Inhibitory actions of the selective serotonin re‐uptake inhibitor citalopram on HERG and ventricular L‐type calcium currents

Witchel, Harry J.; Pabbathi, Vijay K; Hofmann, Giovanna; Paul, Ashok A; Hancox, Jules C.

doi:10.1016/s0014-5793(01)03320-8

Cited by 105 publications

(61 citation statements)

References 30 publications

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“…It is notable that, in the present study, the pro®le of I HERG blockade during a sustained depolarization for each of FLEC, QUIN and PROPAF di ered from that characteristic for methanesulphonanilide agents (e.g. Snyders & Chaudhary, 1996;Zhou et al, 1998;Witchel et al, 2002). This suggests that the likely site(s) of action of these Class I agents and the methanesulphonanilides is/are likely to di er in some respects.…”

Section: Herg and Ligmentioning

confidence: 49%

“…Snyders & Chaudhary, 1996;Zhou et al, 1998). Some other HERG-blocking agents show a di erent pro®le, with blockade evident early during depolarization (Teschemacher et al, 1999;Walker et al, 2000;Mergenthaler et al, 2001;Witchel et al, 2002). In order to study the development of I HERG blockade by FLEC, longduration (10 s) depolarizing pulses were applied from a holding potential of 780 to 0 mV to elicit I HERG in control solution, as shown in Figure 5A.…”

Section: Deactivation Of I Herg Tailsmentioning

confidence: 99%

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Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine

Paul¹,

Witchel²,

Hancox³

2002

British J Pharmacology

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1 The inhibition of the cardiac`rapid' delayed recti®er current (I Kr ) and its cloned equivalent HERG mediate QT interval prolonging e ects of a wide range of clinically used drugs. In this study, we investigated the e ects of the Class Ic antiarrhythmic agent¯ecainide (FLEC) on ionic current (I HERG ) mediated by cloned HERG channels at 378C . We also compared the inhibitory potency of FLEC with other Class I agents: quinidine (QUIN, Class Ia); lignocaine (LIG, Class Ib) and propafenone (PROPAF, Class Ic). 2 Whole cell voltage clamp recordings of I HERG were made from an HEK293 cell line stably expressing HERG. FLEC inhibited I HERG`t ails' following test pulses to +30 mV with an IC 50 of 3.91+0.68 mM (mean+s.e.mean) and a Hill co-e cient close to 1 (0.76+0.09).3 In experiments in which I HERG tails were monitored following voltage commands to a range of test potentials, I HERG inhibition by FLEC was observed to be voltage-dependent and to be associated with a *75 mV shift of the activation curve for the current. Voltage-dependence of inhibition was greatest over the range of potentials corresponding to the steep portion of the I HERG activation curve. The time-course of I HERG tail deactivation was not signi®cantly altered by FLEC. 4 In experiments in which 10 s depolarizing pulses were applied from 780 to 0 mV, the level of current inhibition by FLEC did not increase between 1 and 10 s. Some time-dependence of inhibition was observed during the ®rst 200 ± 300 ms of depolarization. This observation and the voltage-dependence of inhibition are collectively consistent with FLEC exerting a rapid open channel state inhibition of I HERG . 5 Under similar recording conditions QUIN inhibited I HERG with an IC 50 of 0.41+0.04 mM and PROPAF inhibited I HERG with an IC 50 of 0.44+0.07 mM. Similar to FLEC, both QUIN and PROPAF showed voltage-dependence of inhibition and blockade developed rapidly during a sustained depolarization. 6 LIG showed little e ect on I HERG at low micromolar concentrations, but could inhibit the current at higher concentrations; the observed IC 50 was 262.90+22.40 mM. 7 Our data are consistent with FLEC, PROPAF and QUIN exerting I HERG blockade at clinically relevant concentrations. The rank potency as HERG blockers of the Class I drugs tested in this study was QUIN=PROPAF4FLEC44LIG. British Journal of Pharmacology (2002) 136, 717 ± 729 Keywords: Antiarrhythmic; Class Ia; Class Ib; Class Ic;¯ecainide; HERG; I Kr ; QT interval; QT prolongation; quinidine Abbreviations: ANOVA, analysis of variance; d, fractional distance in the transmembrane ®eld sensed at drug receptor site; DISO, disopyramide; FLEC,¯ecainide; HERG, Human ether-a-go-go related gene; IC 50 , half maximal inhibitory drug concentration; I Ca,L , L-type calcium current; I HERG , current mediated by the HERG channel; I K , delayed recti®er potassium current; I Kr`r apid' delayed recti®er potassium current; I Ks`s low' delayed recti®er potassium current; I to , transient outward potassium current; k, slope factor describing voltage de...

