QT Prolongation and Torsade de Pointes Ventricular Tachycardia Produced by Ketanserin

Aldariz, Antonio E.; Romero, Horacio; Baroni, M.; Baglivo, Hugo; Esper, Ricardo J.

doi:10.1111/j.1540-8159.1986.tb06633.x

Cited by 31 publications

(11 citation statements)

References 13 publications

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“…Moreover, ketanserin was also applied for pharmacological management of complex regional pain syndrome ( Luca‐Vinhas et al ., 2006 ; Rowbotham, 2006 ). However, ketanserin was found to have the cardiac toxicity that prolongs cardiac QTc interval in the ECG ( Aldariz et al ., 1986 ; Zehender et al ., 1989 ; Frishman and Grewall, 2000 ).…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study demonstrated the existence of both I Kr and I Ks in human ventricular myocytes ( Li et al ., 1996 ). The prolonged QTc interval of the ECG observed in clinical patients ( Aldariz et al ., 1986 ; Zehender et al ., 1989 ; Frishman and Grewall, 2000 ) is likely to be related to the block of cardiac I Kr and/or I Ks . We found, however, that ketanserin blocked hERG channels, but not I Ks channels.…”

Section: Discussionmentioning

confidence: 99%

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The 5‐HT₂ antagonist ketanserin is an open channel blocker of human cardiac ether‐à‐go‐go‐related gene (hERG) potassium channels

Tang

et al. 2008

British J Pharmacology

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Background and purpose: Ketanserin, a selective 5-HT receptor antagonist, prolongs the QT interval of ECG in patients. The purpose of the present study was to determine whether ketanserin would block human cardiac ether-à-go-go-related gene (hERG) potassium channels. Experimental approach: Whole-cell patch voltage-clamp technique was used to record membrane currents in HEK 293 cells expressing wild type or mutant hERG channel genes. Key results: Ketanserin blocked hERG current (I hERG ) in a concentration-dependent manner (IC 50 ¼ 0.11 mM). The drug showed an open channel blocking property, the block increasing significantly at depolarizing voltages between þ 10 to þ 60 mV. Voltage-dependence for inactivation of hERG channels was negatively shifted by 0.3 mM ketanserin. A 2.8 fold attenuation of inhibition by elevation of external K þ concentration (from 5.0 to 20 mM) was observed, whereas the inactivation-deficient mutants S620T and S631A had the IC 50 s of 0.84±0.2 and 1.7±0.4 mM (7.6 and 15.4 fold attenuation of block). In addition, the hERG mutants in pore helix and S6 also significantly reduced the channel block (2-59 fold) by ketanserin. Conclusions and implications: These results suggest that ketanserin binds to and blocks the open hERG channels in the pore helix and the S6 domain; channel inactivation is also involved in the blockade of hERG channels. Blockade of hERG channels most likely contributes to the prolongation of QT intervals in ECG observed clinically at therapeutic concentrations of ketanserin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The 5‐HT₂ antagonist ketanserin is an open channel blocker of human cardiac ether‐à‐go‐go‐related gene (hERG) potassium channels

Tang

et al. 2008

British J Pharmacology

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“…4 In addition, prolongation of the QT interval has been reported in KT-treated patients. [5][6][7] The antiarrhythmic action of KT in ischemic/reperfused rat heart has been ascribed to a prolongation of APD. 8 Recently, we reported that KT prolongs APD by exerting an open channel block of the fast component of the delayed rectifier potassium current (IKr) in guinea pig ventricular myocytes, with little or no effect on the inward rectifier potassium current (IK1) .9 It has been shown that transient potassium outward current (Ito) is the major outward repolarizing current in ferred to a 500-,uL chamber mounted on the stage of an inverted microscope (Nikon Inc).…”

Section: Ketanserin Inhibits Depolarization-activatedmentioning

confidence: 99%

Ketanserin inhibits depolarization-activated outward potassium current in rat ventricular myocytes.

Zhang

Boutjdir

El‐Sherif

1994

Circulation Research

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Ketanserin (KT), an antihypertensive agent, has been shown to prolong action potential duration (APD) and QT interval and to induce torsade de pointes in some patients. We previously suggested that the prolongation of APD could be due to KT inhibition of the fast component of the delayed rectifier current (IKr) in guinea-pig myocytes. However, in other tissue such as human atrium, Purkinje fibers, epicardial cells, and rat ventricular myocytes, the transient outward potassium current (ItO) is one of the major repolarizing currents. We investigated the possibility that KT could also increase APD by blocking 'to. Action potentials and membrane currents were recorded from rat ventricular myocytes known to have a large ItO by using whole-cell patch-clamp techniques. We found that KT (50 gmol/L) significantly prolonged APD at 50% repolarization by 218% (P<.05) the cardiac action potential of several mammalian tissues, including human atrium10 l" and rabbit, dog, and rat ventricular myocytes.12-"6 In these preparations, it is possible that KT could alter APD by interacting with ,to.To test this hypothesis, we used rat ventricular myocytes known to have a large IO to study the electrophysiological and pharmacological effect of KT on 'to recorded by whole-cell patch-clamp techniques. Materials and Methods Isolation of Cardiac MyocytesCardiac myocytes were obtained from hearts of Wistar rats (200 to 250 g) by enzymatic dissociation according to the method of Wittenberg et al,17 with some modifications.'8 The heart was perfused with a HEPES-buffered solution containing (mmol/L) NaCl 117, KCI 5.7, NaHCO3 4.4, KH2P04 1.5, MgCl2 1.7, HEPES 20, glucose 11, creatine 10, and taurine 20, along with 21 mU/mL insulin, and the pH was adjusted to 7.4 with NaOH. The heart was then perfused with fresh buffer mixed with 1.5 mg/mL collagenase type A or B (Boehringer Mannheim Corp) and 20 ,umol/L calcium for 50 to 60 minutes. The ventricles were then cut off and stirred to obtain cells.Cells were suspended in Petri dishes containing HEPES buffer with 1 mmol/L CaCl2 and 0.5% bovine serum albumin (pH 7.4). All solutions used for perfusion were gassed with 100% 02 and warmed to 37°C. After incubation for 30 minutes, a small aliquot of the medium containing single cells was trans-

