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Key Event Title
Dysregulation of heart rate and vascular tone
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|AChE inhibition - acute mortality||KeyEvent||Dan Villeneuve (send email)||Under Development: Contributions and Comments Welcome||Under Development|
Key Event Description
Heart rate and vascular function are sensitive to increases in cholinergic signalling. While specific cellular-molecular signalling pathways direct cardiovascular responses in a specific direction, acetylcholine acts at multiple cardiovascular regulatory input points such that the sum impact is best described as a dysregulation event.
In response to elevated levels of acetylcholine, muscarinic M2 receptors are hyperactivated to slow heart rate and induce hypotension. In contrast, nicotinic receptors respond to increased acetylcholine by increasing heart rate (tachycardia) and producing hypertension. The timing of how these contrasting inputs are integrated is complex (Campen, Lodish)
How It Is Measured or Detected
The methods used to detect and measure dysregulation of heart rate and vascular tone vary depending on the taxa and life stage. In some cases, special apparatuses are needed to stabilize an animal, in order to collect cardiovascular measurements.
In human patient cohort studies, cardiovascular status is determined from various measurements collected in medical settings: pulse rate, blood pressure and ECG recordings (Peter, Karki).
In experimental settings, blood pressure and pulse rate measurements in rats have been collected using a pressure transducer (Utah Medical, Midvale UT) connected to polyethylene tubing. Pulse rate was calculated using peak systolic blood pressure of the arterial pressure tracing as the marker for a single heartbeat. The mean arterial pressure was calculated from the analogue signal (Gaspari, 2007).
Heart rate and vascular measurements can be collected from fish using various laboratory systems suited for the species size and life stage (for example, embryonic or adult).
Fish - heart rate in embryos
One study measured heart beats in embryos by direct observation of heartbeats observed under a dissecting microscope over 30 second time intervals (Steele, 2009)
Fish - cardiovascular dynamics in adults
Collection of heart rate and vascular measurements in fish can require that the fish is hooked up to special respirometer-metabolism chambers (McKim, 1982). Individuals were anesthetized with 100 mg/L MS-222 (tricaine methanesulfonate) and immobilized by spinal transection. Coated 30 gauge copper wire electrodes were implanted to collect electrocardiography (ECG) and heart rate (HR) measurements. ECG and HR measurements were collected every 2 hours during a 24-48 hour time period. Blood pressure was monitored with an indwelling dorsal aortic cannula that was filled with heparinized saline and attached to a pressure transducer (Statham Model No. P23Db; Could Inc., Medical Products Division, Oxnard, CA). The pressure transducer was manometrically calibrated with a water column to read in millimeters of mercury. The pressure transducer and electrodes were connected to a Beckman dynograph recorder (Beckman Instrument Co., Skokie, IL) (McKim, 1987).
Domain of Applicability
Cardiovascular dysregulation has been observed in many taxa.
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)
Gaspari RJ, Paydarfar D. Pathophysiology of respiratory failure following acute dichlorvos poisoning in a rodent model. Neurotoxicology. 2007 May;28(3):664-71.
Campen. Toxic Responses of the Heart and Vascular System. In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. 999-952.
Karki P, Ansari JA, Bhandary S, Koirala S. Cardiac and electrocardiographical manifestations of acute organophosphate poisoning. Singapore Med J. 2004;45:385–9.
Lodish, Harvey, Arnold Berk, S. Lawrence Zipursky, Paul Matsudaira, David Baltimore, and James Darnell. 2000. “Neurotransmitters, Synapses, and Impulse Transmission.” Molecular Cell Biology. 4th Edition. https://www.ncbi.nlm.nih.gov/books/NBK21521/.
McKim, JM, Goeden, HM. A direct measure of the uptake efficiency of a xenobiotic chemical across the gills of brook trout (Salvelinus fontinalis) under normoxic and hypoxic conditions, Comparative Biochemistry and Physiology Part C: Comparative Pharmacology, Volume 72, Issue 1, 1982, pgs 65-74
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.
Peter, J.V., Sudarsan, T.I. and Moran, J.L. 2014. vas. Indian J Crit Care Med. 18(11): 735–745.