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Section: Herg and Ligmentioning

confidence: 49%

Section: Deactivation Of I Herg Tailsmentioning

confidence: 99%

Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine

Paul¹,

Witchel²,

Hancox³

2002

British J Pharmacology

Self Cite

150

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“…The significant inhibitory effect (p<0.05) at a relatively low insulin concentration (100 nmol/l) suggests that this finding has physiological and pathological relevance. Halfmaximal activation voltage and slope factor parameters derived from Boltzmann fits to current-voltage plots [7] were −11.25±2.29 mV and 7.55±1.01 mV respectively in controls (n=5), and −11.10±1.36 mV (p>0.1 vs control) and 4.56±0.32 mV (p<0.05 vs control) respectively in 1 µmol/l insulin (n=5). For voltage-dependent inactivation, half-maximal inactivation voltage and slope factor values were −30.60±1.58 mV and 7.10±1.13 mV respectively in controls (n=5), and −27.53±2.27 mV and 9.03±1.05 mV (both p>0.05 vs control) respectively in 1 µmol/l insulin (n=6).…”

Section: Resultsmentioning

confidence: 95%

“…These mean values were used to produce the activation and inactivation plots in Fig. 1f [7], where the relations for control and insulin tests are closely overlaid. Thus, in contrast to previous data from vascular smooth muscle cells [8], the decrease in cardiac I Ca,L with insulin did not correlate with shifts in voltage-dependent I Ca,L kinetics.…”

Section: Resultsmentioning

confidence: 99%

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Paradoxical effects of insulin on cardiac L-type calcium current and on contraction at physiological temperature

2004

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Aims/hypothesis. L-type calcium current (I Ca,L ) is a major determinant of mammalian cardiac contraction, and data from studies performed at room temperature suggest that this current is stimulated by insulin. This investigation aimed to determine whether or not insulin stimulates cardiac I Ca,L at 37°C. Methods. Isolated guinea pig ventricular myocytes were studied at room temperature and at 37°C. Myocytes were either field stimulated or whole-cell voltage clamped, and cell shortening was measured using video edge detection. Results. Insulin stimulated I Ca,L at ambient temperature. However, at 37°C the effect of insulin was to decrease rather than to increase I Ca,L . This action was concentration dependent and was not associated with voltage shifts in steady-state activation or inactivation properties of I Ca,L . At 37°C, insulin increased the extent of myocyte contraction despite producing a significant decrease in I Ca,L amplitude. Conclusions/interpretation. The findings of this study indicate that temperature is a key experimental variable in the study of the physiological actions of insulin. Furthermore, the increase in cardiac cell contraction by insulin at physiological temperature is not due to an increase in I Ca,L , but is probably due to stimulation of excitation-contraction coupling downstream of I Ca,L .

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Cellular Mechanisms, Molecular Targets, and Structure–Function Relationships in Drug‐Induced Arrhythmias: Antihistamines, Psychoactive Drugs, and Antimicrobial Agents

Soldovieri

Taglialatela

2010

Cardiotoxicity of Non‐Cardiovascular Drugs

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Inhibitory actions of the selective serotonin re‐uptake inhibitor citalopram on HERG and ventricular L‐type calcium currents

Cited by 105 publications

References 30 publications

Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine

Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine

Paradoxical effects of insulin on cardiac L-type calcium current and on contraction at physiological temperature

Cellular Mechanisms, Molecular Targets, and Structure–Function Relationships in Drug‐Induced Arrhythmias: Antihistamines, Psychoactive Drugs, and Antimicrobial Agents

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