thiourea and Coronary-Disease

There is increasing evidence for a fatal interaction of myocardial ischemia, ventricular arrhythmias and sudden cardiac death in some patients with coronary artery disease. Evidence comes from autopsy studies, from the evaluation of patients who survived an episode of sudden cardiac death, from follow-up data of these patients either treated or not by revascularization therapy and/or an implantable cardioverter-defibrillator and indicate that reducing the individual ischemic burden will be beneficial to reduce the incidence of sudden cardiac death. Studies in patients with stable and especially with unstable angina using Holter monitoring could demonstrate that there is a close and causal relationship between myocardial ischemia inducing or aggravating life-threatening ventricular arrhythmias and sudden cardiac death particularly in patients with unstable and postinfarction status. This review summarizes some of our clinical knowledge on this topic and indicates that preventive strategies for myocardial ischemia are the antiarrhythmic treatment of choice in patients with severe coronary artery disease and patients with evidence or at risk for ischemic proarrhythmia.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Autopsy; Blood Coagulation; Coronary Disease; Death, Sudden, Cardiac; Defibrillators, Implantable; Electrocardiography; Humans; Ligation; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Myocardial Revascularization; Potassium Channel Blockers; Risk; Risk Factors; Sulfonamides; Tachycardia, Ventricular; Thiourea; Time Factors

Previous studies have suggested an association of hyperhomocysteinemia-induced vascular pathology with enhanced apoptotic potential of endothelial progenitor cells in patients with coronary heart disease. Our results indicate that 500 µmol/L homocysteine induced endothelial progenitor cell apoptosis and activation of caspase-3, both of which were abolished by 100 µmol/L and 200 µmol/L salubrinal, an agent that prevents endoplasmic reticulum stress-induced apoptosis. The addition of 500 µmol/L homocysteine caused a release of Ca(2+) from intracellular stores, and enhanced phosphor-eukaryotic initiation factor 2α phosphorylation at Ser51 and the expression of a glucose-regulated protein of 78 kDa and a C/EBP homologous protein independently of extracellular Ca(2+). These effects of homocysteine on endothelial progenitor cells were significantly greater in patients with coronary heart disease than in healthy donors. These findings suggest that homocysteine induces endoplasmic reticulum stress-mediated activation of caspase-3 in endothelial progenitor cells, an event that is enhanced in patients with coronary heart disease. Furthermore, enhanced endoplasmic reticulum stress-mediated activation of caspase-3 in endothelial progenitor cells might be involved in hyperhomocysteinemia-associated vascular pathology.

Topics: Animals; Apoptosis; Blood Donors; Calcium Signaling; Caspase 3; Cell Line; Cinnamates; Coronary Disease; Endoplasmic Reticulum; Endothelial Cells; Homocysteine; HSP70 Heat-Shock Proteins; Humans; Male; Membrane Proteins; Oxidative Stress; Phosphorylation; Stem Cells; Thiourea

ATP-sensitive potassium (K(ATP)) channels are activated during myocardial ischemia. The ensuing potassium efflux leads to a shortening of the action potential duration and depolarization of the membrane by accumulation of extracellular potassium favoring the development of reentrant arrhythmias, including ventricular fibrillation. The sulfonylthiourea HMR 1883 was designed as a cardioselective blocker of myocardial K(ATP) channels for the prevention of arrhythmic sudden death in patients with ischemic heart disease. We investigated the effect of HMR 1883 on sudden cardiac arrhythmic death and electrocardiography (ECG) changes induced by 20 min of left anterior descending coronary artery occlusion in pentobarbital-anesthetized pigs. HMR 1883 (3 mg/kg i.v.) protected pigs from arrhythmic death (91% survival rate versus 33% in control animals; n = 12; p<.05). Ischemic areas were of a similar size. The compound had no effect on hemodynamics and ECG, including Q-T interval, under baseline conditions and no effect on hemodynamics during occlusion. In control animals, left anterior descending coronary artery occlusion lead to a prompt and significant depression of the S-T segment (-0.35 mV) and a prolongation of the Q-J time (+46 ms), the former reflecting heterogeneity in the plateau phase of the action potentials and the latter reflecting irregular impulse propagation and delayed ventricular activation. Both ischemic ECG changes were significantly attenuated by HMR 1883 (S-T segment, -0.14 mV; Q-J time, +15 ms), indicating the importance of K(ATP) channels in the genesis of these changes. In conclusion, the K(ATP) channel blocker HMR 1883, which had no effect on hemodynamics and ECG under baseline conditions, reduced the extent of ischemic ECG changes and sudden death due to ventricular fibrillation during coronary occlusion.

