Diverse Toxicity Associated with Cardiac Na⁺/K⁺ Pump Inhibition: Evaluation of Electrophysiological Mechanisms

Modulation of Sarcoplasmic Reticulum Function by Na+/K+Pump Inhibitors with Different Toxicity: Digoxin and PST2744 [(E,Z)-3-((2-Aminoethoxy)imino)androstane-6,17-dione Hydrochloride]

“…Similarity between PST2744 and isoproterenol effects might suggest a receptor-or protein kinase A-mediated mechanism (Tsien et al, 1986). However, PST2744 did not enhance I CaL (Rocchetti et al, 2003), and binding studies showed that this agent is not a ligand of ␤-adrenergic receptors (Micheletti et al, 2002). During Na ϩ /Ca 2ϩ exchanger blockade, digoxin effects were compatible with a slight inhibition of the SR reloading process.…”

“…[Ca] SR-tot estimate can be biased by removal of Ca 2ϩ by the Na ϩ /Ca 2ϩ exchanger, which may be differently affected by the agents under the study (Rocchetti et al, 2003). To obtain an unbiased estimate of [Ca] SR-tot , Ca NCX during the ascending phase of the caffeine-induced Ca 2ϩ transient was added back to Ca tot measured at its peak (Table 1, Fig.…”

“…Cellular electrophysiology studies showed that the changes in action potential contour and relevant membrane currents caused by equi-inotropic PST2744 and digoxin concentrations were roughly similar (Rocchetti et al, 2003). The only effect potentially accounting for the different toxicity was the inhibition of the Na ϩ /Ca 2ϩ exchanger current by PST2744 through a mechanism independent of Na ϩ /K ϩ pump blockade (Rocchetti et al, 2003). Nonetheless, those studies could not discriminate whether such an effect resulted from PST2744 action on the exchanger itself or was secondary to changes in the dynamics of intracellular Ca 2ϩ .…”

“…In single-cell, tissue, and whole animal studies, the incidence of arrhythmias observed at similar inotropy (increase in unloaded cell shortening in single myocytes) was markedly lower for PST2744 than for digoxin (Micheletti et al, 2002;Rocchetti et al, 2003). Cellular electrophysiology studies showed that the changes in action potential contour and relevant membrane currents caused by equi-inotropic PST2744 and digoxin concentrations were roughly similar (Rocchetti et al, 2003). The only effect potentially accounting for the different toxicity was the inhibition of the Na ϩ /Ca 2ϩ exchanger current by PST2744 through a mechanism independent of Na ϩ /K ϩ pump blockade (Rocchetti et al, 2003).…”

Effect of Cardiac Glycosides on Action Potential Characteristics and Contractility in Cat Ventricular Myocytes: Role of Calcium Overload

“…In addition, AP shortening appears to be an action of some but not all cardiac glycosides. This could be a result of other drug actions, including the possibility that certain glycosides might also block I Ks , the slowly activating component of the delayed rectifier current (Rocchetti et al, 2003), which could explain why DHO (and not ouabain or actodigin) caused AP prolongation. The balance of opposing direct and indirect actions on net membrane current could then be responsible for the variety of glycoside effects on AP duration, especially in different species with varying dependencies of repolarization on I Ks .…”