John H. Coote

The influence of bulbospinal monoaminergic pathways on sympathetic nerve activity

1. Spontaneous and reflex activity was recorded from renal and splanchnic nerves and thoracic white rami during discrete electrical stimulation within the medulla oblongata of anaesthetized cats.

Identification of branching paraventricular neurons of the hypothalamus that project to the rostroventrolateral medulla and spinal cord

The paraventricular nucleus of the hypothalamus has efferent connections to autonomic nuclei known to ultimately regulate cardiovascular function. Studies have revealed projections to the sympathetic preganglionic neurons of the spinal cord and presympathetic motor neurons of the rostral ventrolateral medulla. This study set out to establish whether the same neurons in the paraventricular nucleus innervate both these regions. In rats the fluorescent neuroanatomical tracers FluoroGold, Fast Blue or Dextran tetramethyl rhodamine were injected into either the rostral ventrolateral medulla or T2 region of the spinal cord. After a suitable survival period (five to seven days) three populations of neurons could be identified in the paraventricular nucleus, double-labelled neurons and single-labelled neurons resulting from the injections into the spinal cord or injections into the rostral ventrolateral medulla. The neurons were of similar size regardless of the dye content. Most neurons were found in the parvocellular subdivision of the mid rostral paraventricular nucleus. The number of labelled neurons decreased in the caudal sections. This study provides an anatomical basis for three means of influence that the paraventricular nucleus can have on sympathetic activity; a hierarchical in series projection via the rostral ventrolateral medulla; a projection running in parallel with this but bypassing the rostroventrolateral medulla; and a branching population innervating neurons in both the rostral ventrolateral medulla and spinal cord. The paraventricular nucleus of the hypothalamus is an important brain area concerned with maintaining cardiovascular homeostasis. This anatomical study has not only provided confirmatory evidence that direct projections arising from the paraventricular hypothalamic nucleus do project to the rostral ventrolateral medulla and spinal cord, regions known to influence cardiovascular regulation. The study has identified a branching projection originating in the paraventricular nucleus of the hypothalamus that projects to both the rostral ventrolateral medulla and the spinal cord. Thus the paraventricular nucleus of the hypothalamus has three pathways in which to influence cardiovascular homeostasis.

The influence of the paraventriculo-spinal pathway, and oxytocin and vasopressin on sympathetic preganglionic neurones.

In anaesthetized rats the effect of two procedures was studied on antidromically identified sympathetic preganglionic neurones (SPN) in the second thoracic (T) segment of the spinal cord: the application of iontophoresed oxytocin and vasopressin, and bipolar electrical stimulation of the paraventricular nucleus of the hypothalamus (PVN). In the majority of cases (16/23) oxytocin inhibited SPN firing, 1/23 being excited. Vasopressin inhibited 8/14 neurones and excited 4/14. PVN stimulation inhibited SPN apparently by an action on the membrane of SPN. The possibility that oxytocin and vasopressin act as transmitters in the paraventriculo-spinal pathway, and their possible involvement in the mediation of PVN evoked inhibition of SPN activity has been discussed.

A role for the paraventricular nucleus of the hypothalamus in the autonomic control of heart and kidney

It is now well accepted that the sympathetic nervous system responds to specific afferent stimuli in a unique non‐uniform fashion. The means by which the brain transforms the signals from a single type of receptor into an appropriate differential sympathetic output is discussed in this brief review. The detection of and response to venous filling are used for illustration. An expansion of blood volume has been shown in a number of species to increase heart rate reflexly via sympathetic nerves and this effect is primarily an action of volume receptors at the venous–atrial junctions of the heart. Stimulation of these volume receptors also leads to an inhibition of renal sympathetic nerve activity. Thus the reflex response to an increase in plasma volume consists of a distinctive unique pattern of sympathetic activity to maintain fluid balance. This reflex is dependent on neurones in the paraventricular nucleus (PVN). Neurones in the PVN show early gene activation on stimulation of atrial receptors, and a similar differential pattern of cardiac sympathetic excitation and renal inhibition can be evoked by activating PVN neurones. Cardiac atrial afferents selectively cause a PVN GABA neurone‐induced inhibition within the PVN of PVN spinally projecting vasopressin‐containing neurones that project to renal sympathetic neurones. A lesion of these spinally projecting neurones abolishes the reflex. With regard to the cardiac sympathetics, there is a population of PVN spinally projecting neurones that selectively increase heart rate by the release of oxytocin, a peptide pathway that has no action on renal sympathetic outflow. In heart failure the atrial reflex becomes blunted, and evidence is emerging that there is a downregulation of nitric oxide synthesis and reduced GABA activity in the PVN. How this might give rise to increased sympathetic activity associated with heart failure is briefly discussed.

