Efeitos dos glicosídeos cardioativos (digoxina ouabaína e oleandrina) na fisiologia cardiorrenal em ratos Wistar hígidos

Abstract

Cardioactive glycosides (GCs) are substances that act on the sodium and potassium pump of the heart (NKA) exerting inotropic activity. The best known GC is digoxin, used to date in the treatment of heart failure (HF). However, its narrow range of safety drives the discovery of new cardioactive substances. In this context, little is known about cardiovascular performance of oleandrin and ouabain. The aim of this study was to evaluate the comparative effects of GCs on cardiorenal physiology. Initially, a digoxin dosage study was performed, determining that the effective dose capable of altering the contractility of cardiomyocytes without causing serious arrhythmias is 50 ug/kg via SC for 21 days. The reference values for the electrocardiographic parameters (ECG) and the best QT interval correction formula were determined for especially Wistar rats. An anesthetic protocol was established for ECG with isoflurane and determination of mean values, standard deviation, minimum and maximum of the main parameters: heart rate (HR), duration and amplitude of P wave, duration of PR and QT intervals, duration of the QRS complex, amplitude of the R and T waves. The comparative evaluation of the QT formulas was also performed, where the Hodges formula presented a better correlation with the HR. Finally, the comparative effects of digoxin, ouabain, and oleandrin on the cardiorenal system were evaluated. The comparative analysis between GCs revealed important differences in their action on the cardiovascular system. GCs altered the red blood cell series, which was confirmed by the presence of echinocytes observed by scanning microscopy. Animals receiving oleandrin had more severe cardiac lesions observed by increased serum LDH activity, relative increase of CK-MB, and moderate focal necrosis of cardiomyocytes seen in light microscopy; rupture, shortening and disorganization of cardiac fibers as observed in scanning electron microscopy. The three treatments caused a relative increase of the creatinine and discrete lesions observed in renal optic microscopy. The expression of troponin I and alpha-1 isoform were not altered, however, the protein levels of BNP and alpha-2 were higher in the groups that received oleandrin and ouabain in relation to digoxin group. All GCs affected the production of ROS, without causing lipid peroxidation, through the activation of different antioxidant pathways. It is concluded that the effects of GCs are variable, possibly due to the difference between the affinity and inhibition of the NKA pump.