心筋梗塞の修復過程の定量的分析に関する研究 ―第2報 梗塞治癒過程に対するPrednisolone,Indomethacin,Thromboxane A?合成阻害剤,MetoprololならびにVerapamilの影響―
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The delaying effect of prednisolone on the healing process of myocardial infarction was quantitatively estimated and whether its effect is mediated via inhibition of prostaglandin synthesis was investigated using DP 1904 (a new thromboxane A2 synthetase inhibitor) and indomethacin. In addition, the effects of metoprolol and verapamil on the infarct healing process were also studied. A rabbit model was employed, and the coronary artery was occluded for 30 min and reperfused for 72 hr. The infarcted area and the central core of necrosis were delineated by hematoxylineosin and Mallory's staining modified by Heidenhein. The area of the occluded coronary artery (area at risk) was determined by fluorescent particles. As an index of infarct healing, the volume ratio of the central core of necrosis to the whole infarct (%N/I) was calculated. The thinning of the infarcted wall was evaluated by the thickness ratio of the infarcted wall to the normal wall adjacent to the infarcted area (thinning ratio). The rabbits were divided into 7 groups: 1) prednisolone (5mg/kg)-treated group (PSL5), 5mg/kg of prednisolone was i.m. injected every 24 hr; 2) prednisolone (10 mg/kg)-treated group (PSL10), 10mg/kg of prednisolone was i.m. injected every 24 hr; 3) DP 1904-treated group (DP group), 10mg/kg of DP 1904 was i.v. injected every 24 hr starting 2 hr prior to coronary occlusion; 4) indomethacin-treated group (IND group), 5mg/kg of indomethacin was i.v. injected after 15 min ischemia, which was followed by 10mg/kg s.c. 5 min after reperfusion and then every 24 hr; 5) metoprolol-treated group (MET group), 0.15mg/kg of metoprolol was injected i.v. bolus 25 min prior to coronary occlusion, and followed by constant infusion at 0.003mg/kg/min for 70 min from 15 min after bolus injection; 6) verapamil-treated group (VER group), 0.2mg/kg of verapamil was injected i.v. bolus 15 min prior to ishemia, followed by constant infusion at 0.04mg/kg/min for 45 min, and 7) untreated control group. In IND group, serum indomethacin level at 30 min and 72 hr after reperfusion was assayed using HPLC. The following results were obtained. 1) The size of area at risk, absolute infarct size, and infarct size as the percentage of area at risk were comparable for all 7 groups. 2) In PSL5 and PSL10 groups, %N/I were 51.5±5.0%, and 73.2±2.5%, respectively, both of ?which were significantly higher than that in the control group (30.4±4.5%). 3) In IND group, serum indomethacin level was 10532±2907ng/ml at 30 min and 367±140ng/ml at 72 hr after reperfusion. However, %N/I of IND group (46.6±4.7%) was not significantly different from that of the control group. The %N/I of DP group, 36.3±6.2%, was not different from that of the control group, even though the dose of DP 1904 used in this study is considered to be sufficient to completely inhibit thromboxane B2 formation after 2 hr and by about 60% even 24 hr after its administration. 4) MET group showed a higher value of %N/I (50.0±9.0%) compared with that of the control group (30.4±4.5%), though it was not statistically significant. %N/I in VER group (27.8±5.9%) was similar to that of the control group. 5) There were no significant differences in the thinning ratio for the 7 experimental groups. These results suggest that prednisolone delayed infarct healing dose dependently. Since indomethacin and DP 1904 failed to modify %N/I, the effect of prednisolone on infarct healing is unlikely to be mediated by the reduction of thromboxane A2 formation. Metoprolol and verapamil may not have any delaying effects on the healing process of myocardial infarction.
- 1990-04-01
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