Upstream eventAchE Inhibition
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Acetylcholinesterase inhibition leading to acute mortality||non-adjacent|
Life Stage Applicability
Key Event Relationship Description
Inhibition of AChE can lead to cardiovascular dysregulation when elevated acetylcholine levels overstimulate cholinergic receptors that regulate heart rate and vascular tone. In fish, acute mortality due to AChE inhibition is mediated by cardiovascular manifestations and the relationship between blood flow, gills, and respiratory physiology (Duangsawasdi and Klaverkamp 1979; Duangsawasdi 1978; McKim, Schmieder, Carlson, et al. 1987; McKim, Schmieder, Niemi, et al. 1987). In humans, cardiac effects are rarely the predominant factors leading to acute mortality caused by AChE inhibition because acute mortality is nearly always caused by respiratory failure in those cases. Nonetheless, it is still worth noting that cohort studies of patients exposed to organophosphate poisonings have documented a range of cardiovascular manifestations, including: abnormal electrocardiogram patterns, abnormal heart rate and blood pressure, and noncardiogenic pulmonary edema (Marrs 1993; Peter, Sudarsan, and Moran 2014).
Evidence Supporting this KER
The cardiovascular system is sensitive to AChE inhibition due to vagal innervation of heart tissue and due to the presence of non-neuronal acetylcholine released by cardiomyocytes in the heart. Acetylcholine acts on muscarinic receptors in the heart and overstimulation of the main muscarinic receptor (M2) leads to bradycardia in humans and in fish (Costa, Duagsawasdi 1978, Hsieh, 2002).
Studies in Rainbow Trout have consistently showed decreased heart rate in response to AChE inhibitor exposure. This has been shown for malathion, carbaryl (McKim et al. 1987), acephate, and fenitrothion (Duangsawasdi and Klaverkamp 1979)
Zebrafish and Xenopus embryos exposed to AChE organophosphate inhibitors exhibited cardiovascular impairments.
High concentrations (100 uM) of diazinon caused pericardial edema and compromised blood flow in Zebrafish embryos.
Chlorpyrifos treatment elicited a dose-dependent decrease in heart rate in both zebrafish and Xenopus embryos (Watson, 2014).
In a study of pigs, dichlorvos treatment inhibited AChE activity and impacted multiple measures of cardiovascular impairment. Heart rate was significantly lowered from the first time point measured until the last time point (0.5-6 hours post-dichlorvos treatment). Pulmonary vascular resistance increased and peaked at 1 hour post-dichlorvos treatment (reported as PVRI, an index calculated based on a standard formula, “PVRI = (mean pulmonary arterial pressure minus pulmonary artery wedge pressure) / CI x 80” (Cui, 2013)
Impaired cardiovascular function has been observed in laboratory studies of beagle dogs exposed to the organophosphorus nerve agent, VX (S-(2-diisopropylaminoethyl)-O- ethylmethyl phosphonothiolate). Authors concluded that VX exposure increased capillary permeability in the lungs and they propose this could lead to high-permeability edema (Lainee, 1991). In another study in beagles, VX treatment was associated with small but significant decreases in heart rate, arterial and left intraventricular pressure, and contractility index (Robineau, 1987).
According to an electronic search of PubMed records published between 1966-April 2014, two-thirds of patients with organophosphate poisoning experienced cardiac manifestations. The search terms were “organophosphorus compounds or phosphoric acid esters AND poison or poisoning AND manifestations”. As reviewed in Peter, 2014, specific cardiac manifestations observed across organophosphate poisoning cases included:
Abnormal electrocardiogram patterns: QTc prolongation, ST-T segment changes and T wave abnormalities.
Heart rate (HR) abnormalities: brachycardia (slow HR), tachycardia (fast HR), supraventricular and ventricular arrhythmias, and ventricular premature complexes
Blood pressure alterations in the form of hypotension and hypertension
Noncardiogenic pulmonary edema
Histologic evidence of myocardial damage has been reported in animal studies and in autopsies from fatal human poisonings (Reviewed by Mars, 1993).
Uncertainties and Inconsistencies
While cardiovascular complications leading to death have been reported in cases of intermediate syndrome following OP poisoning in humans, the timeframe for these cases fall outside of the scope of AChE inhibition leading to acute mortality.
Quantitative Understanding of the Linkage
Known modulating factors
In fish, OP insecticide toxicity at cardiovascular sites of action is dependent on physicochemical properties such as lipid solubility, degree of ionization, and environmental factors such as temperature (Duagsawasdi 1978, 1979).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
In fish, cardiovascular impairments are tightly connected to respiratory physiology, such that the cardio-respiratory manifestations of AChE inhibition lead to to acute mortality (McKim, 1987).
