the protein expression level of cleaved caspase-3 were significantly increased in M group (p<0.01). However, the expression level of B-cell lymphoma-2/Bcl-2 associated X protein (Bcl-2/Bax) was significantly decreased (p<0.01). The number of apoptotic myocardial cells and the protein expression level of cleaved caspase-3 were significantly declined in I group when compared with those of M group (p<0.01). However, the expression level of Bcl-2/Bax was significantly increased in I group (p<0.01). The expression level of miR-154 in myocardial cells of M group and I group was remarkably increased when compared with that of S group (p<0.01). Furthermore, the expression levels of β-catenin and Cyclin D1 in myocardial cells of M group were remarkably higher than those of S group and I group (p<0.01).. AMI significantly increases the expression level of miR-154. Moreover, miR-154 can activate Wnt/β-catenin signaling pathway, eventually promoting myocardial apoptosis.

Topics: Animals; Apoptosis; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; MicroRNAs; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Pyrimidinones; Rats; Rats, Sprague-Dawley; Stroke Volume; Ventricular Function, Left; Wnt Proteins; Wnt Signaling Pathway

Treatment of myocardial infarction within the first 1 to 2 hours with a thrombolytic agent, percutaneous coronary intervention, or an αIIbβ3 antagonist decreases mortality and the later development of heart failure. We previously reported on a novel small molecule αIIbβ3 antagonist, RUC-2, that has a unique mechanism of action. We have now developed a more potent and more soluble congener of RUC-2, RUC-4, designed to be easily administered intramuscularly by autoinjector to facilitate its use in the prehospital setting. Here, we report the properties of RUC-4 and the antiplatelet and antithrombotic effects of RUC-2 and RUC-4 in animal models.. RUC-4 was ≈ 20% more potent than RUC-2 in inhibiting human ADP-induced platelet aggregation and much more soluble in aqueous solutions (60-80 mg/mL). It shared RUC-2's specificity for αIIbβ3 versus αVβ3, did not prime the receptor to bind fibrinogen, or induce changes in β3 identified by a conformation-specific monoclonal antibody. Both RUC-2 and RUC-4 prevented FeCl3-induced thrombotic occlusion of the carotid artery in mice and decreased microvascular thrombi in response to laser injury produced by human platelets infused into transgenic mice containing a mutated von Willebrand factor that reacts with human but not mouse platelets. Intramuscular injection of RUC-4 in nonhuman primates at 1.9 and 3.85 mg/kg led to complete inhibition of platelet aggregation within 15 minutes, with dose-dependent return of platelet aggregation after 4.5 to 24 hours.. RUC-4 has favorable biochemical, pharmacokinetic, pharmacodynamic, antithrombotic, and solubility properties as a prehospital therapy of myocardial infarction, but the possibility of increased bleeding with therapeutic doses remains to be evaluated.

Topics: Animals; Binding Sites; Blood Platelets; Carotid Stenosis; Chlorides; Disease Models, Animal; Emergency Medical Services; Ferric Compounds; Fibrinolytic Agents; Humans; Macaca fascicularis; Male; Mice; Mice, Transgenic; Molecular Dynamics Simulation; Myocardial Infarction; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Binding; Protein Conformation; Pyrimidinones; Solubility; Thiadiazoles; Thrombosis; von Willebrand Factor

Topics: Animals; Blood Platelets; Carotid Stenosis; Emergency Medical Services; Fibrinolytic Agents; Humans; Male; Myocardial Infarction; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pyrimidinones; Thiadiazoles; Thrombosis

The adult mammalian heart has limited capability for self-repair after myocardial infarction. Therefore, therapeutic strategies that improve post-infarct cardiac function are critically needed. The small molecule ICG-001 modulates Wnt signaling and increased the expression of genes beneficial for cardiac regeneration in epicardial cells. Lineage tracing experiments, demonstrated the importance of β-catenin/p300 mediated transcription for epicardial progenitor contribution to the myocardium. Female rats given ICG-001 for 10 days post-occlusion significantly improved ejection fraction by 8.4%, compared to controls (P<0.05). Taken together, Wnt modulation via β-catenin/CBP inhibition offers a promising therapeutic strategy towards restoration of myocardial tissues and an enhancement of cardiac functions following infarction.

Topics: Animals; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation; Growth Differentiation Factor 15; Muscle Contraction; Myoblasts, Cardiac; Myocardial Infarction; Myocardium; Paracrine Communication; Pericardium; Proto-Oncogene Proteins c-kit; Pyrimidinones; Rats; Regeneration; Wnt Signaling Pathway

An "electrical storm" is a life-threatening condition defined as a recurrent attack of ventricular tachycardia or fibrillation. The current report is a case study of a patient who had electrical storms developing unexpectedly after undergoing coronary artery bypass grafting. The electrical storms were terminated dramatically by the administration of nifekalant hydrochloride. We suggest that nifekalant hydrochloride has great therapeutic potential for the suppression of intractable ventricular tachyarrhythmias refractory to amiodarone.

