Upstream eventIncreased Cholinergic Signaling
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Acetylcholinesterase inhibition leading to acute mortality||adjacent||High||High|
Life Stage Applicability
Key Event Relationship Description
In the context of cholinergic toxicity induced by AChE inhibition, increased cholinergic signaling leads to impaired cardiovascular function because acetylcholine is an important signalling molecule in the heart. The vagus nerve and cardiomyocytes produce neuronal and non-neuronal acetylcholine, respectively (Saw, 2018, Beckmann, 2013). Cardiac function is controlled by the sympathetic and parasympathetic nervous systems.The heart is innervated by the vagus nerve, a cholinergic nerve that activates muscarinic acetylcholine receptors (M-ChR) on heart smooth muscle tissue.
While five different muscarinic receptors classes have been identified (M1-M5), the M2 receptor is most abundant in the heart and it is the most well-studied of the muscarinic receptors (Dhein, 2001, Zang, 2005). The M2 receptor is an inhibitory G-protein-coupled receptor that opens potassium channels in the cell membrane, which alters the heart smooth muscle cell electrophysiology and leads to arrhythmia and decreased heart rate (bradycardia) (Lodish, Zang, 2005).
Evidence Supporting this KER
- The cardiovascular system is responsive to acetylcholine released by the vagus nerve and to non-neuronal acetylcholine released by cardiomyocytes. Acetylcholine acts on muscarinic receptors in the heart and overstimulation of the main muscarinic receptor (M2) leads to bradycardia in mammals and in fish. In addition to being responsive to muscarinic effects, cardiovascular function can also be impaired by neuronal nicotinic signalling, which produces tachycardia or increased heart rate (Costa, Duagsawasdi 1978).
- 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).
The presence of cholinergic muscarinic receptors and the effects of muscarinic signalling in the heart has been extensively studied. It is widely accepted that increased M2 muscarinic signalling in the heart leads to slowed heart rate (bradycardia). For reviews on cholinergic signalling in the heart, see Coot, 2013 and Olshansky, 2008,
A genetic M2-knockout in zebrafish demonstrated that the M2 receptor mediates bradycardia induced under hypoxic conditions. Heart rates were significantly lower in Zebrafish raised under hypoxic conditions from the time of fertilization. However, bradycardia was abolished or significantly reduced in the fish that lacked M2 expression, indicating that M2 is directly slowing heart rate in zebrafish (Steele, 2009)
- An acute (24-h) exposure of fingerling rainbow trout to acephate found a dose-dependent relationship between inhibition of AChE, decreased heart rate, and mortality. The LC50 values ranged from 1880-3160 mg/L, with 76-89% inhibition of AChE in dead fish (at a concentration of 950-4000 mg/L), and significant effects on the heart rate (significant decrease) and respiration rates (significant increase) at a concentration of 2,000 mg/L (Duangsawasdi 1978, 1979).
Uncertainties and Inconsistencies
- No known qualitative inconsistencies or uncertainties associated with this relationship.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The presence of cholinergic effects mediated by the vagus nerve innervation of the heart has been extensively studied in many mammals, including humans, dogs, cats, rabbit, and monkeys (comprehensive review in Coote, 2013).
In fish, increased transmission of acetylcholine overstimulates the M2 muscarinic receptor regulating heart rate, causing hypoxic bradycardia.
Dhein S, van Koppen CJ, Brodde OE. Muscarinic receptors in the mammalian heart. Pharmacol Res. 2001 Sep;44(3):161-82.
Zang WJ, Chen LN, Yu XJ. Progress in the study of vagal control of cardiac ventricles. Sheng Li Xue Bao. 2005 Dec 25;57(6):659-72.
Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. 4th edition. New York: W. H. Freeman; 2000.
Costa. Toxic effects of pesticides. In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 1055-1106.
Steele SL, Lo KH, Li VW, Cheng SH, Ekker M, Perry SF. 10.1152/ajpregu.00036.2009. Epub 2009 Jun 10. Loss of M2 muscarinic receptor function inhibits development of hypoxic bradycardia and alters cardiac beta-adrenergic sensitivity in larval zebrafish (Danio rerio). Am J Physiol Regul Integr Comp Physiol. 2009 Aug;297(2)
Coote, JH, Myths and realities of the cardiac vagus. J Physiol. 2013 Sep 1; 591(Pt 17): 4073–4085.
Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation. 2008; 118(8): 863–871
Saw, Eng Leng et al. The non-neuronal cholinergic system in the heart: A comprehensive review. Journal of Molecular and Cellular Cardiology, v125, 129 - 139
Beckmann, J. Lips, K.S. The Non-Neuronal Cholinergic System in Health and Disease, Pharmacology 2013;92:286–302
Duangsawasdi M. 1978. Organophosphate insecticide toxicity in rainbow trout (Salmo gairdneri). Effects of temperature and investigations on the sites of action. PhD thesis. University of Manitoba, Manitoba, Canada.
Duangsawasdi M, Klaverkamp JF. 1979. Acephate and fenitrothion toxicity in rainbow trout: Effects of temperature stress and investigations on the sites of action. In Aquatic Toxicology, Vol 2, STP 667. ASTM International, Philadelphia, PA, USA, pp 35–51.