PROTECTION OF ISCHEMIC AND REPERFUSED RAT MYOCARDIUM BY THE NONGLUCOCORTICOID 21-AMINOSTEROID U-74389G, A NEW INHIBITOR OF LIPID-PEROXIDATION

We studied the effects of the aminosteroid U-74389G (21-[4-(2,6-di-1 d inyl-4-pyrimidinyl)-1-piperazinyl]-pregna-1,4,9(1 1)-triene-3,20-dione (2)-2-butenenedionate), a putative inhibitor of lipid peroxidation, wh ich protects the rat myocardium after ischemia and reperfusion. Pentob arbital-anesthetized (50 mg/kg) rats were subjected to 60 min of occlu sion of the left main coronary artery followed by 60 min of reperfusio n. Myocardial ischemia/reperfusion produced a large cardiac necrosis ( 81 +/- 8.6% of the area at risk and 65 +/- 14.8% of the total left ven tricle), polymorphonuclear infiltration in the jeopardized tissue (mye loperoxidase activity = 4.2 +/- 2.1 U x 10(-3)/g tissue in the area at risk and 7.0 +/- 3.6 U x 10(-3)/g tissue in the necrotic area), hydro xyl radical (OH) formation (0.55 +/- 0.16 nmol/ml), increased plasma m alonylaldehyde (40.2 +/- 3.9 nmol/ ml) and lactate dehydrogenase(431 /- 30 mlU/ml) and caused a decrease in the survival rate. Treatment wi th U-74389G (15 and 30 mg/kg i.v.) at the onset of reperfusion caused a reduction of necrotic area expressed as a percentage of either the a rea at risk (76 +/- 7.4% with 15 mg/kg and 69 +/- 13.5% with 30 mg/kg; P < .05) or the total left ventricle (53 +/- 13.6% with 15 mg/kg and 46 +/- 16.8% with 30 mg/kg; P < .05). Treatment with U-74389G reduced the myeloperoxidase activity, evaluated as an index of neutrophil infi ltration, both in the area at risk (2.7 +/- and 2.2 +/- 1.7 U x 10(-3) /g tissue with the doses of 15 and 30 mg/kg, respectively; P < .05) an d in the necrotic area (4.3 +/- 2.4 and 3.8 +/- 2.9 U x 10(-3)/g tissu e with 15 and 30 mg/kg, respectively; P < .05); decreased OH formation (measured indirectly by the administration of the trapping agent sali cylic acid); and analyzing the hydroxylation product 2,5-dihydroxybenz oic acid during reperfusion (0.35 +/- 0.12 and 0.32 +/- 0.15 nmol/ml w ith the doses of 15 and 30 mg/kg, respectively; P < .005). Treatment i nhibited lipid peroxidation by blunting plasma malonylaldehyde (26.7 /- 3.1 and 20.8 +/- 3.3 with the doses of 15 and 30 mg/kg, respectivel y; P < .001), prevented cellular disruption by reducing the increase o f plasma lactate dehydrogenase (288.6 +/- 28 and 201.3 +/- 16 mlU/ml w ith the doses of 15 and 30 mg/kg, respectively; P < .001). Finally, U- 74389G enhanced the survival rate evaluated at the end of the experime nt (from 40 to 87%). These outcomes suggest that the drug may have pot ential for cardioprotective use in acute myocardial infarction.