Topics: Anesthesia; Animals; Arrhythmias, Cardiac; Coronary Disease; Death, Sudden, Cardiac; Electrocardiography; Hemodynamics; Myocardial Ischemia; Potassium; Sulfonamides; Swine; Thiourea

The role of oxygen-derived free radicals as initiators of vascular dysfunction observed 24 hr after transient coronary artery occlusion (15 or 30 min) was examined in the anesthetized dog. A 15-min occlusion increased human serum (HSA) albumin extravasation within anterior myocardium without producing myocardial necrosis or edema. Minimal leukocyte uptake and free radical formation were present at 24 hr. 2-Mercaptoproprionyl glycine (MPG) (a free radical scavenger), deferoxamine (a chelator of ferrous ions) and dimethylthiourea (a hydroxyl ion scavenger), administered 15 min before coronary artery occlusion and extending 1.5 hr into reperfusion, reduced HSA uptake within anterior myocardium. A different pattern of injury was present after a 30-min occlusion. Subendocardial necrosis (1.2 +/- 0.8 g), edema, HSA extravasation and leukocyte uptake were observed at 24 hr. MPG failed to reduce the extent of necrosis, HSA extravasation, edema, leukocyte uptake or free radical formation. HSA extravasation, leukocyte uptake, tissue edema and free radical formation present 24 hr after a 30-min occlusion were reduced by acute deferoxamine and dimethylthiourea, but not by acute MPG administration. The failure of MPG to reduce HSA extravasation observed 24 hr after a 30-min coronary artery occlusion was associated with both leukocyte uptake and continued free radical formation, whereas dimethylthiourea and deferoxamine reduced leukocyte uptake, free radical formation and HSA extravasation.

Topics: Animals; Capillary Permeability; Coronary Disease; Coronary Vessels; Deferoxamine; Dogs; Lipid Peroxidation; Myocardial Reperfusion Injury; Myocardium; Reactive Oxygen Species; Serum Albumin; Thiourea; Time Factors; Tiopronin

This study examined the effect of treatment with dimethylthiourea (DMTU), a highly cell-permeable scavenger of hydroxyl radicals, on tissue necrosis in rabbit hearts during myocardial ischemia and reperfusion. Sixty-two rabbits underwent 45 minutes of coronary occlusion with, or without, coronary reperfusion for 3 hours. A saline vehicle, or DMTU (500 mg/kg intravenously [iv]) was administered over 45 minutes starting either 10 minutes before or 10 minutes after coronary occlusion, or 10 minutes before coronary reperfusion. Anatomic risk zone size was assessed using microsphere autoradiography, and the area of necrosis was determined using tetrazolium staining. Cardiac hemodynamics and risk zone size were similar for all treatment groups. No differences were observed in the extent of tissue necrosis (normalized to risk zone size) for saline- and DMTU-treated rabbits subjected to 45 minutes (61.2 +/- 23.1% vs. 70.6 +/- 16.5%) or 225 minutes (82.8 +/- 5.4% vs. 78.3 +/- 5.9%) of permanent coronary occlusion without reperfusion. Similarly, tissue necrosis in rabbits with 45 minutes coronary occlusion followed by 3 hours reperfusion was not significantly reduced when DMTU was administered either 10 minutes before coronary occlusion, 10 minutes after coronary occlusion, or 10 minutes before coronary reperfusion (67.0 +/- 9.9%; 57.6 +/- 10.6%; 68.3 +/- 13.3%) compared to saline-treated controls (76.6 +/- 10.5%). These results demonstrate that the hydroxyl radical scavenger DMTU does not appear to influence the progression of myocyte injury in this experimental model of acute myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Coronary Disease; Hemodynamics; Male; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Necrosis; Rabbits; Thiourea

