Cardioprotective Effects of an Active Metabolite of Furnidipine in 2 Models of Isolated Heart and on In Vivo Ischemia–induced and Reperfusion-induced Arrhythmias in Rats

Abstract

Dihydropyridines are known not only to have antiarrhythmic effects but also to exert a significant cardiac depressive influence. We previously showed that M-2, an active and final metabolite of furnidipine, had cardioprotective effects without the marked cardiac depression seen with this dihydropyridine. We studied the influence of M-2 infusion (10(-7) M) on hemodynamics during low-flow and regional ischemia in the rat working heart. We examined the protection conferred by M-2 infusion (10(-7) M) against effects of veratridine-induced intracellular calcium overload in the Langendorff heart. Additionally, we performed an in vivo study to explore the effects of oral administration of M-2 at different times and doses, in the ischemia- and reperfusion-induced arrhythmias model. M-2 improved coronary flow during low-flow and regional ischemia while favorably maintaining aortic pressure parameters. M-2 provided outstanding protection against deleterious effects of calcium overloading by significantly preventing rise in left ventricular diastolic pressure and decrease in coronary flow. M-2 reduced mortality and incidence and duration of severe arrhythmias while exhibiting differential influence on blood pressure, which depended on dose and time of administration and could suggest its clinical indication. The results of our entire study establish a beneficial cardioprotective role of M-2, which exhibited pleiotropic effects on the ischemic heart by imparting protection in various ways. This combined with 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 cardioprotective drugs.

Differential Effects of Furnidipines’ Metabolites on Reperfusion-Induced Arrhythmias in Rats In Vivo

“…It must be mentioned that oxy nifedipine is metabolized to a final product – M-2 and that means that M-2 is not only a final metabolite of FUR, but also of nifedipine. Hence, M-2, as a common molecule to NIF and FUR, evokes the most beneficial effects on heart tissue, what we previously proved [13], [14]. Few years earlier others proved that NIF evoke vasodilatation of coronary artery through NO mediated process in dogs [29].…”

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

“…The molecular mechanism of M-2 action on hemodynamic parameters is probably composed of its’ many various properties such as: L-type calcium channel blocking, outward potassium ATP-dependent channels activation and nitric oxide (NO) donation [28,32–33]. …”

“…The lack of cardiodepressive action of M-2 is attributed to its stronger affinity to outward potassium ATP-dependent channels than calcium channels [28,33,56]. Previous experiments have shown the reduction in anoxia-induced shortening of action potential (> 90% reduction) [33] indicate on M-2 direct role as an outward potassium ATP-dependent channels gating protector.…”

“…Previous experiments have shown the reduction in anoxia-induced shortening of action potential (> 90% reduction) [33] indicate on M-2 direct role as an outward potassium ATP-dependent channels gating protector. Additionally, revealed decrease of the intracellular free calcium ion concentration during hypoxia in non-stimulated isolated guinea pig cardiomyocytes after M-2 administration could be explained due to an effect on an alternative calcium entry via modified sodium channels or via sodium/calcium ions exchange [28].…”

“…Our former research with M-2 conducted on various experimental in vivo and ex vivo rat models established its beneficial effects on mortality [31,34], ischemia- and reperfusion-induced lethal arrhythmias [31,33–34] as well as hemodynamic parameters (e.g. blood pressure or coronary flow) [33–34]. …”