Such grouped patterns are known to enhance neurotransmitter release. Therefore, these data provide a new mechanism by which clonidine can further potentiate parasympathetic actions on the heart.

Spontaneous oscillations of blood pressure (BP) and interbeat interval (IBI) may reveal important information on the underlying baroreflex control and regulation of BP. We evaluated the method of continuously measured instantaneous baroreflex sensitivity by cross correlation (xBRS) validating its mean value against the gold standard of phenylephrine (Phe) and nitroprusside (SNP) bolus injections, and focusing on its spontaneous changes quantified as variability around the mean. For this purpose, we analyzed data from an earlier study of eight healthy males (aged 25–46 years) who had received Phe and SNP in conditions of baseline and autonomic blocking agents: atropine, propranolol, and clonidine. Average xBRS corresponds well to Phe/SNP‐BRS, with xBRS levels ranging from 1.2 (atropine) to 102 msec/mmHg (subject asleep under clonidine). Time shifts from BP‐ to IBI‐signal increased from ≤1 sec (maximum correlations within the current heartbeat) to 3–5 sec (under atropine). Plotted on a logarithmic vertical scale, xBRS values show 40% variability (defined as SD/mean) over the whole range in the various conditions, except twice when the subjects had fallen asleep and it dropped to 20%. The xBRS oscillates at frequencies of 0.1 Hz and lower, dominant between 0.02–0.05 Hz. Although xBRS is the result of IBI/BP‐changes, no linear coherence was found in the cross‐spectra of the xBRS‐signal and IBI or BP. We speculate that the level of variability in the xBRS‐signal may act as a probe into the central nervous condition, as evidenced in the two subjects who fell asleep with high xBRS and only 20% of relative variation.

Cividjian A, Toader E, Wesseling KH, Karemaker JM, McAllen R, Quintin L. Effect of clonidine on cardiac baroreflex delay in humans and rats. Am J Physiol Regul Integr Comp Physiol 300: R949-R957, 2011. First published January 26, 2011 doi:10.1152/ajpregu.00438.2010The delay between rising systolic blood pressure (SBP) and baroreflex bradycardia has been found to increase when vagal tone is low. The ␣2-agonist clonidine increases cardiac vagal tone, and this study tested how it affects . In eight conscious supine human volunteers clonidine (6 g/kg po) reduced , assessed both by cross correlation baroreflex sensitivity and sequence methods (both P Ͻ 0.05). Experiments on urethane-anaesthetized rats reproduced the phenomenon and investigated the underlying mechanism. Heart rate (HR) responses to increasing SBP produced with an arterial balloon catheter showed reduced (P Ͻ 0.05) after clonidine (100 g/kg iv). The central latency of the reflex was unaltered, however, as shown by the unchanged timing with which antidromically identified cardiac vagal motoneurons (CVM) responded to the arterial pulse. Testing the latency of the HR response to brief electrical stimuli to the right vagus showed that this was also unchanged by clonidine. Nevertheless, vagal stimuli delivered at a fixed time in the cardiac cycle (triggered from the ECG R-wave) slowed HR with a 1-beat delay in the baseline state but a 0-beat delay after clonidine (n ϭ 5, P Ͻ 0.05). This was because clonidine lengthened the diastolic period, allowing the vagal volleys to arrive at the heart just in time to postpone the next beat. Calculations indicate that naturally generated CVM volleys in both humans and rats arrive around this critical time. Clonidine thus reduces not by changing central or efferent latencies but simply by slowing the heart. sequences; lag; latency; cardiac vagal motoneurons; ␣ 2-agonist THE GAIN OF THE ARTERIAL baroreceptor-heart rate reflex (cardiac baroreflex) has been calculated from the relationship between spontaneous (10, 13) or drug-induced (47) increases in systolic blood pressure (SBP) and the accompanying decrease in heart rate (HR). In humans, the best correlations were initially obtained by relating cardiac intervals to the preceding SBP (delay ϭ 1 beat) (47), although later studies (14, 38) found a delay of 0 beat was appropriate in subjects with lower initial HRs. In unanesthetized rats, delays of between 2 and 14 beats gave the best correlation for spontaneous baroreflex measurements (35); the best fit for tachycardic responses was 2 to 3 beats longer than that for bradycardic responses (35). The sequence technique of baroreflex sensitivity (sBRS) (13) traditionally uses a constant delay ϭ 1 beat to measure spontaneous baroreflex slope in humans, although the method may be applied using delays of any whole number of beats. This approach has been expanded to give a near-continuous assessment of the slope of the cardiac baroreflex [time-domain cross-correlation BRS (xBRS)] (56). The algorithm of xBRS (56) adjusts in seconds...

