Attenuation of isoproterenol-mediated myocardial injury in rat by an inhibitor of polyamine synthesis

Objective: Ornithine decarboxylase (ODC) is an initial rate-limiting enzyme in the synthesis of polyamines (putrescine, spermidine, and spermine) that play a role in cell growth and differentiation. Recent studies have shown that spermidine and spermine cause injury to a variety of cells including m yocytes in vitro. In this investigation, we used alpha -difluoromethylornit hine (DFMO), a specific and irreversible inhibitor of ODC activity and poly amine synthesis to test the hypothesis that polyamines contribute to myocar dial injury in rat. Methods: Male Sprague Dawley rats were treated with (i) saline (0.2 ml/day, s.c.), (ii) isoproterenol (ISO) (5 mg/kg/day for 8 day s, s.c.) to produce necrotizing myocardial injury, or with (iii) DFMO + ISO . DFMO was started 2 days before the initiation of ISO and both ISO and DFM O were continued until the end of the experimental period. Myocardial injur y was assessed by determining the increased release of creatine phosphokina se (CPK) and lactate dehydrogenase (LDH) into the plasma, and by morphometr ic analysis of the lesion area in heart sections stained with Gomori trichr ome. Results: ISO induced the release of CPK and LDH by 6 hr and 24 hr, res pectively, and produced subendocardial necrosis, which was both acute and r esolving following 8 days of ISO. DFMO treatment inhibited ISO-induced incr eases in (i) ODC activity and putrescine and spermidine levels in heart, (i i) CPK and LDH activity in plasma, and (iii) the area of subendocardial les ions. Conclusions: These observations suggest that polyamines are one of th e intracellular factors that contribute to ISO-mediated cardiac injury in t he rat. Cardiovasc Pathol 2000;9:273-280 (C) 2000 by Elsevier Science Inc.