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“…Furthermore, side effects are more abundant after intravenous administration (usually lOmg) which initially leads Table VII. In several placebo-controlled studies ketanserin has caused a slight and dose-dependent prolongation of the QT interval (Aldariz et al 1986;Cameron et al 1987;Stott et al 1986), which has clinical implications with respect to the development of ventricular arrhythmias. to higher Cmax values than those reported for the common oral dosages (Jennings & Opie 1987;Milei et al 1987;).…”

Section: Relationship Between Plasma Concentration and Adverse Effectsmentioning

confidence: 99%

Clinical Pharmacokinetics of Ketanserin

Persson

Heykants

Hedner

1991

Clinical Pharmacokinetics

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Ketanserin is a serotonin S2-receptor antagonist introduced for the treatment of arterial hypertension and vasospastic disorders. Plasma concentrations of ketanserin (and some metabolites) can be measured with high performance liquid chromatography using ultraviolet or fluorescence detection, or by radioimmunoassay. The methods are sensitive, accurate and specific. Following oral administration ketanserin is almost completely (more than 98%) and rapidly absorbed and peak concentrations in plasma are reached within 0.5 to 2 hours. It is subject to considerable extraction and metabolism in the liver (first-pass effect) and the absolute bioavailability is around 50%. The compound is extensively distributed to tissues and the volume of distribution is in the order of 3 to 6 L/kg. In plasma ketanserin binds avidly to plasma proteins, mainly albumin, and the free fraction is around 5%. Ketanserin is extensively metabolised and less than 2% is excreted as the parent compound. The major metabolic pathway is by ketone reduction leading to formation of ketanserin-ol which is mainly excreted in the urine. Ketanserin-ol, which by itself does not contribute to the overall pharmacological effect, is partly reoxidised into ketanserin, and it is likely that the terminal half-life of the parent compound is related to the slow ketanserin regeneration from the metabolite. Following intravenous administration plasma ketanserin concentrations decay triexponentially with sequential half-lives of 0.13, 2 and 14.3 h. The terminal half-life is similar after oral administration. Following long term oral dosing (20 or 40 mg twice daily) the pharmacokinetics remain linear and steady-state concentrations, which can be predicted from single-dose kinetics, are reached within 4 days. During long term treatment with the common dosage of 40 mg twice daily, steady-state concentrations fluctuate between 40 micrograms/L (trough) and 100 to 140 micrograms/L (peak). The pharmacokinetic properties of ketanserin are predictable in a wide group of patients and there is no influence from the duration of treatment, age and sex of the patient or concomitant treatment with beta-blockers or diuretics. There is no direct relationship between plasma concentrations of ketanserin and the antihypertensive effect in a group of patients. Side effects, including prolongation of the Q-T interval, are dose-dependent and, at least in the individual patient, related to peak plasma concentrations. In separate studies the pharmacokinetics of ketanserin were investigated in special patient groups, namely the elderly and patients with hepatic and renal insufficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

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QT Prolongation and Torsade de Pointes Ventricular Tachycardia Produced by Ketanserin

Cited by 31 publications

References 13 publications

The 5‐HT₂ antagonist ketanserin is an open channel blocker of human cardiac ether‐à‐go‐go‐related gene (hERG) potassium channels

The 5‐HT₂ antagonist ketanserin is an open channel blocker of human cardiac ether‐à‐go‐go‐related gene (hERG) potassium channels

Ketanserin inhibits depolarization-activated outward potassium current in rat ventricular myocytes.

Clinical Pharmacokinetics of Ketanserin

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QT Prolongation and Torsade de Pointes Ventricular Tachycardia Produced by Ketanserin

Cited by 31 publications

References 13 publications

The 5‐HT2 antagonist ketanserin is an open channel blocker of human cardiac ether‐à‐go‐go‐related gene (hERG) potassium channels

The 5‐HT2 antagonist ketanserin is an open channel blocker of human cardiac ether‐à‐go‐go‐related gene (hERG) potassium channels

Ketanserin inhibits depolarization-activated outward potassium current in rat ventricular myocytes.

Clinical Pharmacokinetics of Ketanserin

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The 5‐HT₂ antagonist ketanserin is an open channel blocker of human cardiac ether‐à‐go‐go‐related gene (hERG) potassium channels

The 5‐HT₂ antagonist ketanserin is an open channel blocker of human cardiac ether‐à‐go‐go‐related gene (hERG) potassium channels