title: Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: effect of dose on survival, ventricular arrhythmias, function, and remodeling.
abstract: Angiotensin receptor blockers (ARBs) reduce adverse left ventricular (LV) remodeling and improve LV function and survival when started postmyocardial infarction (MI). ARBs also reduce ventricular arrhythmias during ischemia-reperfusion injury when started pre-MI. No information exists regarding their efficacy and safety when started pre-MI and continued peri- and post-MI. We evaluated whether the ARB losartan improves the outcome when started pre-MI and continued peri- and post-MI. Male Wistar rats (n = 502) were treated for 7 days pre-MI with losartan at a high dose (30 mg.kg(-1).day(-1)), progressively increasing dose (3 mg.kg(-1).day(-1) increased to 10 mg.kg(-1).day(-1) 10 days and 30 mg.kg(-1).day(-1) 20 days post-MI), or no treatment. Ambulatory systolic blood pressure and Holter monitoring were performed for 24 h post-MI. Echocardiography was done 30 days post-MI, and LV remodeling, cardiac hemodynamics, and fetal gene expression were assessed 38 days post-MI. High-dose losartan reduced 24-h post-MI survival compared with the progressive dose and control (21.9% vs. 36.6% and 38.1%, P = 0.033 and P = 0.009, respectively). This was associated with greater hypotension in the high dose and no change in ventricular arrhythmias in all groups. In 24-h post-MI survivors, the progressive dose group had reduced mortality from 24 h to 38 days (8.5% vs. 28.6% for control vs. 38.9% for high dose, P = 0.032 and P = 0.01, respectively). Survivors of both losartan groups demonstrated improved LV remodeling, cardiac hemodynamics, preserved GLUT-4, and reduced cardiac fetal gene expression. Pretreatment with ARBs does not reduce 24-h post-MI ventricular arrhythmias or survival, and high doses increase mortality by causing excessive hypotension. In 24-h post-MI survivors, progressively increasing doses of losartan have multiple beneficial effects, including improved survival.
authors.affiliation: Division of Cardiology, St. Michael's Hospital, Rm. 6-044 Queen Wing, 30 Bond St., Toronto, Ontario M5B 1W8, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Pourdjabbar
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Parker
authors.forename: Quang Trinh
authors.initials: QT
authors.lastname: Nguyen
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Desjardins
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lapointe
authors.forename: James N
authors.initials: JN
authors.lastname: Tsoporis
authors.forename: Jean-Lucien
authors.initials: JL
authors.lastname: Rouleau
mesh_terms: D000199:Actins / Q000235:genetics; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D001794:Blood Pressure; D018660:Blood Pressure Monitoring, Ambulatory; D002306:Cardiac Volume; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D051275:Glucose Transporter Type 4; D015994:Incidence; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D017180:Tachycardia, Ventricular / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017725:Ventricular Pressure; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D051275:Glucose Transporter Type 4; C000594638:MYH7 protein, rat; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C495694:Slc2a4 protein, rat; D009320:Atrial Natriuretic Factor; D018995:Myosin Heavy Chains; D019808:Losartan