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Desipramine (DMI) is a blocker of neuronal norepinephrine (NE) uptake transporter. Although intravenous DMI has been shown to cause centrally-mediated sympathoinhibition and peripheral NE accumulation, its parasympathetic effect remains to be elucidated. We hypothesized that intravenous DMI activates the cardiac vagal nerve via an α2-adrenergic mechanism. Using a cardiac microdialysis technique, changes in myocardial interstitial acetylcholine (ACh) levels in the left ventricular free wall in response to intravenous DMI (1mg·kg-1) were examined in anesthetized rats. In rats with intact vagi (n=7), intravenous DMI increased ACh from 1.67±0.43 to 2.48±0.66nM (P

An α2A-adrenergic agonist guanfacine improves autonomic imbalance in attention-deficit hyperactivity disorder, suggesting that it may be useful to correct autonomic imbalance in chronic heart failure (CHF) patients. To investigate the effects of guanfacine on cardiac autonomic nerve activities, a microdialysis technique was applied to anesthetized rabbit heart. Acetylcholine (ACh) and norepinephrine (NE) concentrations in atrial dialysates were measured as indices of cardiac autonomic nerve activities. Guanfacine at a dose of 100 μg/kg significantly decreased heart rate and increased dialysate ACh concentration without decreasing sympathetic NE release. Guanfacine may be useful for vagal activation therapy in CHF patients.

To directly monitor vagal acetylcholine (ACh) release into the sinoatrial node, which regulates heart rate, we implanted a microdialysis probe in the right atrium near the sinoatrial node and in the right ventricle of anesthetized rabbits, and perfused with Ringer's solution containing eserine. (1) Electrical stimulation of right or left cervical vagal nerve decreased atrial rate and increased dialysate ACh concentration in the right atrium in a frequency-dependent manner. Compared to left vagal stimulation, right vagal nerve stimulation decreased atrial rate to a greater extent at all frequencies, and increased dialysate ACh concentration to a greater extent at 10 and 20 Hz. However, dialysate ACh concentration in the right atrium correlated well with atrial rate independent of whether electrical stimulation was applied to the right or left vagal nerve (atrial rate=304-131 x log[ACh], R(2)=0.77). (2) Right or left vagal nerve stimulation at 20 Hz decreased atrial rate and increased dialysate ACh concentrations in both the right atrium (right, 17.9+/-4.0 nM; left, 7.9+/-1.4 nM) and right ventricle (right, 0.9+/-0.3 nM; left, 1.0+/-0.4 nM). However, atrial dialysate ACh concentrations were significantly higher than ventricular concentrations, while ventricular dialysate ACh concentrations were not significantly different between right and left vagal nerve stimulation. (3) The response of ACh release to right and left vagal nerve stimulation was abolished by intravenous administration of a ganglionic blocker, hexamethonium bromide. In conclusion, ACh concentration in dialysate from the right atrium, sampled by microdialysis, is a good marker of ACh release from postganglionic vagal nerves to the sinoatrial node.

A 14-day, 6 degrees head-down bed rest (HDBR) study was conducted with 12 healthy young men to determine whether there are transient responses of the cardiovascular autonomic regulatory system including cardiovascular, autonomic nervous, and cardiac baroreceptor reflex functions in the acute phases of HDBR and post-HDBR. Compared with the supine position before bed rest, the high-frequency band power (HF(RRI)) of RR intervals (RRIs) decreased significantly at 3, 6, and 24 h of HDBR. This tendency went on until 24 h post-HDBR. Three kinds of cardiac baroreceptor reflex sensitivity (BRS) were estimated from closed-loop approaches to simultaneously recorded spontaneous RRI and systolic arterial pressure (SAP) fluctuations. BRSsequence is based on the simultaneous changes between RRI and SAP. alphaLF and alphaHF are based on a cross-spectrum analysis for low- and high-frequency bands of RRI and SAP. Although BRSsequence decreased significantly at acute phases of both HDBR and post-HDBR, neither alphaLF nor alphaHF decreased significantly at any of the acute phases of HDBR and post-HDBR. Our results suggest that HF(RRI) and BRSsequence can be used effectively to reveal reductions in cardiac vagal nervous modulation on the sinus node and cardiac BRS within 24 h of both HDBR and post-HDBR.

This study aimed at examining whether the properties of microneurographically recorded muscle sympathetic nerve activity (MSNA) were altered during hypotensive attacks. A retrospective study was performed on 74 subjects who participated in tilt studies when vasodepressive syncope was induced incidentally in six subjects. The specific features of MSNA that distinguish this activity from skin sympathetic nerve activity are (1) rhythmic pulse synchronous burst discharge, (2) a duration of approximately 150-300 ms, and (3) no response to arousal stimuli were abolished during the syncopal attack. The altered features observed during the syncopal attack in these six subjects were (1) scattered reflex latencies of MSNA peak from the ECG R-wave, (2) elongated burst duration twice to five times as long as that in conscious state, and (3) response to arousal stimuli. The reduced input from the baroreceptors due to suppression on the central sympathetic volley proximal to the nucleus tractus solitarius might be attributed to the lost features characteristic of MSNA.

Although large conductance Ca(2+)-activated K(+) (BK) channels play an important role in determining vascular tone, their role in the efferent cardiac vagal system remains to be elucidated. In anesthetized rabbits (n=9), acetylcholine (ACh) was measured at the right atrium near the sinoatrial node by a cardiac microdialysis technique, and the ACh release in response to electrical stimulation of the cervical preganglionic vagal nerves was examined. Local administration of a BK channel blocker iberiotoxin (2 microM) through a dialysis fiber increased the stimulation-induced ACh release from 7.6+/-2.7 to 9.0+/-3.2 nM (P0.05). Addition of intravenous administration of iberiotoxin (0.11 mg/body) did not increase the stimulation-induced ACh release further (10.8+/-4.4 nM). These results indicate that the BK channels play an inhibitory role in the vagal ACh release to the sinoatrial node.