Effects of angiotensin II type 1 receptor blockade in ApoE-deficient mice with post-ischemic heart failure.
We investigated in mice whether atherosclerosis exacerbates the development of post-ischemic heart failure and alters the beneficial effects of long-term angiotensin II type 1 receptor blockade in this model. ApoE-deficient (ApoE(-/-)) and C57BL/6J (C57) mice with myocardial infarction (coronary ligation) received vehicle (C57 and ApoE(-/-)) or irbesartan (Ir, 50mg/kg/d orally, C57-Ir and ApoE(-/-)-Ir). Ten months post myocardial infarction, survival rates were similar in C57 (58%) and ApoE(62%). Atherosclerosis induced no significant alteration in blood pressure, cardiac output (fluospheres), total peripheral resistance, or shortening fraction (echocardiography) but increased renal resistance (+50%, P<0.05). Chronic Ir treatment significantly improved survival to a similar extent in both C57-Ir (85%) and ApoE(-/-)-Ir (86%). It also decreased blood pressure to a similar extent in both strains (-16% and -18%, both P<0.05). In C57-Ir mice, Ir did not modify cardiac output or total peripheral resistance, but it decreased renal resistance (-28%, P<0.001) and left-ventricular weight (-28%, P<0.05). In ApoE(-/-)-Ir mice, Ir limited atherosclerotic lesions (-13%, P<0.05), increased cardiac output (+28%, P<0.05) and shortening fraction (+24%, P<0.05), and decreased total peripheral resistance (-33%, P<0.01), renal resistance (-61%, P<0.001), and left-ventricular weight (-27%, P<0.001). In conclusion, atherosclerosis does not worsen heart failure development in mice and, although the beneficial cardiovascular effects of AT1 receptor blockade are greater in ApoE(-/-) than in C57, reduction in mortality is similar in both strains.
Pons
Sandrine
S
Département de Pharmacologie, INSERM E 00-01, Faculté de Médecine, La Kremlin-Bicêtre, France.
Hagège
Albert
A
Fornes
Paul
P
Gervais
Marianne
M
Giudicelli
Jean-François
JF
Richer
Christine
C
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000150:complications / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004195:Disease Models, Animal; D004452:Echocardiography; D000077405:Irbesartan; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000077405:Irbesartan