Abstract
We have previously shown that the furnidipines’ metabolite M-2 improved coronary flow during low-flow and regional ischemia in vitro. This resulted in reduced mortality and incidence, or duration, of severe arrhythmias in in vivo models. The aim of this study was to establish the optimal period of oral treatment with M-2 for preventing or delaying the post-myocardial infarction (MI) cardiomyopathy development in rats. The male Sprague-Dawley rats (n=120) were used to model the experimental MI in vivo and also to model physiological perfusion of the isolated rat heart. The MI was invoked by permanent left coronary artery occlusion. The surviving rats were treated with M2 (4 mg/kg daily) administered from 21st-28th, 21st-35th, 11-28th, 11-35th or from 6-35th day, post MI, for the routine estimation of morphological features of cardiomyopathy. We summarized that the major vectors of the effects of treatment with M-2 were: 1) “Revitalisation” of the vessels and infarct scars. 2) Intensification of angiogenic events. 3) Inhibition of cardiomyopathic re-modeling of the myocardial tissue as a consequence of two mentioned above processes. Rats treated with M-2 for the longest periods had complete protection from developing cardiomyopathy. The early beginning and long treatment with M-2 was found the most effective for inhibiting the cardiomyopathic development. The good tolerance, long duration of action, low toxicity and relatively large therapeutic window, makes M-2, a promising candidate as a precursor for a new chemical class of cardio-protective drugs.
Highlights
We reported previously [1] that the experimental model of Myocardial Infarction (MI) in rats, where the hemodynamic parameters of the heart are measured ex vivo and with a complementary histological estimation, could accomplish understanding of pathophysiological processes to optimize the cardioprotective strategy with potentially active drugs
We found that the M-2 reduced mortality and the incidence and duration of severe arrhythmias while exhibiting differential influence on blood pressure which depended on the dose and timing of administration [3]
The fibrosing process was first found on day 3 remained elevated until day 28 [37]
Summary
We reported previously [1] that the experimental model of Myocardial Infarction (MI) in rats, where the hemodynamic parameters of the heart are measured ex vivo (working heart set-up) and with a complementary histological estimation, could accomplish understanding of pathophysiological processes to optimize the cardioprotective strategy with potentially active drugs.Prior findings suggested that evaluation for the optimal treatment time interval for the administration of cardio-protective drugs to prevent post-MI pathology was necessary. We reported previously [1] that the experimental model of Myocardial Infarction (MI) in rats, where the hemodynamic parameters of the heart are measured ex vivo (working heart set-up) and with a complementary histological estimation, could accomplish understanding of pathophysiological processes to optimize the cardioprotective strategy with potentially active drugs. A previously published study of ours using the rat working heart screening model [2] confirmed such a difference in effects of the prodrug, FUR, and its two active metabolites, M-2 and M-3. In this study, both metabolites caused a marked increase in coronary flow while FUR evoked a significantly lesser change in this parameter. A distinct shift in flow from the aorta to the coronary arteries was observed with M-2 and to a lesser extent, with M-3
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