Vasopeptidase inhibition peri- and post-MI in Zucker insulin resistant rats: effect on MI size, arrhythmias, remodeling, function and fetal gene expression.
Mortality peri-myocardial infarction (MI) is increased with insulin resistance. As the vasopeptidase inhibitor (VPI) omapatrilat improves insulin sensitivity, it may be beneficial peri-MI in Zucker Insulin Resistant rats (ZIR). ZIR rats (n = 228) received omapatrilat 10 mg/kg/day, 7 days pre-MI, to 38 days post-MI, or control. Twenty-four protocol (n = 72): a subgroup of rats received the kinin receptor antagonist icatibant. Ambulatory ECG recordings, and MI size were evaluated. Thirty-eight-day protocol (n = 156): left ventricular (LV) remodeling, cardiac hemodynamics, morphology, infarct size, and RT-PCR for GLUT-4 and fetal genes were measured. Omapatrilat improved post-MI survival 24 h (62% vs 38%, P = 0.0007) which was maintained 38 days. There was a kinin-induced reduction of ventricular arrhythmias and there appeared to be a kinin-independent reduction in MI size (23.5 +/- 2.4% vs 17.0 +/- 2.2%, P = 0.053) for 24-h post-MI. Omapatrilat reduced but did not prevent LV dilatation, dysfunction, and fetal gene expression 38 days post-MI. Omapatrilat did not prevent reduced cardiac GLUT-4 expression. In ZIR rats, mortality post-MI is reduced by omapatrilat, due and a kinin-dependent reduction in ventricular arrhythmias and possibly a kinin-independent reduction in MI size. Ventricular dilatation, dysfunction, and fetal gene expression are variably attenuated but not prevented.
Lapointe
Nathalie
N
Division of Cardiology, Toronto General Hospital, University Health Network, Canada.
Nguyen
Quang Trinh
QT
Desjardins
Jean-François
JF
Tsoporis
Jim
J
Marcotte
François
F
Pourdjabbar
Ali
A
Parker
Thomas G
TG
Moe
Gordon
G
Adam
Albert
A
Rouleau
Jean-Lucien
JL
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D015870:Gene Expression / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D007333:Insulin Resistance; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D016019:Survival Analysis; D013841:Thiazepines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; C000594638:MYH7 protein, rat; D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D018995:Myosin Heavy Chains