Attenuation of dysfunction in the postischemic 'stunned' myocardium by dimethylthiourea.

Abstract

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 < .03) at 1 hr, 55 ± 9% vs 23 ± 13% (p < .05) at2hr, 60 + 9% vs28 ± 14% (p< .05)at3hr,and67 ± 5%vs36 + 13% (p< .05)at4hr. 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. Circulation 76, No. 2, 458-468, 1987. MYOCARDIUM reperfused after a reversible ischemic insult exhibits prolonged contractile dysfunction ("stunned" myocardium).1-3 Despite considerable investigative efforts, the mechanism responsible for this phenomenon remains unclear. Recently, several studies have demonstrated that the recovery of the stunned myocardium is enhanced by agents that decrease the concentration of superoxide anion ( 02) and hydrogen

Reactive Oxygen Intermediates Induce Monocyte Chemotactic Protein-1 in Vascular Endothelium after Brief Ischemia

“…11,12,21 After instrumentation, animals were allowed to recover for 72 hours before occlusion. Coronary artery occlusion was initiated by inflating the hydraulic occluder until mean blood flow in the coronary artery was zero as determined by Doppler flow probe.…”

“…30 To further examine the potential mechanism of oxidant induction of MCP-1 in venular endothelium, we used CJVECs as an in vitro endothelial cell culture model. ROI scavenger experiments by Bolli and colleagues 12 used a glucose/glucose oxidase reaction to generate H 2 O 2 and measured its rate of production to be 11 mol/L/min. Experiments by Wung and colleagues 31 induced MCP-1 expression in bovine artery endothelial cells with exogenous H 2 O 2 at a concentration of 100 mol/L.…”

“…8 These observations led to the current study that examines the hypothesis that the highly localized induction of MCP-1 is induced by reactive oxygen generated from ischemic myocardium. [12][13][14] Because both leukocyte transmigration and angiogenic budding occur at the postcapillary venular level, understanding this highly localized induction is an important issue.…”

“…[12][13][14] The absence of postinfarction inflammation obviates the complications associated with inflammatory cell adhesion to the postcapillary venular network that might induce MCP-1 in these venules via a paracrine-or adhesion-dependent signal mechanism. The results demonstrate that MCP-1 expression after 15 minutes of ischemia and 5 hours of reperfusion occurs specifically in the small venular endothelium and is inhibited by pretreatment with the anti-oxidant, N-(2-mercaptopropionyl)-glycine (MPG).…”

Dimethylthiourea inhibition of B16 melanoma growth and induction of phenotypic alterations; relationship to ATP levels

“…Doses up to 1 gr kg-' administered to sheep, rats and mice were reported to protect animals from free radical mediated lung, kidney, heart and brain injury (Fox, 1982(Fox, , 1984Paller et al, 1984;Bolli et al, 1987;Morel et al, 1988;Martz et al, 1989). DMTU doses of 750 mg kg-', producing plasma concentrations of 10 mM, prevented granulocyte mediated lung injury in sheep, without altering normal neutrophil functions (Fox, 1984;Wong et al, 1985).…”