Effects of the 21-aminosteroid U74389G in a model of chronic myocardial infarction in the rat

21-Aminosteroids are a group of new synthetic compounds developed as antipe roxidants. Although several studies have demonstrated their cardioprotectiv e properties in acute ischemic models, none has assessed their long-term be nefits after chronic myocardial infarction. In this investigation, we exami ned the cardioprotective effects of U74389C, a novel 21-aminosteroid, in a model of chronic myocardial infarction in the rat. After permanent ligation of the proximal branch of the left coronary artery, the experimental anima ls were treated daily by gavage with U74389G (10 mg/kg) for 21 days. After the study period, harvested hearts were perfused ex vivo and submitted to c old cardioplegia with 90-min global ischemia and 30-min reperfusion (surgic al stress). Myocardial function and coronary endothelial (bradykinin, 1 mu M) and smooth muscle (sodium nitroprusside, 1 mu M) reactivity were assesse d before and after exposure to the surgical stress. Percentage infarct size of the left ventricle was computed as the ratio of infarct area (mg)/total left ventricle (mg) x 100. During or immediately after surgery, there were eight deaths, which were considered technical failures. No further deaths occurred during the follow-up period (21 days). Compared with vehicle-treat ed rats, long-term administration of U74389G elicited a significant reducti on of infarct size (percentage of left ventricle, 9 +/- 5% in the U74389G-t reated group vs. 32 +/- 5% in the vehicle-treated group; p < 0.01). Ex vivo heart-perfusion studies showed no significant difference in baseline coron ary flow, left ventricular developed pressure, and heart rate between norma l and chronic infarcted hearts treated with the vehicle or with U74389G. Ho wever, a reduced endothelium-dependent coronary dilator response was observ ed in infarcted hearts from vehicle-treated controls but not in those from U74389G-treated rats. When cardioplegia and global myocardial ischemia/repe rfusion were added, most of the benefits from U74389G were lost. These resu lts indicate that 21-aminosteroids can reverse oxygen-derived free radicals and lipid peroxidation-induced myocardial and coronary dysfunction associa ted with chronic myocardial infarction. However, additive protective measur es are required when an acute ischemic stress is superimposed.