Effects of KATP openers on the QT prolongation induced by HERG-blocking drugs in guinea-pigs

Testai, Lara; Cecchetti, Violetta; Sabatini, Stefano; Martelli, Alma; Breschi, Maria Cristina; Calderone, Vincenzo

doi:10.1211/jpp.62.07.0014

Cited by 15 publications

(7 citation statements)

References 40 publications

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“…One of these, NS1643, supressed dofetilide-induced QT prolongation and TdP in a rabbit model [45]. Activators of cardiac ATPsensitive potassium channels (K ATP ) such as pinacidil and cromakalim have also had beneficial effects for aLQTS associated with some but not all culprit drugs [46]. α 2 -adrenoceptor agonists attenuate L-type calcium channels and supress EADs.…”

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confidence: 99%

Pharmacological treatment of acquired QT prolongation and torsades de pointes

Thomas

Behr

2015

Brit J Clinical Pharma

120

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Torsades de pointes (TdP) is a characteristic polymorphic ventricular arrhythmia associated with delayed ventricular repolarization as evidenced on the surface electrocardiogram by QT interval prolongation. It typically occurs in self-limiting bursts, causing dizziness and syncope, but may occasionally progress to ventricular fibrillation and sudden death. Acquired long QT syndromes are mainly caused by cardiac disease, electrolyte abnormalities or exposure to drugs that block rectifying potassium channels, especially IKr. Management of TdP or marked QT prolongation includes removal or correction of precipitants, including discontinuation of culprit drugs and institution of cardiac monitoring. Electrolyte abnormalities and hypoxia should be corrected, with potassium concentrations maintained in the high normal range. Immediate treatment of TdP is by intravenous administration of magnesium sulphate, terminating prolonged episodes using electrical cardioversion. In refractory cases of recurrent TdP, the arrhythmia can be suppressed by increasing the underlying heart rate using isoproterenol (isoprenaline) or transvenous pacing. Other interventions are rarely needed, but there are case reports of successful use of lidocaine or phenytoin. Anti-arrhythmic drugs that prolong ventricular repolarization should be avoided. Some episodes of TdP could be avoided by careful prescribing of QT prolonging drugs, including an individualized assessment of risks and benefits before use, performing baseline and periodic electrocardiograms and measurement of electrolytes, especially during acute illnesses, using the lowest effective dose for the shortest possible time and avoiding potential drug interactions. These steps are particularly important in those with underlying repolarization abnormalities and those who have previously experienced drug-induced TdP.

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confidence: 99%

Pharmacological treatment of acquired QT prolongation and torsades de pointes

Thomas

Behr

2015

Brit J Clinical Pharma

120

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“…The QTc interval was 240±3 ms, 247±10 ms and 254±5 ms immediately following amidarone administration and increased to 272±17, 279±14 and 284±14 ms following 40 min in 18, 36 and 54 mg/kg amiodarone groups, respectively (all P<0.05), which demonstrated a significant difference when compared with the normal saline group 40 min following amidarone administration (246±4 ms) in these groups (all P<0.05). The data demonstrated that the mechanism underlying the prolongation of QTc intervals induced by terfenadine and amiodarone was similar, since terfenadine as well as amiodarone are blockers of the K + channel encoded by the human ether-à-go-go-related gene (hERG) (23,24).…”

Section: Resultsmentioning

confidence: 92%

Comparative study of the protective effects of terfenadine and amiodarone on barium chloride/aconitine-induced ventricular arrhythmias in rats: A potential role of terfenadine

