Autonomic cardiocirculatory control in mice with reduced expression of the vesicular acetylcholine transporter

Abstract

In cardiovascular diseases, sympathetic tone has been comprehensively studied, whereas parasympathetic tone has received minor attention. The vesicular ACh transporter (VAChT) knockdown homozygous (VAChT KD HOM ) mouse is a useful model for examining the cardiocirculatory sympathovagal balance. Therefore, we investigated whether cholinergic dysfunction caused by reduced VAChT expression could adversely impact hemodynamic parameter [arterial pressure (AP) and heart rate (HR)] daily oscillation, baroreflex sensitivity, hemodynamic variability, sympathovagal balance, and cardiovascular reactivity to restraint stress. Wild-type and VAChT KD HOM mice were anesthetized for telemetry transmitter implantation, and APs and HRs were recorded 10 days after surgical recovery. Changes in HR elicited by methylatropine and propranolol provided the indexes of sympathovagal tone. Cardiovascular reactivity in response to a restraint test was examined 24 h after continuous recordings of AP and HR. VAChT KD HOM mice exhibited reduced parasympathetic and elevated sympathetic tone. Daily oscillations of AP and HR as well as AP variability were similar between groups. Nevertheless, HR variability, patterns with two dissimilar variations from symbolic analysis, and baroreflex sensitivity were reduced in VAChT KD HOM mice. The change in mean AP due to restraint stress was greater in VAChT KD HOM mice, whereas the tachycardic response was not. These findings demonstrate that the cholinergic dysfunction present in the VAChT KD HOM mouse did not adversely impact basal hemodynamic parameters but promoted autonomic imbalance, an attenuation of baroreflex sensitivity, and a greater pressure response to restraint stress. These results provide a framework for understanding how autonomic imbalance impacts cardiovascular function. daily hemodynamic oscillations; heart rate variability; mice; parasympathetic nervous system; vesicular acetylcholine transporter IN A NUMBER of cardiovascular diseases, e.g., heart failure, one of the most important changes to maintain cardiac output is sympathetic overactivity (79). This outcome is accompanied by a reduction in parasympathetic tone (47). Derangement of the autonomic nervous system seems to contribute to cardiac dysfunction and remodeling (17). However, although control of sympathetic tone in cardiovascular diseases has been extensively studied, less attention has been given to the role played by parasympathetic function (47).Regulation of cholinergic activity in the heart has recently emerged as an important step in the preservation of long-term cardiac function (64). Indeed, recent epidemiological evidence suggests improved outcomes for cardiovascular diseases in patients with Alzheimer's disease receiving anticholinesterase treatment (40,46). In addition, studies using acetylcholinesterase inhibitors in animals and patients with heart failure have demonstrated that it may be potentially useful for cardiovascular protection, resulting in beneficial effects for markers of cardiovascular risk and dysfu...

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