IKr Channel Blockers: Novel Antiarrhythmic Agents

Lee, K; Park, J Y; Ryu, Pan Dong; Kwon, Lae-Sung; Kim, H Y

doi:10.2174/1568016033477414

Cited by 18 publications

(6 citation statements)

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“…Selective block of the ventricular repolarizing I Kr or I Ks channels could be beneficial under special conditions, and several companies developed selective blockers [13,14]. Indeed, some of the most effective anti-arrhythmic drugs, amiodarone and its newly released (possibly less potent) analog dronedarone, have several ion channel targets including I Kr channels.…”

Section: Pharmacological Inhibition Of Cardiac Potassium Channelsmentioning

confidence: 99%

K Channel Openers as New Anti-arrhythmic Agents

Strutz‐Seebohm

Seebohm

2011

Heart Rate and Rhythm

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Ion channels are membrane integral proteins that allow controlled passage of ions through cellular membranes. Cation-selective channels play key roles in physiological processes such as control of ion homeostasis and cell volume, vesicle trafficking, neurotransmitter and hormone secretion, and electrical control of excitable tissues. Many therapeutic drugs mediate their effects by targeting cation channel proteins. Potassium-selective channels are the most genetically and functionally diverse family of cation channels. After the cloning of the first potassium-selective ion channel, Shaker from Drosophila, several hundred potassium channel genes have been identified in the human genome. The number of functionally distinct channels in native tissues is further increased by heteromultimeric coassembly of potassium channel a-subunits with other a-and b-subunits and by posttranscriptional or posttranslational modifications such as alternative splicing of mRNAs, glycosylation, sumoylation, and phosphorylation. In light of the broad range of physiological roles of K channels it is not surprising that channel impairment results in a variety of pathophysiological conditions.The following text will give an overview of molecular details and availability of potassium channel modulators and try to address their potential as anti-arrhythmic drugs.

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Section: Pharmacological Inhibition Of Cardiac Potassium Channelsmentioning

confidence: 99%

K Channel Openers as New Anti-arrhythmic Agents

Strutz‐Seebohm

Seebohm

2011

Heart Rate and Rhythm

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“…This might be unobserved in clinical trials unless continuous ECG monitoring takes place. In certain cases an IKr block might even be intended by antiarrhythmic drugs [72] .…”

Section: Expert Opinionmentioning

confidence: 99%

New cell models and assays in cardiac safety profiling

Meyer¹,

Sartipy²,

Blind

et al. 2007

Expert Opinion on Drug Metabolism & Toxicology

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Drug-induced prolongation of the QT interval in the electrocardiogram has been associated with life-threatening ventricular tachycardia of the Torsades de Pointes type. To prevent this risk to patients, all new drug entities must undergo thorough in vitro and preclinical in vivo testing. Because a hERG channel block is the primary reason for ventricular repolarisation, disturbances causing a QT interval prolongation, established in vitro test systems focus on the analysis of drug action on hERG channel function. More sophisticated assays study ventricular repolarisation directly with cardiac tissue preparations. In addition, in the future, novel biological models, such as stem-cell-derived cardiomyocytes and cardiac tissue slices, may allow the design of innovative assay systems to address relevant cardiac safety pharmacology parameters. In this review, established as well as innovative assays and cell models used in these assays are discussed.

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“…In cardiac tissue, voltage-gated K + channels have been identified as the rapid (IKr) and slow (IKs) components of the delayed rectifying K + currents. In cardiac tissue, class III antiarrhythmic drugs like ibutilide, dofetilide and sotalol decrease membrane excitability by blocking IKr channels, leading to prolongation of the action potential duration (for a review see Lee et al, 2003). In other words, pharmacologically induced delay in phase 3 repolarization increases the effective refractory period of myocytes.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of bupivacaine local anesthesia with the potassium channel blocker ibutilide

Smith¹,

Lindsay²

2007

European Journal of Pain

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In some clinical settings it is necessary to inject large volumes of local anesthetic--and consequently very high doses--in order to provide an adequate level of block. Subsequent absorption of these high doses, or inadvertent intravenous administration of even small doses, has led to systemic toxicity. Thus, it is desirable to develop adjuvants that are inert alone, but would enhance the potency and/or efficacy of local anesthetics to improve their safety. Adelta/C fibers possess K(+) channels identified as sustained delayed rectifier type K(DR) currents and transient A-type K(A) currents. In the heart, the class III antiarrhythmic drug ibutilide blocks the cardiac component of the rapid delayed rectifying K(+) current (IKr). Experiments were conducted to determine whether co-administration of the K(+) channel blocker ibutilide would enhance the local anesthetic bupivacaine in mice. After injecting bupivacaine mixed with vehicle or ibutilide in the popliteal region of mice, paw withdrawal latencies were determined by applying the plantar aspect of a single hind-paw to the surface a 55 degrees C hot-plate device. 0.5% Bupivacaine+ibutilide (7.8x10(-5) M) elicited significantly longer hot-plate latencies than 0.5% bupivacaine+vehicle. In addition, bupivacaine was 2.6-fold more potent when co-administered with ibutilide rather than vehicle. Epinephrine extends the tissue concentrations of local anesthetics by inducing localized vasoconstriction. Epinephrine augmented the enhancement by ibutilide of bupivacaine's potency by 6.8-fold. In summary, ibutilide may enhance the effects of bupivacaine by blocking K(+) channels on sensory nociceptive nerves.

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IKr Channel Blockers: Novel Antiarrhythmic Agents

Cited by 18 publications

References 0 publications

K Channel Openers as New Anti-arrhythmic Agents

K Channel Openers as New Anti-arrhythmic Agents

New cell models and assays in cardiac safety profiling

Enhancement of bupivacaine local anesthesia with the potassium channel blocker ibutilide

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