Liu

et al. 2014

Molecular Medicine Reports

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Terfenadine is a second generation histamine receptor antagonist which is widely used as a non‑sedating antihistamine to relieve allergic responses. However, terfenadine has been associated with a number of side effects on cardiac electrical activities through blocking multiple ion channels in the heart, particularly K+ channels. Previous studies have also implied that terfenadine may have a potential antiarrhythmic effect; however, the electrophysiological influence by which terfenadine exerts its antiarrhythmic action remains elusive. Based on evidence from previous studies, it was hypothesized that the antiarrhythmic effect of terfenadine may be similar to that of amiodarone. The present study aimed to examine the effect of terfenadine on the QTc interval and on experimental ventricular arrhythmia in rats by comparing with that of amiodarone. The effect of terfenadine and amiodarone on the QTc interval was evaluated by comparison of multiple electrocardiograms. Barium chloride/aconitine was intraperitoneally injected to induce ventricular arrhythmias. Normal saline was administered to control rats. In comparison with normal saline, terfenadine and amiodarone similarly dose‑dependently prolonged the QTc interval in rats. In the barium chloride/aconitine-induced ventricular arrhythmia model, terfenadine and amiodarone did not only similarly delay the onset time of arrhythmias induced by barium chloride (all P<0.05), but also increased the cumulative dosage of aconitine required to induce various arrhythmias (all P<0.05). Furthermore, the two drugs equivalently caused a significant decrease in the duration of ventricular tachycardia in comparison with the normal saline controls (all P<0.05). The present study suggested that terfenadine prolonged the QTc interval and decreased ventricular tachycardia duration. The potential protective effect of terfenadine in ventricular arrhythmia may be similar to that of amiodarone.

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“…Implications from preclinical SQTS studies for the therapeutic deployment of K + channel activators There has been interest in the development and potential use of K + channel activators as novel antiarrhythmic agents, particularly in the setting of pathologically prolonged repolarization, where deployment of a K + channel activator may act to normalize repolarization [108][109][110]. The presence of endogenous K ATP channels comprised of K ir 6.x and SUR2A subunits, which only conduct significant current when cellular ATP falls, may exert some protective effects for the heart in situations of cardiac ischaemia or hypoxia, although it can lead to AP triangulation and associated arrhythmia risk [109,111].…”

Section: Insights From Preclinical Sqts Studies Into Arrhythmia Substmentioning

confidence: 99%

Learning from studying very rare cardiac conditions: the example of short QT syndrome

Hancox

Whittaker

Zhang

et al. 2019

J Congenit Heart Dis

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Background: Some congenital heart conditions are very rare. In a climate of limited resources, a viewpoint could be advanced that identifying diagnostic criteria for such conditions and, through empiricism, effective treatments should suffice and that extensive mechanistic research is unnecessary. Taking the rare but dangerous short QT syndrome (SQTS) as an example, this article makes the case for the imperative to study such rare conditions, highlighting that this yields substantial and sometimes unanticipated benefits. Genetic forms of SQTS are rare, but the condition may be under-diagnosed and carries a risk of sudden death. Genotyping of SQTS patients has led to identification of clear ion channel/transporter culprits in < 30% of cases, highlighting a role for as yet unidentified modulators of repolarization. For example, recent exome sequencing in SQTS has identified SLC4A3 as a novel modifier of ventricular repolarization. The need to distinguish "healthy" from "unhealthy" short QT intervals has led to a search for additional markers of arrhythmia risk. Some overlap may exist between SQTS, Brugada Syndrome, early repolarization and sinus bradycardia. Genotype-phenotype studies have led to identification of arrhythmia substrates and both realistic and theoretical pharmacological approaches for particular forms of SQTS. In turn this has increased understanding of underlying cardiac ion channels. In silico and pharmacological data have highlighted risks with abbreviation of refractoriness accompanied by local dispersion of repolarization, and this urges caution with the deployment of K + channel activation as a novel antiarrhythmic approach. The association between abbreviated QT c intervals and primary carnitine deficiency, particularly in patients with concomitant cardiomyopathy illustrates a link between metabolism and electrogenesis, in which the correct identification of causation could, in some cases, lead to dietary intervention that may obviate the need for antiarrhythmic or heart failure drugs. Conclusions: As illustrated here for the SQTS, the detailed study of rare disorders is both directly beneficial for the treatment/management of affected patients and for increasing the understanding of associated underlying cardiac physiology and pharmacology. The pursuit of underlying gene mutations can lead to unanticipated new links between particular genes and cardiac electrophysiology, opening new avenues for research and potential therapeutic intervention.

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Effects of KATP openers on the QT prolongation induced by HERG-blocking drugs in guinea-pigs

Cited by 15 publications

References 40 publications

Pharmacological treatment of acquired QT prolongation and torsades de pointes

Pharmacological treatment of acquired QT prolongation and torsades de pointes

Comparative study of the protective effects of terfenadine and amiodarone on barium chloride/aconitine-induced ventricular arrhythmias in rats: A potential role of terfenadine

Learning from studying very rare cardiac conditions: the example of short QT syndrome

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