The antipsychotic drug sertindole is a specific inhibitor of α1A-adrenoceptors in rat mesenteric small arteries

Ipsen, M.; Zhang, Youyi; Dragsted, Nils; Han, Chide; Mulvany, Michael J.

doi:10.1016/s0014-2999(97)01242-9

Cited by 30 publications

(26 citation statements)

References 28 publications

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“…It does also show ␣ 1A -blocking properties in rat mesenteric arteries (Ipsen et al, 1997). New studies are required to test possible additional electrophysiological properties of sertindole in the heart under conditions when physiological levels of these agonists are present.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical phase III trials showed therapeutic effectiveness against both positive and negative symptoms of schizophrenia (Hale et al, 2000), whereas extrapyramidal symptoms were absent (Zimbroff et al, 1997). Sertindole has a high affinity for several serotonin and dopamine receptor subtypes and ␣ 1A -adrenergic receptors (Ipsen et al, 1997;Arnt, 1998;Bigliani et al, 2000). Furthermore, a high inhibitory effect on the current mediated by the potassium channel encoded by HERG has been shown in vitro (Rampe et al, 1998).…”

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confidence: 99%

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Electrophysiological Safety of Sertindole in Dogs with Normal and Remodeled Hearts

Thomsen

Volders

Štengl³

et al. 2003

J Pharmacol Exp Ther

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Inhibition of the potassium current I Kr and QT prolongation are associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of sertindole, an antipsychotic drug reported to prolong the QT interval in schizophrenic patients. In cell cultures, sertindole seemed to be a selective blocker of I HERG over other ion currents. For I HERG , the IC 50 value was 64 Ϯ 7 nM, whereas I SCN5A , I Ca,L , I Ca,T , I KCNQ1/KCNE1 , and I Kv4.3 were blocked in the micromolar range. In canine ventricular myocytes, the IC 50 value for I Kr inhibition by sertindole was 107 Ϯ 21 nM. Action potentials in these cells prolonged in a reverse rate-and concentration-dependent manner at 10 to 300 nM sertindole. In vivo, sertindole was administered to anesthetized dogs at clinically relevant (0.05-0.20 mg/kg) and high doses (1.0 -2.0 mg/kg) i.v. At 0.05 to 0.20 mg/kg sertindole (plasma concentrations 30 -157 nM), QT c was prolonged by 1 to 5% in normal dogs and by 9 to 20% in dogs with remodeled hearts due to chronic atrioventricular block (CAVB). TdP was not induced at these doses in normal dogs or in CAVB dogs with reproducible induction of TdP by dofetilide in previous experiments. At 1.0 to 2.0 mg/kg sertindole (plasma concentrations 0.5-3

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Electrophysiological Safety of Sertindole in Dogs with Normal and Remodeled Hearts

Thomsen

Volders

Štengl³

et al. 2003

J Pharmacol Exp Ther

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“…While all three can mediate vasoconstriction, their degree of involvement depends on the species and vascular bed under investigation (Vargas and Gorman 1995). Noradrenaline-induced constriction of rat mesenteric and renal resistance arteries does not involve α 2 -adrenoceptors and occurs predominantly if not exclusively via α 1A -adrenoceptors (Blue et al 1992(Blue et al , 1995Chen et al 1996Chen et al , 1997Ipsen et al 1997;Williams and Clarke 1995). The present study has used both types of microvessels to investigate modulation of noradrenaline-induced vasoconstriction by inhibitors of PKC (H7, staurosporine, bisindolylmaleimide I, Gö 6976), of tyrosine kinases (genistein, tyrphostin 23), and of the ERK cascade (PD 98059).…”

Section: Discussionmentioning

confidence: 99%

Modulation of noradrenaline-induced microvascular constriction by protein kinase inhibitors

