Mechanism of block by tedisamil of transient outward current in human ventricular subepicardial myocytes

Abstract

1 Tedisamil is a new antiarrhythmic drug with predominant class III action. The aim of the present study was to investigate the blocking pattern of the compound on the transient outward current (I to ) in human subepicardial myocytes isolated from explanted left ventricles. Using the single electrode whole cell voltage clamp technique, I to was analysed after appropriate voltage inactivation of sodium current and block of calcium current. 2 Tedisamil reduced the amplitude of peak I to , but did not a ect the amplitude of non-inactivating outward current. The drug accelerated the apparent rate of I to inactivation. The reduction in time constant of I to inactivation depended on drug concentration, the apparent IC 50 value was 4.4 mM. 3 Tedisamil a ected I to amplitude in a use-dependent manner. After 2 min at 780 mV, maximum block of I to was reached after 4 ± 5 clamp steps either at the frequency of 0.2 or 2 Hz, indicating that the block was not frequency-dependent in an experimentally relevant range. Recovery from block was very slow and proceeded with a time constant of 12.1+1.8 s. Also in the presence of drug, a fraction of channels recovered from inactivation with a similar time constant as in control myocytes (i.e. 81+40 ms and 51+8 ms, respectively, n.s.). 4 From the onset of fractional block of I to by tedisamil during the initial 60 ms of a clamp step, we calculated k 1 =9610 6 mol 71 s 71 for the association rate constant, and k 2 =23 s 71 for the dissociation rate constant. The resulting apparent K D was 2.6 mM and is similar to the IC 50 value.5 The e ects of tedisamil on I to could be simulated by assuming a four state channel model where the drug binds to the channel in an open (activated) conformation. It is concluded that in human subepicardial myocytes tedisamil is an open channel blocker of I to and that this e ect probably contributes to the antiarrhythmic potential of this drug.

Dihydropyridine Ca2+ channel antagonists and agonists block Kv4.2, Kv4.3 and Kv1.4 K+ channels expressed in HEK293 cells

“…Some antiarrhythmic drugs, such as quinidine, tedisamil, disopyramide, propafenone, and flecainide, inhibit I to in a fashion that suggests an openchannel block mechanism (Slawsky & Castle, 1994;Yamashita et al, 1995;Wettwer et al, 1998;Sanchez-Chapula, 1999). Thus, the inhibition of I to by these agents and DHPs is characterized by a concentration-dependent reduction in peak …”

Inhibition of Kv2.1 Voltage-dependent K+Channels in Pancreatic β-Cells Enhances Glucose-dependent Insulin Secretion

“…Compounds related to C-1 are open channel blockers of voltagedependent outward K ϩ currents that increase the inactivation time constant of transient outward K ϩ currents (38,39). More potent effects of these compounds, however, have been reported on a slowly inactivating outward K ϩ current, where tedisamil reduced the current amplitude (40).…”

Brugada syndrome and anesthesia

“…[2] On the other hand, isoproterenol, [15] quinidine, [16] dysopyramide, [17] orciprenaline, [18] tedisamil, [19] cilostazol, [20] and dimethyl lithospermate B [21] are among the pharmacological agents which have been beneficial in the hindrance of an electrical storm.…”