The effects of palmitate on mechanical failure of ischemic hearts were studied in acutely (48-hour) and chronically (6-week) streptozotocin diabetic rats. Coronary flow was reduced by 50% in isolated working hearts perfused at a 15 cm H2O preload and 100 mm Hg afterload by the one-way ball valve model of ischemia. Peak systolic pressure (PSP) and cardiac output (CO) decreased 40% by 4 minutes in control hearts perfused with 11 mM glucose and paced at 280 beats/min, compared with 50% in hearts from acutely diabetic rats. Addition of 1.2 mM palmitate to the perfusate accelerated failure rates, with PSP and CO decreasing 65% and 80% by 4 minutes in control and acutely diabetic rat hearts, respectively. In chronically diabetic rats, mechanical function could not be maintained in palmitate-perfused hearts paced at 280 beats/min, even in the absence of ischemia. If these hearts were paced at 250 beats/min and subjected to ischemia, PSP and CO decreased 90% by 4 minutes, regardless of whether palmitate was added to the perfusate. Under these conditions, PSP decreased less than 10% by 4 minutes in both palmitate- or glucose-perfused control hearts. Etomoxir (10(-9) M), a carnitine palmitoyltransferase I inhibitor, markedly decreased the rate of mechanical failure in both acutely and chronically diabetic rat hearts, in the presence and absence of palmitate. The beneficial effect of Etomoxir on mechanical function did not occur as a result of a decrease in either myocardial long chain acyl-coenzyme A or long chain acylcarnitine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Acyl Coenzyme A; Acyltransferases; Animals; Carnitine O-Palmitoyltransferase; Chronic Disease; Coronary Disease; Diabetes Mellitus, Experimental; Epoxy Compounds; Fatty Acids; Heart; In Vitro Techniques; Male; Myocardium; Phosphocreatine; Rats; Rats, Inbred Strains; Streptozocin; Thiourea

Although the presence of free radicals has been indicated in ischemic-reperfused heart, the exact nature and source of these free radicals are not known. The present study utilized a chemical trap, salicylic acid, to trap hydroxyl radical which could be detected as hydroxylated benzoic acid using high pressure liquid chromatography. Since the hydroxylated product is extremely stable, heart was subjected to subcellular fractionation after ischemia and reperfusion, and each fraction was separately examined for the presence of hydroxyl radical. The results indicated for the first time the presence of hydroxyl radical in the mitochondrial fraction during early reperfusion, which decreased in intensity as the reperfusion progressed.

Topics: Animals; Catalase; Chromatography, High Pressure Liquid; Coronary Disease; Dimethyl Sulfoxide; Free Radicals; Hydroxides; Hydroxyl Radical; Male; Mitochondria, Heart; Myocardial Reperfusion; Rats; Rats, Inbred Strains; Salicylates; Salicylic Acid; Superoxide Dismutase; Thiourea

Three lines of investigation indicated that hydrogen peroxide (H2O2) from xanthine oxidase (XO) contributes to cardiac dysfunction during reperfusion after ischemia. First, addition of dimethylthiourea (DMTU), a highly permeant O2 metabolite scavenger (but not urea) simultaneously with reperfusion improved recovery of ventricular function as assessed by ventricular developed pressure (DP), contractility (+dP/dt), and relaxation rate (-dP/dt) in isolated Krebs-Henseleit-perfused rat hearts subjected to global normothermic ischemia. Second, hearts from rats fed tungsten or treated with allopurinol had negligible XO activities (less than 0.5 mU/g wet myocardium compared with greater than 6.0 mU/g in control hearts) and increased ventricular function after ischemia and reperfusion. Third, myocardial H2O2-dependent inactivation of catalase occurred after reperfusion following ischemia, but not after ischemia without reperfusion or perfusion without ischemia. In contrast, myocardial catalase did not decrease during reperfusion of ischemic hearts treated with DMTU, tungsten, or allopurinol.