Heart rate at the onset of muscle contraction and during passive muscle stretch in humans: a role for mechanoreceptors

Previous evidence suggests that the heart rate (HR) increase observed with isometric exercise is dependent on different afferent mechanisms to those eliciting the increase in blood pressure (BP). Central command and muscle metaboreceptors have been shown to contribute to this differential effect. However, in experimental animals passive stretch of the hindlimb increases HR suggesting that small fibre mechanoreceptors could also have a role. This has not been previously shown in humans and was investigated in this study. Healthy human volunteers were instrumented to record BP, ECG, respiration, EMG of rectus femoris and gastrocnemius and contraction force of triceps surae. Voluntary isometric contraction of triceps surae elicited a significant HR change in the first three respiratory cycles at 40 % of maximum voluntary contraction whereas BP did not change significantly until after 30 s. This suggests that different mechanisms are involved in the initiation of the cardiovascular changes. Sustained passive stretch of triceps surae for 1 min, by dorsiflexion of the foot, caused a significant (P < 0.05) increase in HR (5 ± 2.6 beats min−1) with no significant change in BP. A time domain measure of cardiac vagal activity was reduced significantly during passive stretch from 69.7 ± 12.9 to 49.6 ± 8.9 ms. Rapid rhythmic passive stretch (0.5 Hz for 1 min) was without significant effect suggesting that large muscle proprioreceptors are not involved. We conclude that in man small fibre muscle mechanoreceptors responding to stretch, inhibit cardiac vagal activity and thus increase HR. These afferents could contribute to the initial cardiac acceleration in response to muscle contraction.

Vagus nerve stimulation decreases left ventricular contractility in vivo in the human and pig heart.

1 Studies of the effect of vagus nerve stimulation on ventricular myocardial function in mammals are limited, particularly in the human. 2 The present study was designed to determine the effect of direct electrical stimulation of the left vagus nerve on left ventricular contractile state in hearts paced at 10 % above the natural rate, in anaesthetised pigs and anaesthetised human subjects undergoing open chest surgery for coronary artery bypass grafting. 3 Contractility of the left ventricle was determined from a series of pressure‐volume loops obtained from a combined pressure and conductance (volume) catheter placed in the left ventricle. From the measurements a regression slope of the end‐systolic pressure‐volume relationship was determined to give end‐systolic elastance (Ees), a load‐independent measure of contractility. 4 In six anaesthetised open chest pigs, stimulation of the peripheral cut end of the left cervical vagus nerve induced a significant decrease in Ees of 26 ± 14 %. 5 In nine patients electrical stimulation of the left thoracic vagus nerve close to its cardiac branch resulted in a significant drop in Ees of 38 ± 16 %. 6 The effects of vagal stimulation were blocked by the muscarinic antagonist glycopyrronium (5 mg kg−1). 7 Administration of the β‐adrenoreceptor antagonist esmolol (1 mg kg−1) also attenuated the effect of vagal stimulation, indicating a degree of interaction of vagal and sympathetic influences on contractility. 8 These studies show that in the human and pig heart the left vagus nerve can profoundly decrease the inotropic state of the left ventricular myocardium independent of its bradycardic effect.

Nitric Oxide and Cardiac Autonomic Control in Humans

Cardiac autonomic control is of prognostic significance in cardiac disease, yet the control mechanisms of this system remain poorly defined. Animal data suggest that nitric oxide (NO) modulates cardiac autonomic control. We investigated the influence of NO on the baroreflex control of heart rate in healthy human subjects. In 26 healthy male volunteers (mean age, 23+/-5 years), we measured heart rate variability and baroreflex sensitivity during inhibition of endogenous NO production with N(G)-monomethyl-L-arginine (L-NMMA) (3 mg/kg per hour) and during exogenous NO donation with sodium nitroprusside (1 to 3 mg/h). Increases from baseline (Delta) in high-frequency (HF) indexes of heart rate variability were smaller with L-NMMA in comparison to an equipressor dose of the control vasoconstrictor phenylephrine (12 to 42 microg/kg per hour): Deltaroot mean square of successive RR interval differences (DeltaRMSSD)=23+/-32 versus 51+/-48 ms (P<0.002); Deltapercentage of successive RR interval differences >50 ms (DeltapNN50)=5+/-15% versus 14+/-12% (P<0.05); and DeltaHF normalized power=-2+/-7 versus 9+/-8 normalized units (P<0.01), respectively. Relative preservation of these indexes was observed during unloading of the baroreflex with sodium nitroprusside compared with a matched fall in blood pressure produced by a control vasodilator, hydralazine (9 to 18 mg/h): DeltaRMSSD=-8+/-8 versus -24+/-15 ms (P<0.001); DeltapNN50=-6+/-11% versus -15+/-19% (P<0.01); DeltaHF normalized power=-7+/-13 versus -13+/-11 normalized units (P<0.05), respectively. The change in cross-spectral alpha-index calculated as the square root of the ratio of RR interval power to systolic spectral power in the HF band (although not alpha-index calculated in the same way for the low-frequency bands or baroreflex sensitivity assessed by the phenylephrine bolus method) was attenuated with L-NMMA compared with phenylephrine (Delta=4+/-8 versus 14+/-15 ms/mm Hg, respectively; P<0.02) and with sodium nitroprusside compared with hydralazine (Delta=-7+/-6 and -9+/-7 ms/mm Hg, respectively; P<0.05). In conclusion, these data demonstrate that NO augments cardiac vagal control in humans.

