Effects in rats of endogenous vasodilator substances in myocardial infarction, heart failure and insulin resistance.
Published: 2004
Language: eng
Number of pages: 190
Description: We studied the effect of the VPIs omapatrilat in the normal and the Zucker fatty insulin resistant (ZIR) rats. Rats were sacrificed early and late post-MI to explore survival, LV arrhythmias, LV remodelling and cardiac function. We also compared the effects of a VPI to those of an ACEi in HF when started early and late post-MI and continued in established HF. Techniques that were used include whole organism physiology (ambulatory ECG and blood pressure monitoring, echocardiographic, hemodynamics, passive pressure-volume relationship), molecular analysis (rt-PCR) and histomorphormetry (planimetry, immunohistochemistry, cardiac fibrosis).Heart failure (HF), left ventricular (LV) remodelling and ventricular arrhythmias after myocardial infarction (MI) are major contributors to morbidity and mortality. Taking into account the beneficial effects of angiotensin converting enzyme inhibitors (ACEi) in the post-MI and diabetes setting, and its apparent contribution of kinins in this effect, our hypotheses were that vasopeptidase inhibitor (VPIs), a class of drugs that enhances kinins and other endogenous vasodilator substances to a greater level than the ACEi, would be beneficial early and late after MI.These results suggest that, post-MI, the VPI omapatrilat has beneficial effects in normal and ZIR rats that include reduced mortality, ventricular arrhythmias, MI size, adverse LV remodelling, and preserved LV function. Further enhances in kinins and other endogenous vasodilator substances does not result in significant further benefit but similar beneficial effects. A resistance and/or tolerance to endogenous vasodilator substances may explain our results.In ZIR rats, we found a significant increase in post-MI mortality when compared with Sprague-Dawley rats despite similar infarct size, LV dysfunction and adverse LV remodelling. Omapatrilat significantly reduced post-MI mortality in both strain of rats. The early benefits of omapatrilat were due to a combination of reduced ventricular arrhythmias and reduced MI size, and the late benefits were the result of a combination of reduced MI size, reduced adverse LV remodelling, and preserved LV function. In ZIR rats, the kinin receptor blocker icatibant eliminated the anti-arrhythmic effects of omapatrilat, but had no effect on MI size. We also found that in Wistar rats, captopril and omapatrilat had similar effects on survival, cardiac function and structure.
Notes: Adviser:  Jean-Lucien Rouleau.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-10, Section: B, page: 4928.