INHIBITION OF ISCHEMIA-INDUCED PHOSPHOLIPASE ACTIVATION BY QUINACRINE PROTECTS JEOPARDIZED MYOCARDIUM IN RATS WITH CORONARY-ARTERY OCCLUSION

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Abstract
Phospholipase activation has been proposed as one relevant biochemical step toward irreversible myocardial injury during ischemia. Accordingly, after coronary artery occlusion, the time course of myocardial phospholipid degradation was studied in 83 control rats and 84 rats treated with quinacrine (75 mg/kg s.c. every 8 hr), a phospholipase inhibitor. Animals were sacrificed at different times ranging from 2 to 48 hr postocclusion. In controls a rapid fall in left ventricular phospholipid concentration (from 1.33 .+-. 0.12 to 0.67 .+-. 0.05 .mu.g of P/mg of protein) and creatinkinase (CK) activity (from 9.84 .+-. 0.49 to 6.93 .+-. 0.60 I.U./mg of protein) was observed within 4 hr postocclusion. In quinacrine-treated aniamls phospholipids and CK also fell initially; however, 24 and 48 hr after occlusion they were higher than in controls (phospholipids: 0.99 .+-. 0.05 vs. 0.62 .+-. 0.04 .mu.g of P/mg of protein, P < .001; CK: 7.76 .+-. 0.54 vs. 4.99 .+-. 0.37 I.U./mg of protein, P < .001, at 48 hr). Additional rats surviving coronary occlusion were divided randomly into a control (n = 14) and three treated groups receiving quinacrine every 8 hr at the dose of 5 (n = 13), 20 (n = 13) or 75 mg/kg (n = 15); 13 rats were sham-operated. Forty-eight hours postocclusion myocardial phospholipids wee measured and infarct size calculated by CK depletion. Infarct size was significantly smaller in high dose quinacrine-treated than in control rats (16.6 .+-. 5.7 vs. 42.1 .+-. 4.4% of left ventricle, P < 0.001). In treated animals, myocardial phospholipid concentration was also significantly higher. Finally, to assess the long-term efficacy of quinacrine in preserving ischemic myocardium, additional 50 rats with coronary artery occlusion were divided into an occluded (n = 14), a quinacrine-treated (75 mg/kg s.c.; n = 14) and a sham-operated group (n = 22). Twenty-one days after the procedure the size of myocardial scar, calculated by left ventricular collagen, was significantly smaller in quinacrine-treated rats than in control animals (11.4 .+-. 3.1 vs. 22.7 .+-. 4.3% of left ventricle, P < 0.02). Thus, quinacrine preserves myocardial phospholipids and reduces permanently infarct size after coronary artery occlusion in rats.