| Endothelin(ET), first purified and nomimated by Yanagisawa et al in 1 988,is a family of potent vasoconstrictive polypeptides composed of2l amino acids. ET mainly distributes in the cardiovascular system, and is involved in a variety of cardiovascular diseases and disorders including hypertension, myocardial ischemia/ reperfusion, and chronic pulmonary hypertension. Exogenous ET has been reported to be arrythmogenic, but whether it is contributive or antagonistic to acute ischemic arrhythmia remains unclear. Antisense oligonucleotides(AS-ODN) are short sequences of DNA complementary to target mRNA according to Watson-Crick base pairing rule. AS-ODN inhibits the expression of target gene, so they are considered to be promising agents in the treatment of the diseases associated with gene overexpression. ET- 1 mRNA AS-ODNs designed by Lin Li et al was shown to prevent acute ischemic arrhythmia in rats. Based on the model of acute ischemic arrhythmia caused by occlusion of the left anterior descending branch of coronary artery(LAD) in isolated perfused rat heart, the present study observed the effects of endothelin-1 mRNA antisense oligonucleotide on acute ischemic arrhythmia, coronary flow, heart rate and heart function during 60-mm occlusion of LAD, and cardiac infart size, content of oxygen free radials and myocardial ultrastructure after 60-mm ischemia. The results are as followings: 1. In the normally perfused isolated rat hearts only ventricular premature beats (VPB) and Salvos, not VT/VF occurred, and the arrhythmia score(AS) was 1.00 ?0.00. After LAD occlusion, the ischemic arrhythmias tended to occur during 1 0?0 mm post-occlusion with a peak activity time around 20 mm. In the hearts subjected to LAD occlusion at a low-position (5 mm away from LAD initial point, n6), neither ventricular tachycardia(VT) nor ventricular fibrillation(VF) occurred, and AS was 0.83 ?0.41. AS, VPBs and Salvos were not significantly different from those of normal group(P>0.05). In the hearts subjected to LAD occlusion at a middle position(3 mm away from to LAD initial point, n6), ventricular tachycardia(VT) and ventricular fibrillation occurred frequently in each heart, and AS was 3.00±.00; AS, single VPBs, Salvos and total VPBs were significantly different from that of normal and low-position LAD occlusion groups(P<0.01). When LAD was ligated at 1 mm away from its initial point,all hearts suffered VT, and two of them died of irreversible VF. AS(4.17?.75), VPBs(687± 533), Salvos(116±128) and total VPBs(1516±898) were significantly different from those of normal and low-position LAD occlusion groups(P<0.01); compared to that of the middle-position LAD occlusion group, there was significant difference in AS, Salvos, Salvos and total VPBs(P<0.01). According to the severity of arrhymia, we established the acute ischemic arrhythmia model based on the middle-position occlusion(3 mm away from to LAD initial point). 2.In the three control groups, NS(n=6), S-ODN(w6), and scrambled-ODN groups(n=6) , , VT/VF occurred frequently in each heart during LAD occlusion, AS was 3.00 ?0.00 in each group, and VPBs respectively were609±356,776±578,694± 737; Salvos respectively were69+56 120±12 84±TVT respectively werel99? 95,146 ?50,128 ?48; and total arrhythmias respectively were 877±427 1108± 826,907 ?858. but there was no significant difference between these three groups(P>0.05).VT occurred in all 6 the hearts pretreated with AS-ODN 6 ODIKg VT (43±1 5)was significantly less than that of NS, S-ODN and scrambled-ODN grou... |
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