Following peripheral beta-blockade, clonidine activated CVMs from a very low baseline, increased the slope of the cardiac baroreflex and sinus arrhythmia, and reduced pressure lability.

Toader E, McAllen RM, Cividjian A, Woods RL, Quintin L. Effect of systemic B-type natriuretic peptide on cardiac vagal motoneuron activity. Am J Physiol Heart Circ Physiol 293: H3465-H3470, 2007. First published September 28, 2007; doi:10.1152/ajpheart.00528.2007.-Intravenous B-type natriuretic peptide (BNP) enhances the bradycardia of reflexes from the heart, including the von Bezold-Jarisch reflex, but its site of action is unknown. The peptide is unlikely to penetrate the blood-brain barrier but could act on afferent or efferent reflex pathways. To investigate the latter, two types of experiment were performed on urethane-anesthetized (1.4 g/kg iv) rats. First, the activity was recorded extracellularly from single cardiac vagal motoneurons (CVMs) in the nucleus ambiguus. CVMs were identified by antidromic activation from the cardiac vagal branch and by their barosensitivity. Phenyl biguanide (PBG), injected via the right atrium in bolus doses of 1-5 g to evoke the von Bezold-Jarisch reflex, caused a dose-related increase in CVM activity and bradycardia. BNP infusion (25 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 iv) significantly enhanced both the CVM response to PBG (n ϭ 5 rats) and the reflex bradycardia, but the log-linear relation between those two responses over a range of PBG doses was unchanged by BNP. The reflex bradycardia was not enhanced in five matched time-control rats receiving only vehicle infusions. In five other rats the cervical vagi were cut and the peripheral right vagus was stimulated supramaximally at frequencies of 1-20 Hz. The bradycardic responses to these stimuli were unchanged before, during, and after BNP infusion. We conclude that systemic BNP in a moderate dose enhances the von Bezold-Jarisch reflex activation of CVM, in parallel with the enhanced reflex bradycardia. That enhancement is due entirely to an action before the vagal efferent arm of the reflex pathway.cardiopulmonary; von Bezold-Jarisch; phenyl biguanide; bradycardia; heart; chemoreflex; parasympathetic; vagus; single unit activity INCREASED SYMPATHETIC DRIVE and reduced vagal activity are prognostic of a poor outcome in cardiovascular disease (12,14,29). Many studies have shown the benefits of reducing sympathetic activity in cardiovascular disease (10), but actions on the vagal arm of autonomic nervous system have been underexploited. It is likely that enhancing vagal drive to the heart will be beneficial because efferent vagal stimulation can improve the outcome after myocardial infarction in dogs (29). Mechanisms that may enhance vagal tone are therefore of interest for their therapeutic potential in cardiovascular disease.The cardiac natriuretic peptides-atrial natriuretic peptide (ANP), B-and C-type natriuretic peptides (BNP and CNP)-have actions that may be interpreted as cardioprotective (31). Indeed, BNP (Nesiritide) has proved clinically useful in the treatment of congestive heart failure (5, 16). One of these presumed cardioprotective actions is to enhance bradycardic reflexes such as the von Bezold-Jarisch (cardiopulmonary) ch...