Cardiomyopathy development protection after myocardial infarction in rats: Successful competition for major dihydropyridines’ common metabolite against captopril

<div><p>During the last 25 years angiotensin-converting enzyme inhibitors spectacularly conquered the field of cardiovascular diseases therapy. Nevertheless, lack of new studies concerning side effects associated with their chronic administration seems to be rather confusing. In our previous research, we proved that the main furnidipines’ metabolite (M-2) possess multiple cardioprotective actions. Currently, we compared effects of post-infarction long-term oral treatment with M-2 and captopril on hemodynamic parameters and “ischemic cardiomyopathy” development in rats. Myocardial infarction was evoked by permanent left anterior descending coronary artery occlusion for 35 days. Surviving rats were treated with captopril (2 × 25 mg/kg) or M-2 (4 mg/kg) from 6^th– 35^th day. At 35^th day rats’ hearts were tested on working heart setup, where following parameters were measured: heart rate, preload pressure, aortic systolic and diastolic pressures, aortic maximum rise and fall, aortic and coronary flow, myocardial oxygen consumption and oximetry in perfusate. Subsequently, heart tissue specimens were assessed during morphological estimation. Captopril caused significant heart rate increase and markedly diminished preload pressure in comparison to M-2. Both drugs evoked essential aortic pressure increase. Aortic flow was significantly decreased after M-2, whereas captopril increased this parameter in comparison to M-2. Both agents caused marked coronary flow increase. Morphologic examination in captopril revealed cardiomyopathic process in 70% of hearts, whereas in M-2 this value reached 30%. Neovascularization of post-infarcted myocardium was visible only after M-2 therapy. Concluding, M-2 presented itself as more attractive agent in long-term post-infarction treatment by preventing cardiomyopathy development, angiogenesis stimulation and preserving cardiac performance.</p></div

The influence of long-term oral treatment (6^th– 35^th day) with captopril (2 × 25 mg/kg) and M-2 (4 mg/kg) after experimental myocardial infarction (MI) on: (A) heart rate (HR), (B) preload pressure (PP), (C) aortic systolic pressure (AoS), (D) aortic diastolic pressure (AoD), (E) aortic maximum rise of the first pressure derivative (+d<i>P</i>/d<i>t</i>) and (F) aortic maximal fall of the first pressure derivative (-d<i>P</i>/d<i>t</i>), tested in working heart setup.

<p>Data are expressed as mean values for each minute. For simplicity sake, standard error of the mean is presented only in control group. Non-parametric Kruskal-Wallis ANOVA test was used for all comparisons.</p> <p>Values marked with ✩<i>P</i><0.05, ✩✩<i>P</i><0.01 or ★<i>P</i><0.001 are significantly different from control group.</p> <p>Values marked with ○<i>P</i><0.05 or ○○<i>P</i><0.01 are significantly different from DMSO group.</p> <p>Values marked with ^<i>#</i><i>P</i><0.05 or ^<i>##</i><i>P</i><0.01 are significantly different between captopril and M-2 group.</p

Incidence of cardiomyopathy development in rats treated orally with captopril (2 × 25 mg/kg) or M-2 (4 mg/kg) from 6^th to 35^th day after experimental myocardial infarction.

<p>Incidence of cardiomyopathy development in rats treated orally with captopril (2 × 25 mg/kg) or M-2 (4 mg/kg) from 6^th to 35^th day after experimental myocardial infarction.</p

Representative histological findings of epicardial vessels evaluation at 35^th day post-infarction after long-term oral treatment (6^th– 35^th day) with captopril (2 × 25 mg/kg) or M-2 (4 mg/kg) (hematoxylin and eozine-stained).

<p>(A) Captopril group, (B) M-2 group (scanned with 20× objective, magnification 30×, bar represents 50 μm). </p><p></p><p>(A)</p><p>Small vessels composed of flattened endothelial cells observed inside fibrotic area.</p><p></p><p>(B)</p><p>Multiple, small capillary vessels composed of enlarged endothelial cells. Predominant part of endothelial cells reveals basophilic cytoplasm suggesting progressive neovascularization process.</p><p></p><p></p> <p></p> <p>Small vessels composed of flattened endothelial cells observed inside fibrotic area.</p> <p>Multiple, small capillary vessels composed of enlarged endothelial cells. Predominant part of endothelial cells reveals basophilic cytoplasm suggesting progressive neovascularization process.</p

Inflammatory infiltrations in studied material.

<p>Inflammatory infiltrations in studied material.</p

Schedule of the protocol study in the model of experimental myocardial infarction in rats.

<p>LH indicates Langedorff mode and WH the working heart mode. Aortic systolic pressure (<i>AoS</i>), aortic diastolic pressure (<i>AoD</i>), aortic flow (<i>AF</i>), coronary flow (<i>CF</i>), maximum rate of aortic systolic pressure increase (+<i>dP/dt</i>), maximum rate of aortic systolic pressure decrease (-<i>dP/dt</i>), oxygen partial pressure (<i>pO</i>_<i>2</i>) and carbon dioxide partial pressure (<i>pCO</i>_<i>2</i>) and pH values in pulmonary effluent, myocardial oxygen consumption (<i>MVO</i>_<i>2</i>), preload pressure (<i>PP</i>), heart rate (<i>HR</i>).</p

The influence of long-term oral treatment (6^th– 35^th day) after experimental myocardial infarction with captopril (2 × 25 mg/kg) or M-2 (4 mg/kg) on biochemical parameters measured in rats’ blood serum.

<p>The influence of long-term oral treatment (6^th– 35^th day) after experimental myocardial infarction with captopril (2 × 25 mg/kg) or M-2 (4 mg/kg) on biochemical parameters measured in rats’ blood serum.</p