Effects of pre-, peri-, and postmyocardial infarction treatment with omapatrilat in rats: survival, arrhythmias, ventricular function, and remodeling.
We showed previously that the vasopeptidase inhibitor (VPI) omapatrilat improves peri-myocardial infarction (MI) survival, but the mechanisms involved and whether these effects are sustained remained to be determined, and are the subject of this study. Rats (n = 272) received omapatrilat (20 mg x kg-1x day-1) starting 7 days before MI and continued peri- and post-MI, or no treatment (control). One group of rats had continuous ambulatory ECG and blood pressure recordings started 6 h before MI and continued until 24 h after MI, when survival was evaluated, and the rats were killed, and MI size was evaluated. A second group had left ventricular (LV) remodeling evaluated by echocardiography at 30 days and, at 38 days, had cardiac hemodynamics and morphology done and survival evaluated. Survival 24 h after MI (n = 255) improved with omapatrilat (60% vs. 46% for control; P = 0.0378). Over the next 37 days, there was no further improvement with omapatrilat but the early benefit was sustained. Omapatrilat reduced MI size 24 h after MI (36 +/- 2 vs. 42 +/- 2 mm2 for controls; P = 0.034). Omapatrilat reduced ventricular arrhythmia score 1-12 h after MI. Omapatrilat decreased blood pressure, but not during the first 24 h after MI. Omapatrilat reduced LV diastolic and systolic dimensions and LV and right ventricular weights compared with control large MI, indicating a decrease in reactive hypertrophy. Improvement in cardiac remodeling was accompanied by improved cardiac hemodynamics. Thus this study indicates that pre-, peri-, and post-MI treatment with the VPI omapatrilat is beneficial in survival, ventricular arrhythmias, LV remodeling, and cardiac function.
Lapointe
Nathalie
N
Division of Cardiology, Toronto General Hospital, Toronto, Ontario, Canada M5G 2C4.
Nguyen
Quang Trinh
QT
Desjardins
Jean-François
JF
Marcotte
Francois
F
Pourdjabbar
Ali
A
Moe
Gordon
G
Calderone
Angelino
A
Rouleau
Jean-Lucien
JL
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D004452:Echocardiography; D004562:Electrocardiography / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013534:Survival; D013841:Thiazepines / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D000806:Angiotensin-Converting Enzyme Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat