Propafenone and 5-hydroxypropafenone concentrations in the right atrium of patients undergoing heart surgery

Latini, Roberto; Barbieri, Enrico; Castello, C; Marchi, Stefano de; Sica, Anthony L.; Gerosa, Gino; Rossi, Renato; Zardini, Piero

doi:10.1016/0002-8703(89)90804-1

Cited by 7 publications

(3 citation statements)

References 10 publications

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“…Thus, these results would suggest that both drugs block hKvl.5 channels only at concentrations much higher than the therapeutic plasma levels. However, it has been demonstrated that propafenone and 5‐hydroxy‐propafenone accumulates in myocardium at concentrations 10‐ and 20 fold higher than those observed in plasma, respectively (Latini et al , 1989). These data suggested that propafenone may reach cardiac concentrations ranging between 2‐6 μM, which correspond to the range at which propafenone can block cardiac ion channels.…”

Section: Discussionmentioning

confidence: 99%

Effects of propafenone and 5‐hydroxy‐propafenone on hKv1.5 channels

Franqueza

Valenzuela

Delpón

et al. 1998

British J Pharmacology

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1 The goal of this study was to analyse the e ects of propafenone and its major metabolite, 5-hydroxypropafenone, on a human cardiac K + channel (hKv1.5) stably expressed in Ltk 7 cells and using the whole-cell con®guration of the patch-clamp technique. 2 Propafenone and 5-hydroxy-propafenone inhibited in a concentration-dependent manner the hKv1.5 current with K D values of 4.4+0.3 mM and 9.2+1.6 mM, respectively. 3 Block induced by both drugs was voltage-dependent consistent with a value of electrical distance (referenced to the cytoplasmic side) of 0.17+0.55 (n=10) and 0.16+0.81 (n=16). 4 The apparent association (k) and dissociation (l) rate constants for propafenone were (8.9+0.9)610 6 M 71 s 71 and 39.5+4.2 s 71 , respectively. For 5-hydroxy-propafenone these values averaged (2.3+0.3)610 6 M 71 s 71 and 21.4+3.1 s 71 , respectively. 5 Both drugs reduced the tail current amplitude recorded at 740 mV after 250 ms depolarizing pulses to +60 mV, and slowed the deactivation time course resulting in a`crossover' phenomenon when the tail currents recorded under control conditions and in the presence of each drug were superimposed. 6 Both compounds induced a small but statistically signi®cant use-dependent block when trains of depolarizations at frequencies between 0.5 and 3 Hz were applied. 7 These results indicate that propafenone and its metabolite block hKv1.5 channels in a concentration-, voltage-, time-and use-dependent manner and the concentrations needed to observe these e ects are in the therapeutical range.

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Section: Discussionmentioning

confidence: 99%

Effects of propafenone and 5‐hydroxy‐propafenone on hKv1.5 channels

Franqueza

Valenzuela

Delpón

et al. 1998

British J Pharmacology

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“…Some studies also showed that QRS duration was increased with or without QT interval prolongation in humans after treatment with propafenone [ 48 , 49 , 50 , 51 , 52 ]. Therapeutic plasma levels of propafenone in humans were estimated to range from 0.53 to 5.28 µM [ 33 , 53 , 54 ]. Furthermore, propafenone concentrations in human atrial tissues were on average ten times higher than those found in the plasma [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…Therapeutic plasma levels of propafenone in humans were estimated to range from 0.53 to 5.28 µM [ 33 , 53 , 54 ]. Furthermore, propafenone concentrations in human atrial tissues were on average ten times higher than those found in the plasma [ 53 ]. Such concentrations approach or are even similar to the concentrations found in our work, in which the chronic effect on K IR 2.1 protein results in an increase in expression levels.…”

Section: Discussionmentioning

confidence: 99%

Chronic Propafenone Application Increases Functional KIR2.1 Expression In Vitro

Kool

Woolschot

et al. 2023

Pharmaceuticals

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Expression and activity of inwardly rectifying potassium (KIR) channels within the heart are strictly regulated. KIR channels have an important role in shaping cardiac action potentials, having a limited conductance at depolarized potentials but contributing to the final stage of repolarization and resting membrane stability. Impaired KIR2.1 function causes Andersen-Tawil Syndrome (ATS) and is associated with heart failure. Restoring KIR2.1 function by agonists of KIR2.1 (AgoKirs) would be beneficial. The class 1c antiarrhythmic drug propafenone is identified as an AgoKir; however, its long-term effects on KIR2.1 protein expression, subcellular localization, and function are unknown. Propafenone’s long-term effect on KIR2.1 expression and its underlying mechanisms in vitro were investigated. KIR2.1-carried currents were measured by single-cell patch-clamp electrophysiology. KIR2.1 protein expression levels were determined by Western blot analysis, whereas conventional immunofluorescence and advanced live-imaging microscopy were used to assess the subcellular localization of KIR2.1 proteins. Acute propafenone treatment at low concentrations supports the ability of propafenone to function as an AgoKir without disturbing KIR2.1 protein handling. Chronic propafenone treatment (at 25–100 times higher concentrations than in the acute treatment) increases KIR2.1 protein expression and KIR2.1 current densities in vitro, which are potentially associated with pre-lysosomal trafficking inhibition.

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