Heart Rate Variability, Respiratory Sinus Arrhythmia, and Mathematical Modeling of Acetylcholine Pharmacokinetics/Pharmacodynamics in Sinus Node Neuroeffector Junctions

To the Editor: van Vlymen and Parlow [1] showed that administration of acetylcholinesterase and muscarinic antagonists decreases the amplitude of high-frequency heart rate variability in anesthetized patients. The authors' results are particularly exciting to me because they confirm predictions made by my mathematical modeling study [2]. The mathematical model also explains the authors observation that "neostigmine … [does] not prevent the inhibition of baroreflex sensitivity [from anticholinergic drugs]." I wholeheartedly agree with the authors that "effects of neostigmine on baroreflex sensitivity … are … difficult to study." The approach I used to circumvent this problem was to model acetylcholine pharmacokinetics and pharmacodynamics based on experimental data and then to make clinical predictions [3,4]. Briefly, spontaneous oscillations in blood pressure (from cardiac cycle to cardiac cycle) cause oscillations in efferent vagal activity. These oscillations in efferent vagal activity cause oscillations in acetylcholine release from postganglionic parasympathetic neurons. Oscillations in acetylcholine release cause oscillations in the concentration of acetylcholine in sinus node neuroeffector junctions. Anticholinesterases prolong the time required for acetylcholine degradation to well beyond the duration of a cardiac cycle. Thus, anticholmesterases decrease the magnitude of the oscillation of the concentration of acetylcholine in neuroeffector junctions, which pharmacodynamically causes a decrease in high-frequency heart rate variability. Franklin Dexter, MD, PhD Department of Anesthesia; University of Iowa; Iowa City, IA 52242