Topics: Aged; Anti-Arrhythmia Agents; Coronary Angiography; Coronary Artery Bypass; Coronary Stenosis; Follow-Up Studies; Humans; Infusions, Intravenous; Male; Myocardial Infarction; Postoperative Complications; Pyrimidinones; Severity of Illness Index; Tachycardia, Ventricular; Treatment Outcome

Omi/HtrA2 is a mitochondrial serine protease that has a dual function: while confined in the mitochondria, it promotes cell survival, but when released into the cytoplasm, it participates in caspase-dependent as well as caspase-independent cell death. To investigate the mechanism of Omi/HtrA2's function, we set out to isolate and characterize novel substrates for this protease. We have identified Thanatos-associated protein 5 (THAP5) as a specific interactor and substrate of Omi/HtrA2 in cells undergoing apoptosis. This protein is an uncharacterized member of the THAP family of proteins. THAP5 has a unique pattern of expression and is found predominantly in the human heart, although a very low expression is also seen in the human brain and muscle. THAP5 protein is localized in the nucleus and, when ectopically expressed, induces cell cycle arrest. During apoptosis, THAP5 protein is degraded, and this process can be blocked using a specific Omi/HtrA2 inhibitor, leading to reduced cell death. In patients with coronary artery disease, THAP5 protein levels substantially decrease in the myocardial infarction area, suggesting a potential role of this protein in human heart disease. This work identifies human THAP5 as a cardiac-specific nuclear protein that controls cell cycle progression. Furthermore, during apoptosis, THAP5 is cleaved and removed by the proapoptotic Omi/HtrA2 protease. Taken together, we provide evidence to support that THAP5 and its regulation by Omi/HtrA2 provide a new link between cell cycle control and apoptosis in cardiomyocytes.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Nucleus; Cisplatin; Coronary Artery Disease; DNA-Binding Proteins; Gene Expression Regulation, Enzymologic; HeLa Cells; High-Temperature Requirement A Serine Peptidase 2; Homeostasis; Humans; Hydrogen Peroxide; Kidney; Mitochondria, Heart; Mitochondrial Proteins; Myocardial Infarction; Myocardium; Nuclear Proteins; Oxidants; Pyrimidinones; RNA, Messenger; Serine Endopeptidases; Substrate Specificity; Thiones; Transfection; Two-Hybrid System Techniques; Yeasts

High temperature requirement A2 (HtrA2)/Omi is a mitochondrial serine protease that is released into the cytosol from mitochondria and in turn promotes caspase activation by proteolyzing inhibitor of apoptosis proteins. Here we asked whether treatment with an HtrA2/Omi inhibitor, 5-[5-(2-nitrophenyl)furfuryliodine]-1,3-diphenyl-2-thiobarbituric acid (UCF-101), restores heart dysfunction following ischemia/reperfusion injury in vivo. Rats underwent a 30-min ischemia by occluding the left anterior descending artery, followed by 24 h reperfusion. UCF-101 (0.75 or 1.5 micromol/kg, i.p.) was administered 10 min before reperfusion. UCF-101 treatment significantly recovered the mean arterial blood pressure and ameliorated contractile dysfunction of the left ventricle 72 h after reperfusion with concomitant reduction of infarct size. Cardio-protection mediated by UCF-101 was correlated with reduced X-linked inhibitor of apoptosis protein (XIAP) degradation and inhibition of Caspase-9, Caspase-3, and Caspase-7 processing. Furthermore, UCF-101 prevented loss of membrane integrity by inhibiting fodrin breakdown in cardiomyocytes. UCF-101-induced cytoprotection was also correlated with reduced Fas ligand expression and inhibition of FLIP degradation following ischemia/reperfusion. These results suggest that UCF-101 rescues cardiomyocytes from ischemia/reperfusion injury by inhibiting XIAP degradation and Fas/Fas-ligand-induced apoptosis, thereby ameliorating ischemia/reperfusion-induced myocardial dysfunction.

Topics: Animals; Blood Pressure; Cardiotonic Agents; Carrier Proteins; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase Inhibitors; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Fas Ligand Protein; Heart; High-Temperature Requirement A Serine Peptidase 2; Kinetics; Male; Microfilament Proteins; Mitochondrial Proteins; Models, Cardiovascular; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Nerve Tissue Proteins; Pyrimidinones; Rats; Rats, Sprague-Dawley; RNA-Binding Proteins; Serine Endopeptidases; Serine-Arginine Splicing Factors; Thiones; Ventricular Dysfunction, Left; X-Linked Inhibitor of Apoptosis Protein

A 75-year-old female complained of severe chest pain and was emergently admitted to our hospital because of anterior acute myocardial infarction. Emergent coronary angiography was performed and revealed occlusion in segment 7, so a stent was implanted. Lidocaine, carvedilol, amiodarone, magnesium, and nifekalant were administered successively because non-sustained ventricular tachycardia (NSVT) frequently appeared like an electrical storm. After nifekalant administration, QTc was significantly prolonged and torsades de pointes was induced. Overdrive pacing was performed and finally the NSVT was completely controlled. If fatal arrhythmias such as NSVT show resistance to medication, overdrive pacing should be considered to stabilize the arrhythmia associated with acute coronary syndrome.

