Effect of early versus late AT(1) receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits.
To characterize the temporal activation of the renin-angiotensin system after myocardial infarction (MI) in rabbits, we examined cardiac ANG II type 1 receptor (AT(1)R) 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. AT(1)R 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 AT(1)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 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.
Institute of Cardiovascular Physiopathology, Department of Pathology, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.
Germán E
GE
González
Ignacio M
IM
Seropian
Maria Laura
ML
Krieger
Jimena
J
Palleiro
Maria A
MA
Lopez Verrilli
Mariela M
MM
Gironacci
Susana
S
Cavallero
Luciana
L
Wilensky
Victor H
VH
Tomasi
Ricardo J
RJ
Gelpi
Celina
C
Morales
D000804:Angiotensin II / Q000097:blood / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D032342:Muscle Cells / Q000473:pathology; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects*; D016019:Survival Analysis; D020257:Ventricular Remodeling / Q000187:drug effects*
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D003094:Collagen; D019808:Losartan