This is a mechanism module, not a specific disease. Do NOT create a "Xenobiotic Cardiac Ion-Channel Perturbation" Disease entry. Disorder entries reference individual nodes via conforms_to, for example "xenobiotic_cardiac_channel_perturbation#Altered Cardiac Action Potential". Conforming nodes substitute the specific xenobiotic, the channel it acts on, and the direction of the gating change (block or persistent activation).
Scope: the xenobiotic must act on the channel itself. A drug that causes arrhythmia through electrolyte disturbance, ischaemia, or structural injury belongs elsewhere, even when the endpoint looks the same.
Direction is deliberately not fixed at the trigger node. Channel blockade and pathological channel activation are opposite gating changes that converge on the same altered action potential, and both are in scope; the node descriptions and the conforming entry carry which one applies.
The action-potential change is likewise not fixed as prolongation. In guinea pig ventricular myocytes the direction depends on agent and concentration -- low-dose verapamil prolongs APD90 while higher concentrations and nisoldipine shorten it (PMID:9335409) -- so the central effector is stated as an altered action potential rather than a prolonged one.
Curation note: the AOP-Wiki pathways covering this mechanism (AOP 552, 555, 560, 95) carry no literature on any of their causal relationships and have never been OECD reviewed, and AOP 552's bibliography contains two citations that do not resolve to the papers it names. Every reference here was found independently of those bibliographies. See dismech issues #10368 and #10773.
Xenobiotic Cardiac Ion-Channel Perturbation
trigger
A drug or toxin binds a cardiac ion channel and changes its gating. The change may be blockade, as with IKr/hERG blockade by QT-prolonging drugs, L-type calcium channel blockade by verapamil-class agents, or funny-current blockade by ivabradine; or it may be pathological activation, as with aconitine binding the open state of the cardiac sodium channel and suppressing its inactivation. This is the acquired counterpart of a germline channel variant and is the entry point for drug- and toxin-induced arrhythmia.
Downstream
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Altered Cardiac Ionic Current
The gating change alters the current carried by the affected channel.
Show evidence (4 references)
"Arrhythmia can also be induced by a blockage of hERG channels by a surprisingly diverse group of drugs."
Review of hERG channel structure and pharmacology; no primary experimental system. Establishes drug blockade of a cardiac potassium channel as a recognized cause of acquired arrhythmia, which is the blockade direction of this trigger node.
"Ivabradine is an open-channel blocker; however, block is exerted preferentially when channels deactivate on depolarization, and is relieved by long hyperpolarizing steps."
Voltage-clamp recording of I(f) in isolated rabbit sino-atrial node myocytes. Characterizes the drug-channel interaction directly, showing a xenobiotic altering the gating of a cardiac pacemaker channel.
"Aconitine and mesaconitine bind with high affinity to the open state of the voltage-sensitive sodium channels at site 2, thereby causing a persistent activation of the sodium channels, which become refractory to excitation."
Clinical toxicology review; no primary experimental system. Establishes the pathological-activation direction of this node, in which a toxin holds a cardiac sodium channel open rather than blocking it.
+ 1 more reference
Altered Cardiac Ionic Current
amplifier
The current carried by the perturbed channel departs from normal. Blockade reduces peak current, as with suppression of L-type calcium current by verapamil or of I(f) by ivabradine; suppressed inactivation instead sustains an inward current beyond its normal window. Agents are frequently not selective for a single conductance, so the net current change may involve several currents at once.
Downstream
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Altered Cardiac Action Potential
The altered current changes the shape or timing of the action potential.
Show evidence (1 reference)
"Applications of Mn2+ and verapamil suppressed amplitudes of the L-type Ca2+ current (ICa), the delayed outward K+ current (IK), and the inward rectifier K+ current (IK1)."
Whole-cell patch clamp in isolated guinea pig ventricular myocytes. Measures the current change produced by channel-blocking agents, and shows that a blocker may suppress several currents rather than one.