Fetscher

Chen

Schäfers

et al. 2001

Naunyn-Schmiedeberg's Archives of Pharmacology

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We have tested the role of various protein kinases in noradrenaline-induced, alpha1A-adrenoceptor-mediated constriction of mesenteric and intrarenal rat microvessels. The protein kinase C inhibitors, H7 and staurosporine, inhibited constriction in both vessel types in concentrations which also inhibit myosin light chain kinase. The more selective protein kinase C inhibitors, bisindolylmaleimide I and Gö 6976, did not inhibit microvessel constriction in concentrations selective for protein kinase C. Moreover, the protein kinase C-activating phorbol ester, phorbol-12-myristate-13-acetate, did not cause constriction. The tyrosine kinase inhibitors, genistein and tyrphostin 23, inhibited constriction in concentrations compatible with tyrosine kinase inhibition. An inhibitor of the extracellular signal-regulated kinase cascade, PD 98059, also caused concentration-dependent inhibition. While chelation of extracellular Ca2+ abolished noradrenaline-induced constrictions, the Ca2+-ATPase inhibitor, thapsigargin, had no effects. We conclude that tyrosine kinases and extracellular signal-regulated kinase (but not protein kinase C) may be involved in noradrenaline-induced rat mesenteric and intrarenal microvessel constriction but this appears to occur independently of an effect on sarcoplasmic Ca2+ storage.

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“…Other electrophysiologic effects of sertindole [i.e., calciumantagonistic effects and/or the blockade of ␣ 1 -receptors (Ipsen et al, 1997;Arnt, 1998), each possibly influencing the others] may also be of importance. It is of note that Carlsson et al (1990) reported that an infusion of the ␣ 1 -agonist methoxamine facilitated the occurrence of TdP in ␣-chloraloseanesthetized rabbits treated with the I Kr blockers clofilium, almokalant, dofetilide, or sematilide.…”

Section: Effects Of Sertindole On Myocardial Repolarizationmentioning

confidence: 99%

Electrophysiologic Characterization of the Antipsychotic Drug Sertindole in a Rabbit Heart Model of Torsade de Pointes: Low Torsadogenic Potential Despite QT Prolongation

Eckardt

Breithardt²,

Haverkamp³

2002

J Pharmacol Exp Ther

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There is growing concern that antipsychotic drugs that prolong the QT interval almost always increase the risk for patients to develop life-threatening ventricular tachyarrhythmias (VTs) of the torsade de pointes type. We therefore sought to compare the electrophysiologic effects of the psychotropic agent sertindole, which prolongs cardiac repolarization by inhibiting the rapid component of the delayed rectifier potassium current (I Kr ) but has a low torsadogenic potential to the antiarrhythmic agent dl-sotalol. In 18 Langendorff-perfused rabbit hearts, sotalol (10 M, n ϭ 8) and sertindole (0.5, 1.0, and 1.5 M; n ϭ 10) led to significant and comparable QT prolongation. In the presence of sotalol, torsade de pointes reproducibly occurred in atrioventricular node-blocked hearts after lowering the potassium concentration to 1.5 mM. High doses of sertindole (1.5 M) only caused monomorphic VT (n ϭ 4) and nonsustained polymorphic VT (n ϭ 2) in the presence of QRS prolongation. Multiple simultaneous epi-and endocardial monophasic action potentials and a volume-conducted ECG demonstrated widening of the T/U wave, early afterdepolarizations, and increased dispersion of repolarization in the presence of dlsotalol. In contrast to sotalol, QT and monophasic action potential prolongation were cycle length-independent in the presence of sertindole. Sertindole had no significant effect on transmural or interventricular dispersion of repolarization. Early afterdepolarizations did not occur. Despite comparable QT prolongation, sertindole did not display the proarrhythmic profile typical of other blockers of I Kr such as dl-sotalol. It is likely that a different mode of interaction between sertindole and the channel and/or additional pharmacological effects of sertindole, e.g., its ability to inhibit I Na and/or its ability to block ␣ 1 -receptors, play a role.

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The antipsychotic drug sertindole is a specific inhibitor of α1A-adrenoceptors in rat mesenteric small arteries

Cited by 30 publications

References 28 publications

Electrophysiological Safety of Sertindole in Dogs with Normal and Remodeled Hearts

Electrophysiological Safety of Sertindole in Dogs with Normal and Remodeled Hearts

Modulation of noradrenaline-induced microvascular constriction by protein kinase inhibitors

Electrophysiologic Characterization of the Antipsychotic Drug Sertindole in a Rabbit Heart Model of Torsade de Pointes: Low Torsadogenic Potential Despite QT Prolongation

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