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This Article Full Text Full Text (PDF) All Versions of this Article: 297/1/H375    most recent 00498.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by González, G. E. Articles by Morales, C. PubMed PubMed Citation Articles by González, G. E. Articles by Morales, C.

Effect of early versus late AT₁ receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits

¹Institute of Cardiovascular Physiopathology and Department of Pathology, School of Medicine, and ²Institute of Biological Chemistry and Physic-chemistry and ³Department of Physiopathology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina

Submitted 25 April 2007 ; accepted in final form 29 April 2009

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·kg^–1·day^–1) 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 < 0.05). ANG II levels increased (P < 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 < 0.05). This shift was even more pronounced in long-term-treated groups (P < 0.05). Contractility decreased (P < 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 ± 0.05 to 3.05 ± 0.02 cells/high-power field (HPF; P < 0.05) and CD45 RO-positive lymphocytes from 2.23 ± 0.05 to 1.48 ± 0.01 cells/HPF (P < 0.05) in the MI zone at 4 days. Long-term treatment reduced the scar collagen (MI: 70.50 ± 2.35% and MI + losartan: 57.50 ± 2.48, P < 0.05), determined the persistency of RAM 11-positive macrophages (3.02 ± 0.13 cells/HPF) and CD45 RO-positive lymphocytes (2.77 ± 0.58 cells/HPF, P < 0.05 vs. MI), and reduced the scar thinning ratio at 35 days (P < 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