In this review, the basic mechanism of the parasympathetic nervous effect on the heart is discussed. This is expanded to clinical situations to clarify what can happen to patients after cholinesterase (ChE) inhibitor is administered and to avoid unnecessary adverse effects. The parasympathetic nervous system can affect heart as well as brain function, and its effect on the heart is more complicated than is generally thought. The best-known effect is the cardioinhibitory effect, i.e. slowing of the heart rate. Its effect is also very sensitive to the time at which the stimulus falls within the cardiac cycle (phase-dependent effect). On some occasions, a cardiostimulatory effect can be observed. The parasympathetic nervous system also interacts with the sympathetic nervous system (sympathetic-parasympathetic interaction). ChE inhibitors or acetylcholinesterase inhibitors are often being administered to improve cognitive function of patients with Alzheimer's disease. The heart is naturally rich with ChE, and its inhibition may affect cardiac function, especially in elderly patients, many of whom have concomitant cardiovascular disease. Inhibition of ChE retards ACh degradation and potentiates the cardioinhibitory effect. However, the effect of ChE inhibitor is only slight in patients that receive a typical dose. After administration of ChE inhibitor in humans, the phase-dependent effect is reduced because the parasympathetic nervous effect is potentiated and saturated (saturation mechanism). Beat-by-beat fluctuation is reduced. ChE inhibitor increases arterial blood pressure through central M1 and M2 subtypes of muscarinic receptors (Br J Pharmacol 127:1657-1665, 1999). However, diastolic blood pressure increases slightly.

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The role of the peripheral parasympathetic nervous system in the development of hypertension was investigated in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Animals were 5-7 weeks old, anesthetized, and in the open-chest condition. The decrement in heart rate evoked by parasympathetic nerve stimulation (62 +/- 8 beats/min) in SHR was greater (p < 0.01) than that in WKY rats (23 +/- 4 beats/min). Furthermore, the decrease in heart rate (73 +/- 9 beats/min) in response to combined stimulation of sympathetic and parasympathetic nerves in SHR was greater (p < 0.05) than that in response to vagal stimulation alone. The extent of the interaction of sympathetic and parasympathetic nerves was calculated as the difference between the decrease in heart rate during combined stimulation and that during vagal nerve stimulation alone. The extent of the interaction in SHR (-11 +/- 5) was not significantly different from that in WKY rats (-8 +/- 3 beats/min). Therefore, the influence of the peripheral parasympathetic nervous system in the early phase of hypertension may be greater than that in the normotensive state. Interaction between the two branches of the autonomic nervous system may occur as accentuated antagonism originating in the early phase of hypertension. The interaction during the early phase of hypertension may not be different in extent from that of the normotensive state.

The influence of the rate of acetylcholine hydrolysis on the magnitude and phase dependency of the cardiac chronotropic response to vagal stimulation was studied in anaesthetised dogs. In one group of animals the chronotropic response to tonic vagal stimulation varied directly with the dose of physostigmine. In a second group of animals one brief stimulus burst was delivered to the right vagus nerve during each cardiac cycle, and the timing (phase) of the stimulus was varied within the cycle. Before physostigmine was given the phase of the stimulus had a substantial influence on the chronotropic response. When each stimulus burst contained 6 pulses the response was changed from its minimum to its maximum value (mean (SEM) change 0.338(0.081) s) when the phase was shifted by a mean value of 0.091(0.031) s. After physostigmine (0.3 mg X kg-1) was given the change in response produced by a phase shift was much less pronounced. A mean shift in phase of 0.593(0.052) s was required to change the chronotropic response from its minimum to its maximum value, and the mean difference between the minimum and maximum response was only 0.140(0.032) s. Hence the rate of acetylcholine hydrolysis in the cardiac tissues is an important determinant of the phase dependency of the chronotropic response to repetitive vagal stimulation-that is, the slower the rate of hydrolysis the less the change in the chronotropic response elicited by a given change in stimulus timing.

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