Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / genetics
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Actins / metabolism
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Angiotensin-Converting Enzyme Inhibitors / administration & dosage
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Angiotensin-Converting Enzyme Inhibitors / pharmacology
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Angiotensin-Converting Enzyme Inhibitors / therapeutic use
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Animals
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Arrhythmias, Cardiac / diagnostic imaging
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Arrhythmias, Cardiac / drug therapy*
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Arrhythmias, Cardiac / metabolism
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Disease Models, Animal
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Drug Administration Schedule
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Gene Expression / drug effects
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Heart Ventricles / drug effects
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Heart Ventricles / metabolism
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Insulin Resistance
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Myocardial Infarction / drug therapy*
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Myocardial Infarction / metabolism
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Myocardial Infarction / mortality
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Myosin Heavy Chains / genetics
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Myosin Heavy Chains / metabolism
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Protease Inhibitors / administration & dosage
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Protease Inhibitors / pharmacology
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Protease Inhibitors / therapeutic use*
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Pyridines / administration & dosage
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Pyridines / pharmacology
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Pyridines / therapeutic use*
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Rats
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Rats, Sprague-Dawley
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Rats, Zucker
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Survival Analysis
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Thiazepines / administration & dosage
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Thiazepines / pharmacology
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Thiazepines / therapeutic use*
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Ultrasonography
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Ventricular Dysfunction, Left / diagnostic imaging
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Ventricular Dysfunction, Left / drug therapy*
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Ventricular Dysfunction, Left / metabolism
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Ventricular Remodeling / drug effects
Substances
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Actins
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Angiotensin-Converting Enzyme Inhibitors
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MYH7 protein, rat
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Protease Inhibitors
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Pyridines
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Thiazepines
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omapatrilat
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Myosin Heavy Chains