González GE, Seropian IM, Krieger ML, Palleiro J, Lopez Verrilli MA, Gironacci MM, Cavallero S, Wilensky L, Tomasi VH, Gelpi RJ, Morales C. Effect of early versus late AT1 receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits. Am J Physiol Heart Circ Physiol 297: H375-H386, 2009. First published May 8, 2009 doi:10.1152/ajpheart.00498.2007.-To characterize the temporal activation of the renin-angiotensin system after myocardial infarction (MI) in rabbits, we examined cardiac ANG II type 1 receptor (AT1R) expression and ANG II levels from 3 h to 35 days. The effects of losartan (12.5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) on functional and histomorphometric parameters when treatment was initiated early (3 h) and late (day 15) post-MI and maintained for different periods of time [short term (4 days), midterm (20 days), and long term (35 days)] were also studied. AT1R expression increased in the MI zone at 15 and 35 days (P Ͻ 0.05). ANG II levels increased (P Ͻ 0.05) in the non-MI zone at 24 h and in the MI zone as well as in plasma at 4 days and then progressively decreased until 35 days. The survival rate was significantly lower in untreated MI and early long-term-treated animals. Diastolic pressure-volume curves in MI at 35 and 56 days shifted to the right (P Ͻ 0.05). This shift was even more pronounced in long-term-treated groups (P Ͻ 0.05). Contractility decreased (P Ͻ 0.05 vs. sham) in the untreated and long-term-treated groups and was attenuated in the midterm-treated group. The early administration of losartan reduced RAM 11-positive macrophages from 4.15 Ϯ 0.05 to 3.05 Ϯ 0.02 cells/high-power field (HPF; P Ͻ 0.05) and CD45 RO-positive lymphocytes from 2.23 Ϯ 0.05 to 1.48 Ϯ 0.01 cells/HPF (P Ͻ 0.05) in the MI zone at 4 days. Long-term treatment reduced the scar collagen (MI: 70.50 Ϯ 2.35% and MI ϩ losartan: 57.50 Ϯ 2.48, P Ͻ 0.05), determined the persistency of RAM 11-positive macrophages (3.02 Ϯ 0.13 cells/HPF) and CD45 RO-positive lymphocytes (2.77 Ϯ 0.58 cells/HPF, P Ͻ 0.05 vs. MI), and reduced the scar thinning ratio at 35 days (P Ͻ 0.05). Consequently, the temporal expressions of cardiac AT1R and ANG II post-MI in rabbits are different from those described in other species. Long-term treatment unfavorably modified post-MI remodeling, whereas midterm treatment attenuated this harmful effect. The delay in wound healing (early reduction and late persistency of inflammatory infiltrate) and adverse remodeling observed in long-term-treated animals might explain the unfavorable effect observed in rabbits.angiotensin II type 1 receptor blockers MYOCARDIAL INFARCTION (MI) leads to global structural alterations that involve infarcted as well as noninfarcted areas in a process collectively known as ventricular remodeling (26). The initial phase of remodeling, which starts in the acute phase of the MI, is associated with geometric changes and dilation of the MI zone, as a consequence of injured wall thinning (14, 26). Shortly afterward, this dilation may progress to the whole ventricle, and...