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Related Concept Videos

Antiarrhythmic Drugs: Class III Agents as Potassium Channel Blockers01:12

Antiarrhythmic Drugs: Class III Agents as Potassium Channel Blockers

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Class III antiarrhythmic drugs are a group of medications that can prolong action potentials in the heart. They achieve this by blocking potassium channels or enhancing inward currents from sodium channels. However, these drugs have a unique property of "reverse use-dependence," which is most pronounced at slower heart rates and can lead to torsades de pointes—a specific type of arrhythmia. However, it is essential to note that excessive QT interval prolongation—a measure of...
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Antihypertensive Drugs: Action of Calcium Channel Blockers01:18

Antihypertensive Drugs: Action of Calcium Channel Blockers

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Calcium ions are essential to contract smooth muscle cells in blood vessels. They enter these cells through voltage-dependent calcium channels, specifically L-type calcium channels in the cell membrane. These L-type calcium channels are integral to the excitation-contraction coupling process in smooth muscle. When a stimulus is received by smooth muscle cells, their membrane depolarizes. This alteration in membrane potential instigates the opening of L-type calcium channels. As a result,...
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Antiarrhythmic Drugs: Class II Agents as β-Adrenergic Blockers01:24

Antiarrhythmic Drugs: Class II Agents as β-Adrenergic Blockers

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Adrenergic stimulation generally impacts cardiac rate and rhythm. Specifically, stimulation of the β-adrenoceptors triggers an increase in intracellular calcium ion influx and pacemaker currents, which may cause arrhythmias. Catecholamines like adrenaline also demonstrate β2-adrenoceptor-mediated hypokalemia, impacting cardiac action potential and disrupting the normal cardiac rhythm. Class II antiarrhythmic drugs are β-adrenoceptor antagonists or β-blockers, which...
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Antiarrhythmic Drugs: Class IV Agents as Calcium Channel Blockers01:20

Antiarrhythmic Drugs: Class IV Agents as Calcium Channel Blockers

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Class IV antiarrhythmic drugs, such as verapamil and diltiazem, block calcium channels. They primarily affect the heart, slowing the conduction in calcium-dependent tissues like the SA and AV nodes. These drugs manage reentrant supraventricular tachycardia (SVT) and reduce ventricular rate in atrial flutter/fibrillation.
Verapamil, a calcium channel blocker, inhibits calcium movement across myocardial cell membranes and vascular smooth muscle. This results in the dilation of coronary and...
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Antiarrhythmic Drugs: Class I Agents as Sodium Channel Blockers01:22

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Class I antiarrhythmic drugs are used to treat various types of arrhythmias or irregular heart rhythms. These drugs block the sodium (Na+) channels in the cardiac cells, thereby affecting the movement of electrical impulses across the heart. Class I antiarrhythmic drugs are divided into three subgroups: Class IA, Class IB, and Class IC, each with distinct mechanisms of action and effects on the heart.
Class 1A Antiarrhythmic Drugs: These drugs work by moderately blocking sodium channels,...
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Adrenergic Antagonists: ɑ and β-Receptor Blockers01:31

Adrenergic Antagonists: ɑ and β-Receptor Blockers

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Third-generation β-blockers, such as labetalol and carvedilol, represent a significant advancement in managing cardiovascular conditions. Unlike conventional β-blockers, which can induce peripheral vasoconstriction, third-generation drugs block α1 adrenoceptors. This promotes vasodilation through several mechanisms, such as increased nitric oxide production, inhibition of calcium ion entry, opening of potassium ion channels, and antioxidant action. Labetalol, for instance, is...
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Related Experiment Video

Updated: May 21, 2025

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Alectinib causes sinus bradycardia by suppressing L-type calcium current in sinus node.

Guo-Xuan Liu1, Fan Diao1, Guang Lu2

  • 1School of Laboratory Animal & Shandong Laboratory Animal Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People's Republic of China.

European Journal of Pharmacology
|March 21, 2025
PubMed
Summary

Alectinib-induced sinus bradycardia in rats is caused by reduced L-type calcium channel Cacna1d expression, leading to cardiac electrophysiology dysfunction. This finding clarifies the mechanism behind this adverse cardiac event in patients.

Keywords:
AlectinibCacna1dCardio-oncologyL-type calcium currentSinus bradycardia

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Area of Science:

  • Cardiology
  • Pharmacology
  • Molecular Biology

Background:

  • Alectinib is a primary treatment for anaplastic lymphoma kinase-positive non-small cell lung cancer.
  • Sinus bradycardia is a significant adverse cardiac event associated with alectinib, impacting patient quality of life.
  • The precise mechanism underlying alectinib-induced sinus bradycardia (AISB) remains unclear.

Purpose of the Study:

  • To investigate the pathogenesis of alectinib-induced sinus bradycardia (AISB) in a rat model.
  • To elucidate the electrophysiological alterations and molecular mechanisms involved in AISB.

Main Methods:

  • Rats were administered alectinib (10 mg/kg/day) for 7-10 days to model AISB.
  • In vivo electrophysiology studies assessed heart rate and sinus node recovery time (SNRT).
  • RNA-sequencing (RNA-seq) analyzed transcriptomic changes in the sinus node.
  • Patch-clamp tests evaluated L-type calcium current (ICaL) density.

Main Results:

  • Alectinib treatment for 7 days, but not 3 days, significantly decreased heart rate and prolonged SNRT.
  • RNA-seq identified dysregulation of cardiac function genes, notably a decrease in Cacna1d (L-type calcium channel) expression.
  • Patch-clamp confirmed reduced ICaL density in alectinib-treated rats.

Conclusions:

  • AISB in rats is attributed to reduced Cacna1d expression.
  • This reduction leads to impaired cardiac electrophysiology via suppressed ICaL.
  • The study reveals a key molecular mechanism underlying alectinib's cardiac adverse effects.