Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: effect of dose on survival, ventricular arrhythmias, function, and remodeling.
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.
Pourdjabbar
Ali
A
Division of Cardiology, St. Michael's Hospital, Rm. 6-044 Queen Wing, 30 Bond St., Toronto, Ontario M5B 1W8, Canada.
Parker
Thomas G
TG
Nguyen
Quang Trinh
QT
Desjardins
Jean-Francois
JF
Lapointe
Nathalie
N
Tsoporis
James N
JN
Rouleau
Jean-Lucien
JL
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*
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