The benzothiazepine derivative K-201 has been suggested as a potential therapeutic agent due to its antiarrhythmogenic action. To understand how the drug alters calcium release from the sarcoplasmic reticulum (SR), we investigated its effects on the SR calcium channel and calcium pump by single channel electrophysiology, whole-cell confocal microscopy, and ATPase activity measurements on control and post-myocardial infarcted (PMI) rat skeletal muscle. In bilayers, K-201 induced two subconductance states corresponding to ∼24% (S 1 ) and ∼13% (S 2 ) of the maximum conductance. Dependence of event frequency and of time spent in S 1 and S 2 on the drug concentration was biphasic both in control and in PMI rats, with a maximum at 50 μM. At this concentration, the channel spends 26 ± 4% and 24 ± 4%, respectively, of the total time in these subconductance states at positive potentials, while no subconductances are observed at negative potentials. K-201 altered the frequency of elementary calcium release events: spark frequency decreased from 0.039 ± 0.001 to 0.023 ± 0.001 s −1 sarcomere −1 , while the frequency of embers increased from 0.011 ± 0.001 to 0.023 ± 0.001 s −1 sarcomere −1 . Embers with different amplitude levels were observed after the addition of the drug. K-201 inhibited the Ca 2+ ATPase characterized by IC 50,contr = 119 ± 21 μM and n Hill,contr = 1.84 ± 0.48 for control and IC 50,PMI = 122 ± 18 μM and n Hill,PMI = 1.97 ± 0.24 for PMI animals. These results suggest that although K-201 would increase the appearance of subconductance states, the overall calcium release is reduced by the drug. In addition, the effect of K-201 is identical on calcium release channels from control and PMI rats.
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Effects of K-201 on the calcium pump and calcium release channel of rat skeletal muscle
Janos, Almassy; Monika, Sztretye; Balazs, Lukacs; Beatrix, Dienes; Laszlo, Szabo; Peter, Szentesi; Guy, Vassort; Laszlo, Csernoch; Istvan, Jona
Follow Pflügers Archiv European Journal of Physiologyl of Physiology
, Volume 457 (1)
Springer Journals – Oct 1, 2008
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