Effects of different preproendothelin-1 mRNA anti-sense oligodeoxynucleotides on ischemic arrhythmias in rats.
The effects of four anti-sense oligodeoxynucleotides (AS-ODNs) against rat or human preproendothelin-1 mRNA on ischemic arrhythmias in anesthetized rats were studied. AS-ODN (60 nmol/kg) or control (normal saline; sense-ODN, and scrambled-ODN, 60 nmol/kg) was injected 2 h before acute myocardial ischemia elicited by the occlusion of the left anterior descending coronary artery. Arrhythmias during 60-min ischemia were assessed, and plasma endothelin-1 was determined with an endothelin-1-specific radioimmunoassay system. The results showed that anti-senses against human preproendothelin-1 mRNA were anti-arrhythmic without significant impact on hemodynamics, whereas two against rat preproendothelin-1 mRNA and the three controls failed to be anti-arrhythmic. In human antisense groups, both the incidence of reversible ventricular fibrillation and the mortality were decreased to zero. The incidences of ventricular tachycardia and salvos were significantly decreased from almost 100% in the controls to < or =30% (p < 0.01), the arrhythmia score from an average of approximately 3.6 to 0 and 0.7, respectively (p < 0.01 versus controls), and the total ventricular ectopic beats from an average of 307-338 to < 40 (p < 0.01). The human AS-ODNs led to less plasma endothelin-1, which was associated with suppressed ischemic arrhythmias in this rat model, indicating a contributory role of endothelin-1 in ischemic arrhythmias. Conversely, considering the two- or three-base mismatches between the human AS-ODNs and rat preproendothelin-1 mRNA, and the failure of the rat AS-ODNs in suppressing arrhythmias, the possibility could not be excluded that human endothelin-1 AS-ODNs acted via an undetermined pathway other than endothelin-1.
Lin
Li
L
Department of Physiology, College of Basic Medical Sciences, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, People's Republic of China.
Yuan
Wen-Jun
WJ
D000595:Amino Acid Sequence; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D019332:Endothelin-1 / Q000097:blood / Q000187:drug effects; D016232:Endothelins / Q000235:genetics / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000150:complications* / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D019332:Endothelin-1; D016232:Endothelins; D020319:Oligodeoxyribonucleotides, Antisense; D011498:Protein Precursors; D012333:RNA, Messenger