Topics: Allopurinol; Amitrole; Catalase; Coronary Disease; Hydrogen Peroxide; In Vitro Techniques; Myocardium; Perfusion; Thiourea; Tungsten; Urea; Xanthine Oxidase

The mechanism for the prolonged contractile dysfunction observed in myocardium reperfused after reversible regional ischemia ("stunned" myocardium) is unclear. Recent studies suggest that myocardial stunning may be mediated by oxygen-derived free radicals, but the precise molecular species involved remain unknown. Thus we explored the role of the highly cytotoxic hydroxyl radical in regional postischemic dysfunction by using dimethylthiourea (DMTU), an effective and highly permeable hydroxyl radical scavenger. Open-chest dogs undergoing a 15 min occlusion of the left anterior descending coronary artery followed by 4 hr of reperfusion received either DMTU (0.5 g/kg iv over 45 min starting 30 min before occlusion, n = 14) or saline (n = 15). Control and treated dogs were comparable with respect to variables that may affect postischemic dysfunction, including heart rate, aortic pressure, left atrial pressure, arterial blood gases and hemoglobin concentration, size of the occluded bed (determined by postmortem perfusion), and collateral blood flow (determined by radioactive microspheres). Regional myocardial function was assessed by measuring wall thickening with an epicardial Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions and similar degrees of dyskinesis during ischemia. After reperfusion, however, wall thickening (expressed as percent of baseline) was considerably greater in treated as compared with control dogs: 53 +/- 9% (mean +/- SEM) vs 9 +/- 14% (p less than .03) at 1 hr, 55 +/- 9% vs 23 +/- 13% (p less than .05) at 2 hr, 60 +/- 9% vs 28 +/- 14% (p less than .05) at 3 hr, and 67 +/- 5% vs 36 +/- 13% (p less than .05) at 4 hr. Thus DMTU produced a significant and sustained improvement in recovery of contractile function. In concentrations greater than the plasma levels attained in vivo, DMTU did not scavenge either hydrogen peroxide or superoxide anion in vitro. These results suggest that the myocardial dysfunction occurring after a brief episode of regional ischemia is mediated in part by the hydroxyl radical.

Topics: Animals; Coronary Circulation; Coronary Disease; Dogs; Female; Heart; Male; Myocardial Contraction; Thiourea

Histamine is released into the systemic circulation during anaphylaxis, by drugs and surgical procedures. Studies in animal models have shown that released histamine is one of the major mediators of arrhythmia occurring during anaphylaxis or the administration of histamine-releasing drugs. The variations in plasma histamine levels in dogs with a subacute coronary thrombosis were investigated and the effects of dimaprit and cimetidine on the electrocardiographic consequence of this thrombosis and on histamine release were assessed. During the first day after the myocardial infarction a ventricular arrhythmia developed and plasma histamine levels were found significantly increased, returning to the basal values when the sinusal rhythm was restored. Dimaprit was able to decrease the number of ventricular extrasystoles and to modulate plasma histamine levels. The action of dimaprit on ECG was not reversed by pretreatment with cimetidine, which on the contrary was able to antagonize the decrease in plasma histamine concentrations induced by dimaprit perfusion.