Topics: Acute Coronary Syndrome; Aged; Anti-Arrhythmia Agents; Cardiac Pacing, Artificial; Drug Resistance; Female; Humans; Myocardial Infarction; Pyrimidinones; Stents; Tachycardia, Ventricular; Treatment Outcome

Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent as well as caspase-independent cell death. However, the role of Omi/HtrA2 in the apoptotic cell death that occurs in vivo under pathological conditions remains unknown. The present study was designed to investigate whether Omi/HtrA2 plays an important role in postischemic myocardial apoptosis.. Male adult mice were subjected to 30 minutes of myocardial ischemia followed by reperfusion and treated with vehicle or ucf-101, a novel and specific Omi/HtrA2 inhibitor, 10 minutes before reperfusion. Myocardial ischemia/reperfusion significantly increased cytosolic Omi/HtrA2 content and markedly increased apoptosis. Treatment with ucf-101 exerted significant cardioprotective effects, as evidenced by less terminal dUTP nick end-labeling staining, a lower incidence of DNA ladder fragmentation, and smaller infarct size. Furthermore, treatment with ucf-101 before reperfusion attenuated X-linked inhibitor of apoptosis protein degradation and inhibited caspase-9 and caspase-3 activities.. Taken together, these results demonstrate for the first time that ischemia/reperfusion results in Omi/HtrA2 translocation from the mitochondria to the cytosol, where it promotes cardiomyocyte apoptosis via a protease activity-dependent, caspase-mediated pathway.

Topics: Animals; Apoptosis; Cardiotonic Agents; Caspase 3; Caspase 9; Caspase Inhibitors; Caspases; Cysteine Proteinase Inhibitors; Cytosol; High-Temperature Requirement A Serine Peptidase 2; Male; Mice; Mitochondria, Heart; Mitochondrial Proteins; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Protein Transport; Proteins; Pyrimidinones; Serine Endopeptidases; Thiones; X-Linked Inhibitor of Apoptosis Protein

Nifekalant hydrocholoride, a novel class III antiarrhythmic agent, was used as the treatment in 4 patients with extensive anterior infarction and severe ventricular dysfunction. The malignant ventricular tachyarrhythmia was effectively suppressed at a relatively low dose, without compromising the hemodynamics, indicating that this potent K+ channel blocker has therapeutic potential for acute myocardial infarction.

Topics: Aged; Anti-Arrhythmia Agents; Electrocardiography; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Potassium Channel Blockers; Pyrimidinones; Tachycardia; Ventricular Dysfunction

Pure class III antiarrhythmic agents cause reverse use-dependent QT prolongation. Nifekalant is a new class III antiarrhythmic agent and blocks rapid component of the delayed rectifier K+ current (Ikr) selectively. To prevent recurrent ventricular tachycardia in a patient with old myocardial infarction, nifekalant was administered by continuous intravenous infusion. There was little variation in the blood level of nifekalant during the 1-day period, but the QTc interval became shorter with an increase of the heart rate early in the morning. It is therefore considered advisable to monitor the heart rate and QTc interval during administration of nifekalant by continuous intravenous infusion.

Topics: Anti-Arrhythmia Agents; Electrocardiography; Heart Ventricles; Humans; Infusions, Intravenous; Male; Middle Aged; Myocardial Infarction; Pyrimidinones; Tachycardia, Ventricular

Topics: Angioplasty, Balloon, Coronary; Anti-Arrhythmia Agents; Coronary Angiography; Electric Countershock; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Pyrimidinones; Stents; Ventricular Fibrillation

Uncontrollable arrhythmia is one of the causes of operative death in CABG. We report two cases of successful treatment of recurrent VT/Vf in CABG operation by MS-551. One case was a 72-year-old male, who had unstable angina and OMI with left ventricular dysfunction (LVEF 24%). After weaning from CPB, the rhythm turned into VT/Vf suddenly. Lidocaine and verapamil were not effective. VT/Vf recurred over the over. The another case was a 52-year-old male, who had OMI and effort angina. He became myocardial infarction during operation. VT/Vf occurred after the weaning from CPB. Lidocaine and amiodarone were of no effect on his VT/Vf. In both cases, intravenous injection of MS-551 promptly stopped VT/Vf. Use of MS-551 was limited mainly on DCM patients. But other antiarrhythmic agents were ineffective on these cases. We have had to continue support circulation for a long time without MS-551. As MS-551 is being used as a trial on medically followed patients, it was unknown how effective clinically on the acute myocardial infarction. In this regard, our cases may suggest a positive answer to that.

