EARLY CAPTOPRIL TREATMENT INHIBITS DNA-SYNTHESIS IN ENDOTHELIAL-CELLSAND NORMALIZATION OF MAXIMAL CORONARY FLOW IN INFARCTED RAT HEARTS

Objectives: Cardiac remodeling due to myocardial infarction (MI) inclu des myocyte hypertrophy, collagen deposition, a rise in DNA synthesis, and normalization of initially diminished maximal coronary bloodflow. Previously, we demonstrated that early captopril treatment can preven t the rise in total DNA synthesis, collagen deposition and hypertrophy . In the present experiments, we investigated the effects of captopril or perindoprilat treatment on cardiac endothelial cell proliferation and maximal coronary flow. Methods: MI was induced by ligation of the left coronary artery in Wistar rats. Sham-operated and infarcted rats were treated with captopril (12 mg/kg.d s.c.) from either day 0-21 (ea rly) or day 21-35 (late) after surgery. In isolated retrogradely perfu sed rat hearts, maximal coronary flow was determined following maximal dilatation with nitroprusside and adenosine (1 mM each). In separate groups, sections of hearts of sham-operated and MI rats treated with B rdU (day 7-14) and either captopril or perindoprilat (1 mg/kg.d s.c.; day 0-14) were double stained with a monoclonal anti-BrdU antibody and the lectin GSI. The total fraction of DNA synthesizing cells and its proportion of endothelial cells was determined. Results: Maximal coron ary flow was completely normalized in MI hearts within three weeks aft er surgery. Early captopril, but not late captopril, inhibited the nor malization of maximal coronary flow in MI hearts (Early: sham, 27.4+/- 1.0; MI, 21.2+/-1.4 ml/min; P<0.05; mean+/-SEM) without affecting the hypertrophic response. The total fraction of DNA synthesizing cells wa s significantly increased in MI hearts (sham: 7.6+/-1.9; MI: 14.9+/-2. 2%). The proportion of endothelial cells, however, was comparable in s ham-operated and infarcted hearts (sham: 30+/-3; MI: 33+/-3%). Both ea rly captopril and perindoprilat treatment inhibited total DNA synthesi s in MI hearts. Only in captopril pre-treated hearts, this inhibition was associated with a disproportionate inhibition of the endothelial c ell proliferation (10.3+/-2.0%). Conclusion: Early captopril treatment inhibits endothelial cell proliferation and coronary vessel growth fo llowing MI, which seems to be partly due to inhibition of the renin an giotensin system. (C) 1998 Elsevier Science B.V. All rights reserved.