Dihydropyridines’ metabolites-induced early apoptosis after myocardial infarction in rats; new outlook on preclinical study with M-2 and M-3

Abstract

Our previous studies established cardio-protective effects of furnidipine and its active metabolites called M-2 and M-3. The aim of current research was to compare the effects of single oral pretreatment with 20 mg kg−1 of M-2 and M-3 on mortality, different forms of arrhythmias, blood pressures parameters and ST-segment changes during occlusion (for 90 min) and reperfusion in the model of myocardial infarction in rats evoked by left anterior descending coronary artery occlusion. Additionally, the development of programmed cell death and biochemical parameters in blood serum were studied at 4th day after infarction. Furnidipines’ metabolites effectively reduced mortality index while did not markedly influence on blood pressures parameters, arrhythmias, ST-segment changes as well as biochemical parameters. Intriguingly, programmed cell death study (TUNEL) showed distinct increase in the amount of apoptotic nuclei in post-infarcted myocardium, granulation tissue and what is more in arteriolar walls after M-2 and M-3 application. Moreover, M-2 turned out to be more powerful in stimulation of apoptosis in granulation tissue surrounding infarcted area whereas M-3 presented balanced profile in this matter. Taking into account that programmed cell death plays positive role in post-infarcted heart healing, M-2 presents itself as more attractive agent for oral pretreatment in early stages of ischemia by non-stable individuals due to its more specific action in stimulation repairing processes in granulation tissue as well as in arteriolar walls. While M-2 and M-3 are common metabolites present in degradation pathways of many widely used dihydropyridines in clinic, this key fact put the new outlook on understanding additional mechanism and effects of not only furnidipines’ metabolites but also other dihydropyridines.

MiR-134-5p Regulates Myocardial Apoptosis and Angiogenesis by Directly Targeting KDM2A After Myocardial Infarction

“…3) As a result, the incidence and mortality of heart failure after MI continue to rise. 4) Studies have confirmed that cardiomyocyte apoptosis is an important cause of ventricular remodeling, cardiac insufficiency, and arrhythmia after MI, 5,6) and myocardial angiogenesis is a key process for ventricular remodeling after MI. 7) Inhibition of cardiomyocyte apoptosis and promotion of angiogenesis can improve the prognosis of patients with MI.…”

Calenduloside E suppresses calcium overload by promoting the interaction between L-type calcium channels and Bcl2-associated athanogene 3 to alleviate myocardial ischemia/reperfusion injury

“…Nisoldipine is a dihydropyridine calcium channel blocker that is clinically used in the treatment of primary hypertension and coronary heart disease [11] , [12] . Bay-K-8644 is instead a highly selective LTCC agonist [48] .…”

“…Notably, our previous study concluded that AS could play cardiac protective role by inhibiting calcium overload and improve contraction function of myocardial cells [8] . Studies have shown that dihydropyridine calcium antagonists, such as furnidipine and diltiazem, can reduce myocardial ischemia–reperfusion injury by inhibiting apoptosis and oxidative stress [11] , [12] . Our research has proved that CE can play a cardioprotective effect by reducing calcium overload.…”

Overexpression of PLK1 relieved the myocardial ischemia-reperfusion injury of rats through inducing the mitophagy and regulating the p-AMPK/FUNDC1 axis

“…Some studies have confirmed that myocardial cell death is a critical cause of ventricular remodeling, cardiac insufficiency and arrhythmia after myocardial infarction. Whereas myocardial ischemia induced mitochondrial dysfunction can result in the death of myocardial cells [ 3 , 4 ]. Mitochondria are organelles which can produce the reactive oxygen species (ROS), while more than ten times ROS will be generated in damaged mitochondria compared to normal mitochondria.…”