Upstream eventAccumulation, Acetylcholine in synapses
Increased, Atrioventricular block and bradycardia
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Directness||Weight of Evidence||Quantitative Understanding|
|Acetylcholinesterase inhibition leading to acute mortality||directly leads to||Strong||Moderate|
Life Stage Applicability
How Does This Key Event Relationship Work
In cardiac tissue, acetylcholine acts on M2 type muscarinic receptors. M2 receptors tend to mediate inhibition of cellular activity through activation of G proteins that inhibit adenylyl cyclase and activation of potassium channels in the plasma membrane. Activation of potassium channels by the M2 receptors alters the electrophysiology of supraventricular cells leading to arrhythmias (such as atrioventricular blockade) and decreased heart rate (bradycardia).
Weight of Evidence
Given the role of acetylcholine in regulating heart rate, it is highly plausible that accumulation of acetylcholine in the synapses associated with cardiac tissue would lead to arrhythmias and decreased heart rate.
Empirical Support for Linkage
- The role of acetylcholine in regulating heart rate via its action on M2 receptors is widely accepted dogma in pharmacology, toxicology, and physiology. There is an extensive body of literature on this relationship.
- Competitive antagonists of muscarinic acetylcholine receptors, like atropine, increase heart rate and are used to treat bradycardia.
- Carbachol-induced bradycardia was abolished by injection of a M2 mAChR morpholino antisense nucleotide in a dose dependent manner (Hsieh and Liao 2002).
Uncertainties or Inconsistencies
Quantitative Understanding of the Linkage
- A mathematical model of the dependence of heart rate on tissue concentrations of acetylcholine has been developed based on studies in dog (Dexter et al. 1989).
Evidence Supporting Taxonomic Applicability
Available data suggests this relationship is relevant to all organisms with heart tissue.
- Dexter F, Saidel GM, Levy MN, Rudy Y. 1989. Mathematical model of dependence of heart rate on tissue concentration of acetylcholine. American J. Physiol. - Heart and Circulatory Physiology. 256: H520-H526.
- Hsieh DJ, Liao CF. 2002. Zebrafish M2 muscarinic acetylcholine receptor: cloning, pharmacological characterization, expression patterns and roles in embryonic bradycardia.
- Golan, David E (editor). “Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy”, 2nd edition. LWW: 2008.
- Katzung, B. “Basic & Clinical Pharmacology”, 10th Edition. Mc Graw Hill Medical: 2007
- Harvey, Richard; Champe, Pamela (series editors). “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009