Cardiotoxicity of digitalis glycosides: roles of autonomic pathways, autacoids and ion channels

Abstract

1 Cardiac glycosides have been used for centuries as therapeutic agents for the treatment of heart diseases. In patients with heart failure, digoxin and the other glycosides exert their positive inotropic effect by inhibiting Na(+)-K(+)-ATPase, thereby increasing intracellular sodium, which, in turn, inhibits the Na(+)/Ca(2+) exchanger and increases intracellular calcium levels. As the therapeutic index of digitalis is narrow, arrhythmias are common problems in clinical practice. The mechanisms and mediators of these arrhythmias, however, are not completely understood. 2 The involvement of the sympathetic and parasympathetic nervous system in digitalis cardiac toxicity is reviewed. 3 Receptors, channels, exchange systems or other cellular components involved in digitalis-induced cardiotoxicity are also reviewed. 4 Possible mediators of digitalis-induced cardiac toxicity are discussed. 5 Management of digitalis toxicity in patients is summarized. 6 The determination of the possible mediators of digitalis-induced cardiac toxicity will enhance our knowledge and lead to the development of new therapeutic strategies to treat these lethal arrhythmias.

Coordinated Regulation of Murine Cardiomyocyte Contractility by Nanomolar (−)-Epigallocatechin-3-Gallate, the Major Green Tea Catechin

“…Na ϩ -K ϩ -ATPase activity importantly regulates intracellular [Na ϩ ]. Na ϩ -K ϩ -ATPase inhibition, e.g., by cardiac glycosides, increases intracellular [Na ϩ ] and thereby inhibits Ca 2ϩ efflux via the NCX, which is a well established mechanism for increasing SR Ca 2ϩ content and cardiac contractility (Demiryü rek and Demiryü rek, 2005). Previous work has demonstrated that micromolar EGCG inhibits Na ϩ -K ϩ -ATPase activity in human red blood cell membranes (Rizvi , 2005).…”

Mortal Furosemide-Hypokalemia-Disturbances in Rats NO-System Related Shorten Survival by L-NAME. Therapy Benefit with BPC 157 Peptide More Than With L-Arginine

“…Therefore, we attempted to define hypokalemia and/or hypokalemia disturbances as particular disturbances related to NO-system and possible therapeutic value of NOsystem-related agents: NO-synthase (NOS)-blocker, L-NAME, NOSsubstrate, L-arginine, and, particularly, stable gastric pentadecapeptide BPC 157 [4][5][6]. In this, we focused on so far not demonstrated with L-NAME/L-arginine application [1,2] NO-system-relations in mortal furosemide-diuresis-hypokalemia course; -ECG changes, carefully analyzed in rats [7] (prolongation of P, R, S, T waves and PR, RR, QRS, QT interval duration, and reduced amplitude of R, S, T wave (although not completely related to hypokalemia) [7]); -arrhythmias (AV conduction block, ventricular premature beats, ventricular tachycardia); -skeletal muscle myoclonus [8]; and -lethality 90-150 min post-furosemide. Likely, this furosemide-hypokalemia-NO-systemsyndrome should be worsened by L-NAME, ameliorated by L-arginine and finally, counteracted by BPC 157.…”

“…NO-system is proposed as endogenous cardioprotectant and antifibrillatory factor [1,2]. Diuretic-hypokalemia is an increasingly common cause of arrhythmias [3].…”

“…Providing that potassium is essential for many body functions, including muscle and nerve activity [31] and the same essential rescuing role of NO-system in both heart [1,2] and skeletal muscle [32] a supportive analogy noted in the severely hypokalemic furosemide- Table 9: Absolute termination of furosemide-induced hypokalemic arrhythmias and myoclonismus after application of pentadecapeptide BPC 157 (10 μg/kg i.p. ), L-NAME (5 mg/kg i.p.…”

“…Namely, BPC 157 interacts with NO-systems in prevention of chronic heart failure, reversal of already established chronic heart failure [9], preventing digitalis arrhythmias and counteracting already advanced digitalis arrhythmias [10], both in vivo and in vitro, always overriding the L-arginine's cardioprotectant and antiarrhythmic effect [10][11][12][13][14]. Since the methyldigoxin toxicity depends particularly on hypokalemia [1,2,15], an analogous life saving effect of BPC 157 would occur in hypokalemic rats overloaded with a huge dose of furosemide. Of note, probably also important for expected cardioprotectant and antiarrhythmic effectiveness [9,10] peptide [4][5][6].…”