1-3-dimethylthiourea and Coronary-Disease

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

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