Submitted on April 25, 2007
Revised on April 27, 2009
Accepted on April 29, 2009
Effect of Early vs Late AT1 Receptor Blockade with Losartan on Post-Myocardial Infarction Ventricular Remodeling in Rabbits
German E Gonzalez1, Ignacio Miguel Seropian, Maria Laura Krieger, Jimena Palleiro2, Maria A López Verrilli3, Mariela M Gironacci4, Susana Cavallero4, Luciana Wilensky5, Victor H Tomasi6, Ricardo J. Gelpi5*, and Celina Morales
1 Cardiovascular Pathophysiology Institute.
2 Cardiovascular Pathophysiology Institute. Faculty of Medicine. University of Buenos Aires
3 Institute of Biological Chemistry, University of Buenos Aires
4 University of Buenos Aires
5 Cardiovascular Physiopathology Institute, School of Medicine. University of Buenos Aires
6 Cardiovascular Pathophysiology Institute. Faculty of Medicine, University of Buenos Aires
* To whom correspondence should be addressed. E-mail: rgelpi{at}fmed.uba.ar.
To characterize the temporal activation of the renin-angiotensin system post-myocardial infarct (MI) in rabbits, we examined cardiac AT1-receptor (AT1-R) expression and Angiotensin II (ANG II) levels from 3h to 35 days. The effects of losartan (L;12,5 mg/kg/d) on functional and histomorphometric parameters when treatment is initiated early (3h) and late (day 15) post-MI and it is maintained for different periods of time (short-term (4 days), middle-term (20 days) and long-term (35 days)) were also studied. AT1-R expression increased in MI zone at 15 and 35 days (P<0,05). ANG II levels increased (P<0,05) in non-MI zone at 24h and in MI zone as well as in plasma at 4 days, then progressively decreased until 35 days. The survival rate was significantly lower in untreated MI and early long term treated animals. The 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 untreated and long-term treated groups and it was attenuated in middle-term treated group. The early administration of L reduced the RAM11+ macrophages from 4,15±0,05 to 3,05±0,02 (cells/HPF; P<0,05) and CD45RO+ lymphocytes from 2,23±0,05 to 1,48±0,01 (P<0,05) in MI zone at 4 days. Long-term treatment reduced the scar-collagen (MI:70,50±2,35%; MI+L:57,50±2,48;P<0,05) and determined the persistency of RAM11+ macrophages (3,02±0,13 cells/HPF), CD45RO+ 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 expression of cardiac AT1-R and ANG II post-MI in rabbits are different from those described in other species. Long-term treatment unfavorably modified post-MI remodeling, whereas middle-term 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.