Altered Cardiac Action Potential
central effector
The cardiomyocyte action potential departs from its normal configuration -- in duration, plateau amplitude, or the slope of diastolic depolarization. This is the key conformance target: it is where every xenobiotic entry point converges regardless of which channel was hit, and it is the step at which this module and the inherited-channelopathy module become the same chain. The direction of change is agent- and concentration-dependent and is not fixed here.
Downstream
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Arrhythmogenic Triggered Activity
An altered action potential in working myocardium supports afterdepolarization-driven triggered activity.
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Pacemaker Rate Depression
A shallower phase 4 depolarization at the sinoatrial node slows the firing rate.
Show evidence (2 references)
"We conclude that different types of Ca2+ channel blocking agents (Mn2+, verapamil, and nisoldipine) diversely modulate APD because of their multiple modes of actions on ICa and IK."
Whole-cell patch clamp in isolated guinea pig ventricular myocytes, measuring action potential duration at 90% repolarization. Supports channel blockade altering the action potential, and supports leaving the direction of change unfixed at this node.
"The degree of activation of the funny current determines, at the end of an action potential, the steepness of phase 4 depolarization; hence, the frequency of action potential firing."
Review of pacemaker physiology; no primary experimental system. Supports the pacemaker branch of this node, in which the altered current changes the slope of diastolic depolarization rather than repolarization.
Arrhythmogenic Triggered Activity
effector
The altered action potential permits afterdepolarizations -- early afterdepolarizations arising from a prolonged plateau, delayed afterdepolarizations from calcium overload -- which reach threshold and generate ectopic beats. This is the working-myocardium branch of the module.
Downstream
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Xenobiotic-Induced Cardiac Arrhythmia
Triggered ectopic beats initiate and sustain clinical arrhythmia.
Show evidence (1 reference)
"The electrophysiological mechanism of arrhythmia induction is triggered activity due to delayed after-depolarization and early after-depolarization."
Clinical toxicology review; no primary experimental system. Names both afterdepolarization types as the mechanism linking a xenobiotic-perturbed action potential to ectopic activity.
Pacemaker Rate Depression
effector
Reduced pacemaker current at the sinoatrial node flattens diastolic depolarization and slows spontaneous firing, producing bradycardia. This is the pacemaker branch of the module, and is the therapeutic mechanism of ivabradine as well as the toxic mechanism of excessive funny-current or calcium-channel blockade.
Downstream
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Xenobiotic-Induced Cardiac Arrhythmia
Excessive rate depression is itself a clinical rhythm disturbance.
Show evidence (2 references)
"Molecules able to bind specifically to and block f-channels can thus be used as pharmacological tools for heart rate reduction with little or no adverse cardiovascular side effects."
Review of pacemaker physiology; no primary experimental system. Graded INDIRECT because it is a therapeutic-response statement: rate reduction on giving an f-channel blocker implies the mechanism rather than measuring it.
"The use-dependence resulting from specific features of I(f) block by ivabradine amplifies its rate-reducing ability at high spontaneous rates and may be useful to clinical applications."
Voltage-clamp recording of I(f) in isolated rabbit sino-atrial node myocytes. Ties the measured channel block to rate reduction, and shows the effect is greater at high spontaneous rates.
Xenobiotic-Induced Cardiac Arrhythmia
consequence
The clinical endpoint: a rhythm disturbance attributable to a drug or toxin acting on a cardiac ion channel. Depending on the branch reached, this presents as torsade de pointes and polymorphic ventricular tachycardia from triggered activity, or as symptomatic bradycardia and sinus arrest from rate depression.
Show evidence (1 reference)
"The cardiovascular features include hypotension, chest pain, palpitations, bradycardia, sinus tachycardia, ventricular ectopics, ventricular tachycardia, and ventricular fibrillation."
Clinical toxicology review; no primary experimental system. Names endpoints on both branches of this module -- bradycardia from the pacemaker branch, ventricular ectopics and tachyarrhythmia from the triggered-activity branch.