Anti-arrhythmic and hemodynamic effects of oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine.

Our previous studies have established cardio-protective effects of furnidipine and its active metabolites. We therefore decided to compare the influence of oral and intravenous administration of furnidipine, nifedipine, nitrendipine and nimodipine to examine their effects on hemodynamics and arrhythmias. Since dihydropyridines are oxidatively metabolized in the body and the oxidized metabolites are among the final products, we studied the influence of four oxidized dihydropyridines (oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine) on the same parameters. In vivo model of ischemia- and reperfusion-induced arrhythmias of rats was used. Dihydropyridines were administered 5 mg/kg orally (24 and 1 h before ischemia) or 5 µg/kg intravenously (10 min before ischemia). 20 mg/kg of the oxidized dihydropyridines was given orally (24 and 1 h before ischemia). The dihydropyridines exhibited significant anti-arrhythmic actions after both forms of administration but their influence on blood pressure was differential and contrasting and depended on route of administration. The oxidized dihydropyridines imparted strong protection against lethal arrhythmias while exerting differential influences on blood pressure with oxy nifedipine and oxy nisoldipine being hypertensive and oxy nitrendipine being most normotensive. The differential effects observed with the dihydropyridines after the two routes of administration lend strength to the hypothesis that their metabolites may have a significant role in mediating the actions of the parent drug. The strong anti-arrhythmic action of the oxidized dihydropyridines along with their differential effect on blood pressure could indicate their potential use as cardio-protective drugs in certain groups of patients.

Beneficial effects of l-leucine and l-valine on arrhythmias, hemodynamics and myocardial morphology in rats.

Branched chain amino acids (BCAA) have been shown to have a general protective effect on the heart in different animal models as well as in humans. However, so far no attempt has been made to specifically elucidate their influence on arrhythmias. Our study was performed to evaluate whether an infusion of either l-leucine or l-valine in a dose of 1mgkg(-1)h(-1) 10min before a 7-min period of left anterior descending artery occlusion followed by 15min of reperfusion, had an effect on arrhythmias measured during the reperfusion phase in the ischemia- and reperfusion-induced arrhythmias model in rats in vivo. The effect of the infusion of these substances on mean arterial blood pressure was monitored throughout the experiment. Both of the tested amino acids exhibited significant antiarrhythmic properties. l-Leucine reduced the duration of ventricular fibrillation (P<0.05) and l-valine decreased the duration of ventricular fibrillation (P<0.001) and ventricular tachycardia (P<0.05). The two amino acids were generally hypotensive. l-Valine lowered blood pressure in all phases of the experiment (P<0.05) while l-leucine lowered this parameter mainly towards the end of occlusion and reperfusion (P<0.05). In addition, 30min infusion of the amino acids in the used dose did not produce any apparent adverse histological changes that were remarkably different from control. In summary, the results of our study suggest that l-leucine and l-valine in the dose that was used attenuates arrhythmias and are hypotensive in their influence. Our findings lend support to the many ongoing investigations into the benefit of the application of l-leucine and l-valine in cardiology like their addition to cardioplegic solutions.

Cardioprotective effects of an active metabolite of furnidipine in 2 models of isolated heart and on in vivo ischemia­induced and reperfusion-induced arrhythmias in rats.

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.