Topics: Aged; Angina, Unstable; Anti-Arrhythmia Agents; Cardiopulmonary Bypass; Coronary Artery Bypass; Humans; Intraoperative Care; Male; Middle Aged; Myocardial Infarction; Pyrimidinones

We studied the electrophysiologic and antifibrillatory properties of MS-551 (1,3-dimethyl-6-((2-[N-hydroxy-ethyl)-3-(4-nitrophenyl) propylamino] ethylamino) 2,4(1H,3H) pyrimidinedione hydrochloride) in a conscious canine model of sudden cardiac death. Three to 5 days after surgically induced myocardial infarction (MI: 2-h occlusion of the left anterior descending coronary artery, LAD), animals were subjected to programmed electrical stimulation (PES) to identify those at risk for sudden cardiac death. MS-551 was administered (2.0, 3.0, or 4 x 2.0 mg/kg intravenously, i.v.). Vehicle-treated animals received 0.9% sodium chloride solution for injection. MS-551 (multiple-dose regimen) increased ventricular effective refractory period (VERP) from 112 +/- 4 to 137 +/- 4 ms (p < 0.05) as compared with vehicle treatment, which did not alter VERP (125 +/- 6 to 121 +/- 5 ms). MS-551 prolonged QTc interval from a predrug value of 293 +/- 8 to 333 +/- 18 ms postdrug. The size of surgically induced MI did not differ among groups: 2.0 mg/kg, 23 +/- 4%; 3.0 mg/kg, 28 +/- 2%; 4 x 2.0 mg/kg, 25 +/- 3%; and vehicle, 28 +/- 3% of the left ventricle. Single bolus administration of MS-551 (2.0 or 3.0 mg/kg i.v.) did not confer significant protection against sudden cardiac death. However, repeated administration of MS-551 protected against sudden cardiac death in 8 of 10 dogs as compared with 2 of 12 in the vehicle-treated group (p < 0.05). The data indicate that a multiple-dose regimen of MS-551 provides protection against ischemia-induced ventricular fibrillation (VF) in the postinfarcted heart. The mechanism by which MS-551 achieves its antifibrillatory effect most likely depends on its ability to prolong VERP of myocardium without altering ventricular conduction velocity.

Topics: Animals; Anti-Arrhythmia Agents; Chromatography, High Pressure Liquid; Death, Sudden, Cardiac; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Electric Stimulation; Electrocardiography; Electrophysiology; Male; Myocardial Infarction; Pyrimidinones; Random Allocation; Ventricular Fibrillation

We examined the effects of MS-551 (1,3-dimethyl-6-[(2-[N-(2-hydroxyethyl)-3-(4- nitrophenyl)propylamino]ethylamino] 2,4(1H,3H)-pyrimidinedione hydrochloride), a new class III antiarrhythmic drug, on programmed electrical stimulation (PES)-induced ventricular arrhythmias, the effective refractory period (ERP), intraventricular conduction, and hemodynamics in a canine myocardial infarction (MI) model. MS-551 was administered intravenously (i.v.) in two consecutive doses; the first dose (low dose) was 0.5 mg/kg/min after a bolus injection of 0.3 mg/kg, and a second dose (high dose) was 0.1 mg/kg/min after a bolus injection of 0.3 mg/kg. PES induced ventricular tachycardia (VT) or ventricular fibrillation (VF) in 10 of 12 animals. MS-551 abolished or lessened the ventricular arrhythmias in 7 of 10 animals at both doses. ERP was significantly prolonged by MS-551 in both the normal and infarcted zones in a dose-dependent fashion. Ventricular conduction of a premature excitation induced by a premature stimulation with various coupling intervals was decreased only at a coupling interval approximating that of ERP. MS-551 at either low or high dose did not significantly change the heart rate (HR), mean blood pressure (MBP), cardiac output (CO), or maximum rate of increase in left ventricular pressure (LVP) significantly. MS-551 produced a suppression of the PES-induced ventricular arrhythmias through prolongation of ERP without having any significant effect on hemodynamics in a canine MI model.

Topics: Animals; Anti-Arrhythmia Agents; Disease Models, Animal; Dogs; Electrocardiography; Hemodynamics; Myocardial Infarction; Pyrimidinones; Refractory Period, Electrophysiological; Tachycardia, Ventricular

Topics: Adult; Aged; Coronary Disease; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Myocardial Infarction; Pyrimidinones

Topics: Angina Pectoris; Humans; Myocardial Infarction; Pyrimidinones