While impaired cardiovascular function is seen in humans and other mammals in cases of AChE inhibition, the subsequent contribution of cardiovascular impairment leading to death from cholinergic toxicity is minimal in humans. Even though cardiovascular effects have been observed in cases of organophosphate poisoning in humans, acute death from poisoning is usually caused by respiratory arrest mediated by the nervous system, independent of cardiovascular factors (Costa).
Duangsawasdi, M. 1978. “Organophosphate Insecticide Toxicity in Rainbow Trout (Salmo Gairdneri). Effects of Temperature and Investigations on the Sites of Action.” Manitoba, Canada.: University of Manitoba.
Duangsawasdi, M, and JF Klaverkamp. 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 667:35–51. Philadelphia, PA.
McKim, James M., Patricia K. Schmieder, Richard W. Carlson, Evelyn P. Hunt, and Gerald J. Niemi. 1987. “Use of Respiratory-Cardiovascular Responses of Rainbow Trout (Salmo Gairdneri) in Identifying Acute Toxicity Syndromes in Fish: Part 1. Pentachlorophenol, 2,4-Dinitrophenol, Tricaine Methanesulfonate and 1-Octanol.” Environmental Toxicology and Chemistry 6 (4): 295–312. https://doi.org/10.1002/etc.5620060407.
McKim, James M., Patricia K. Schmieder, Gerald J. Niemi, Richard W. Carlson, and Tala R. Henry. 1987. “Use of Respiratory-Cardiovascular Responses of Rainbow Trout (Salmo Gairdneri) in Identifying Acute Toxicity Syndromes in Fish: Part 2. Malathion, Carbaryl, Acrolein and Benzaldehyde.” Environmental Toxicology and Chemistry 6 (4): 313–28. https://doi.org/10.1002/etc.5620060408.
Marrs, T. C. 1993. “Organophosphate Poisoning.” Pharmacology & Therapeutics 58 (1): 51–66. https://doi.org/10.1016/0163-7258(93)90066-m.
Peter, John Victor, Thomas Sudarsan, and John Moran. 2014. “Clinical Features of Organophosphate Poisoning: A Review of Different Classification Systems and Approaches.” Indian Journal of Critical Care Medicine 18 (11): 735–45. https://doi.org/10.4103/0972-5229.144017.
Cui, Juan, Chun-Sheng Li, Xin-Hua He, and Yu-Guo Song. 2013. “Protective Effects of Penehyclidine Hydrochloride on Acute Lung Injury Caused by Severe Dichlorvos Poisoning in Swine.” Chinese Medical Journal 126 (24): 4764–70.
Costa, LG. 2019. “Toxic Effects of Pesticides.” In Casarett and Doull’s Toxicology: The Basic Science of Poisons, 9th ed, 1055–1106. McGraw-Hill Education.
Hsieh, Dennis Jine-Yuan, and Ching-Fong Liao. 2002. “Zebrafish M2 Muscarinic Acetylcholine Receptor: Cloning, Pharmacological Characterization, Expression Patterns and Roles in Embryonic Bradycardia.” British Journal of Pharmacology 137 (6): 782–92. https://doi.org/10.1038/sj.bjp.0704930.
Lainee, P., P. Robineau, P. Guittin, H. Coq, and G. Benchetrit. 1991. “Mechanisms of Pulmonary Edema Induced by an Organophosphorus Compound in Anesthetized Dogs.” Fundamental and Applied Toxicology: Official Journal of the Society of Toxicology 17 (1): 177–85. https://doi.org/10.1016/0272-0590(91)90249-4.
Robineau, P., and P. Guittin. 1987. “Effects of an Organophosphorous Compound on Cardiac Rhythm and Haemodynamics in Anaesthetized and Conscious Beagle Dogs.” Toxicology Letters 37 (1): 95–102. https://doi.org/10.1016/0378-4274(87)90173-1.
Watson, Fiona L., Hayden Schmidt, Zackery K. Turman, Natalie Hole, Hena Garcia, Jonathan Gregg, Joseph Tilghman, and Erica A. Fradinger. 2014. “Organophosphate Pesticides Induce Morphological Abnormalities and Decrease Locomotor Activity and Heart Rate in Danio Rerio and Xenopus Laevis.” Environmental Toxicology and Chemistry 33 (6): 1337–45. https://doi.org/10.1002/etc.2559.