Objective Dystrophin is a sarcolemmal membrane protein that prevents the myocyte from oncosis induced by physical stress. Because ischemic preconditioning (IPC) protects mitochondria and prevents oncosis during reperfusion, we hypothesized that dystrophin is an end-target of IPC distal to mitochondrial protection.
SUMMARY 1. In the present study, we investigated the effect of 1‐(3‐ tert‐butyl‐2‐hydroxy‐5‐methoxyphenyl)‐3‐(3‐pyridylmethyl) urea hydrocloride (T‐0970), a novel water‐soluble low‐molecular weight free radical scavenger, on the generation of hydroxyl radicals in vivo and on myocardial infarct size in an in vivo model of myocardial infarction in rabbits. 2. T‐0970 scavenged hydroxyl radicals generated in the myocardium during reperfusion, as assessed by using a microdialysis technique and HPLC in an in vivo model with 30 min coronary occlusion and 30 min reperfusion in rabbits. 3. Another group of rabbits was subjected to 30 min coronary occlusion and 48 h reperfusion. The control group ( n = 10) was infused with saline for 190 min from 10 min before occlusion to 180 min after reperfusion. The treatment group (T‐0970 group; n = 10) was injected with a bolus 2.5 mg/kg T‐0970 and then infused with T‐0970 for 190 min from 10 min before reperfusion to 180 min after reperfusion at a rate of 100 μg/kg per min. The T‐0970 + CHE group ( n = 5) was given chelerythrine (CHE; a selective inhibitor of protein kinase C (PKC); 5 mg/kg, i.v.) 10 min before the administration of T‐0970. The T‐0970 + 5‐HD group ( n = 5) was given 5‐hydroxydecanoate (5‐HD; an inhibitor of mitochondrial K ATP channels; 5 mg/kg, i.v.) 10 min before the administration of T‐0970. The CHE and 5‐HD groups were given CHE (5 mg/kg, i.v.) and 5‐HD (5 mg/kg, i.v.) 20 min before reperfusion, respectively. After 48 h reperfusion, infarct size was measured histologically and expressed as a percentage of the area at risk (AAR). In another series of experiments, the control ( n = 5) and T‐0970 ( n = 5) groups were killed 4 h after reperfusion following 30 min coronary occlusion and DNA fragmentation in myocytes was assessed using in situ dUTP nick end‐labelling (TUNEL) at the light microscopic level. 4. Infarct size, as a percentage of AAR, in the T‐0970 group was significantly reduced compared with the control group (21±4 vs 41±4%, respectively; P < 0.05). This reduction of infarct size by T‐0970 was abolished by pretreatment with CHE and 5‐HD. Neither CHE nor 5‐HD alone had any effect on infarct size. The percentage of infarcted myocytes with DNA fragmentation by TUNEL in the T‐0970 group was significantly reduced compared with the number in the control group (4.0±1.5 vs 10.7±1.9%, respectively; P < 0.05). 5. T‐0970, a free radical scavenger, improved reperfusion injury. This effect seemed to be mediated by activation of PKC, the opening of mitochondrial K ATP channels and inhibition of DNA fragmentation.
Background Stable coronary artery disease (CAD) is classified into 2 types: high-risk (ie, 3-vessel disease, left main trunk lesions, or ostial lesions of the left anterior descending (LAD)) and low-risk (1- or 2-vessel disease other than ostial lesions of the LAD), which comprise the majority of CAD patients. According to ACC/AHA/ACP-ASIM guidelines for low-risk CAD, anti-anginal agents should be initially administered to control attacks, then coronary intervention should be considered when medical therapy is not effective (medical-preceding therapy: M). In Japan, however, the initial treatment is generally percutaneous coronary intervention (PCI) combined with medical therapy (PCI-preceding therapy: P). Methods and Results In the present study the long-term outcomes of 190 M patients and 192 matched P patients at 34 nationwide hospitals were surveyed over 3 years (mean: 3.4 years) starting in 2000. Age, gender, initial severity of anginal symptoms, number of lesion vessels, risk factors and prescriptions were similar between the 2 groups. During the 3.4-year follow-up, additional PCI or coronary artery bypass grafting was required in 9.4% of the M group and in 33.2% of the P group. The rates of cardiac death were similar (1.6% in M and 2.6% in P). The overall rate of cardiac death and acute coronary syndrome was 2.1% in M and 4.7% in P, but the difference was not significant. The grade of anginal symptoms 12 months later was well improved in both M (1.6±1.4 to 0.6±0.9) and P (1.7±1.4 to 0.3±0.7) and there was no significant difference. Averaged annual medical cost was lower in M than in P (4.4-fold lower in the first year and 3.1-fold by the next year). Conclusions The present study suggests that M and P for Japanese low-risk CAD may have a similar effect on long-term prognosis, but M is cheaper. (Circ J 2006; 70: 365 - 369)
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