The paraventricular nucleus of the hypothalamus sends efferents to the spinal cord of the rat that closely appose sympathetic preganglionic neurones projecting to the stellate ganglion

Abstract Using a combination of anterograde and retrograde neuronal tract-tracing techniques, the descending projections from the paraventricular nucleus of the hypothalamus (PVN) to the brain/spinal cord and in particular those axonal projections that appear to be contiguous with sympathetic preganglionic neurones (SPN) projecting to the stellate ganglion have been studied. Descending PVN pathways were located by the anterograde transport of biotinylated dextran amine (BDA), whilst SPN were retrogradely labelled with cholera B toxin subunit conjugated to horseradish peroxidase (CB-HRP). BDA-labelled PVN axons terminated in both hypothalamic and extrahypothalamic (including the midbrain, medulla and spinal cord) brain nuclei, with dense terminal labelling observed particularly in the arcuate hypothalamic nucleus and adjacent median eminence, in the solitary tract, vagal nuclei and in the intermediolateral region of the spinal cord (IML). Varicose descending PVN fibres in the IML were often observed to closely appose both the cell soma and dendrites of retrogradely labelled SPN (projecting to the stellate ganglion) in the spinal cord. In addition, it was shown that PVN descending axons crossing to the contralateral side of the spinal cord were closely associated with retrogradely labelled SPN projecting to the superior cervical ganglion. Such findings suggest that descending pathways from the PVN may exhibit a direct influence on cardiac sympathetic outflow and may also influence the behaviour of the contralateral population of SPN projecting to the superior cervical ganglion.

CONTROL OF SYMPATHETIC OUTFLOWS BY THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS

1. The functional role of the paraventricular nucleus (PVN) has been examined by studying its connections with cardiovascular neurons in the medulla and spinal cord and its influence on activity in several sympathetic nerves.

Influence of the hypothalamic paraventricular nucleus on cardiovascular neurones in the rostral ventrolateral medulla of the rat.

1 The question of whether neurones in the paraventricular nucleus (PVN) of the hypothalamus have an excitatory influence on reticulo‐spinal vasomotor neurones of the rostral ventrolateral medulla (RVL) has been addressed in this study using anaesthetized rats. 2 Extracellular microelectrode recordings were made from sixty vasomotor neurones in the RVL, identified by their cardiac cycle‐related probability of discharge, by the decrease in activity in response to an increase in arterial blood pressure produced by intravenous phenylephrine and by the increase in activity in response to a decrease in blood pressure produced by intravenous nitroprusside. 3 More than 70 % of these RVL vasomotor neurones were identified as spinally projecting by antidromically activating their axons via a stimulating electrode in the lateral funiculus of the T2 or T10 segment of spinal cord. 4 Activation of neurones at different sites in the PVN with a microinjection of d,l‐homocysteic acid (DLH) elicited either pressor or depressor responses. 5 At PVN pressor sites fifteen RVL vasomotor neurones were shown to be activated prior to the blood pressure change. A further twenty RVL vasomotor neurones were observed to decrease activity following the blood pressure rise. At PVN depressor sites twelve RVL neurones were inhibited prior to the blood pressure change whereas another thirteen identified RVL neurones increased their discharge following the fall in blood pressure. 6 In three rats single shock electrical stimulation at a PVN pressor site, first identified with DLH, elicited a single or double action potential in thirteen RVL neurones with a latency of 27 ± 1 ms. 7 It is concluded that PVN neurones may elicit increases in blood pressure via excitatory connections with RVL‐spinal vasomotor neurones, and that other PVN neurones may elicit decreases in blood pressure via inhibitory connections with these RVL neurones.