Topics: Animals; Cimetidine; Coronary Disease; Dimaprit; Dogs; Feedback; Female; Histamine Release; Male; Thiourea; Wakefulness

Recovery of high-energy compounds by ischemic myocardium is believed to be important for its return to normal functioning. While it has been previously shown that oxidative phosphorylation is markedly reduced in mitochondria isolated from ischemic myocardium in the presence of all substrates, alterations in ATPase activity have not been confirmed. This study demonstrates that, although the rate of ATP hydrolysis produced by mitochondria isolated from 2-hr ischemic myocardium does not significantly differ from that produced by non-ischemic mitochondria, the rate produced by 2-hr ischemic, 2 hr reperfused mitochondria is significantly higher. Also, Ca++ content was observed to be higher in reperfused than in non-reperfused ischemic mitochondria. The addition of EDTA, EGTA, or oligomycin to the reperfused ischemic mitochondria resulted in the inhibition of ATPase activity. These results indicate that mitochondrial ATPase in ischemic myocardium is activated by Ca++ ions and that ischemic reperfused myocardium may contain mitochondria with uncontrolled ATPase activity such that high energy phosphate supplies are excessively depleted when the cells are reperfused.

Topics: Adenosine Triphosphatases; Animals; Coronary Disease; Edetic Acid; Egtazic Acid; Hydrolysis; Mitochondria, Heart; Oxidative Phosphorylation; Perfusion; Swine; Thiourea; Time Factors

In acute myocardial ischemia of dogs glycogen is mobilized most completely and its break down products are utilized most efficaciously after administration of izatin rather than after gamma-hydroxybutyric acid (GABA) and guthymin. Izatin potentiates a beneficial effect of GABA on myocardial energy efficiency.

Topics: Animals; Coronary Disease; Dogs; Energy Metabolism; gamma-Aminobutyric Acid; Glycerolphosphate Dehydrogenase; Glycogen; Guanylthiourea; Indoles; Isatin; L-Lactate Dehydrogenase; Male; Myocardium; NADPH Dehydrogenase; Phosphorylase a; Phosphorylase b; Succinate Dehydrogenase; Thiourea

Topics: Coronary Disease; Female; Humans; Indicators and Reagents; Male; Thiones; Thiourea

Using iodine-azide method, it was possible first to quantify the concentration and amount of the excretion of thiamine compounds in the diurnal urine of patients. The concentration of thioketones in human urine is shown to be 11--15 mg equivalents of thiourea per 1 ml urine, that is an order of magnitude lower than the threshold of sensitivity of the reaction with selenonic acid. It was found that the amount of thioketones excretion per day and their concentration in 1 ml of oncological patients' urine statistically do not differ from the corresponding values in the urine of patients with non-oncological diseases.

Topics: Adult; Aged; Circadian Rhythm; Coronary Disease; Female; Humans; Ketones; Male; Methods; Middle Aged; Neoplasms; Thiourea

The therapeutic effect of an antihypoxic drug--Gutimine--was studied in 30 patients with chronic coronary insufficiency. The effect of gutimine on the adaptation for physical exercises connected with motor hypoxy in 5 normal individuals was used as control. The treatment with Gutimine resulted in a clear subjective improvement (less frequent and less intense anginal attacks) in 2/3 of the patients with chronic coronary insufficiency. Objective signs of improvement (positive ECG shifts, phases of the left ventricular systole and hemodynamics; increased tolerance of physical exercises) after Gutimine therapy were noted only in 4 patients who had a comparatively mild course of their disease and less distinct sclerotic changes in the myocardium. When Gutimine was used in normals, significant improvement of their capacity for work was noted, as well as an improvement of their cardiovascular functions and gas exchange parameters during "extreme" exercises. The positive effect of Gutimine was more distinct after 1-2 weeks of its administration. Side effects were absent.

Topics: Adult; Aged; Chronic Disease; Coronary Disease; Female; Guanine; Heart; Hemodynamics; Humans; Male; Middle Aged; Physical Exertion; Thiourea

Topics: Angina Pectoris; Coronary Disease; Electrocardiography; Geriatrics; Isocarboxazid; Tachycardia; Tachycardia, Paroxysmal; Thiourea