John Coote | University of Birmingham (original) (raw)

Papers by John Coote

Journal of the Autonomic Nervous System, 1988

ABSTRACT

Cardiovascular Research, 2007

Objective: Abnormal autonomic nerve activity is a strong prognostic marker for ventricular arrhyt... more Objective: Abnormal autonomic nerve activity is a strong prognostic marker for ventricular arrhythmias but the mechanisms underlying the autonomic modulation of ventricular fibrillation (VF) initiation are poorly understood. We examined the effects of direct sympathetic (SS) and vagus (VS) nerve stimulation on electrical restitution, alternans and VF threshold (VFT) in a novel isolated rabbit heart preparation with intact dual autonomic innervation. Methods: Monophasic Action Potentials (MAPs) were recorded from a left ventricular epicardial site on innervated, isolated rabbit hearts (n = 16). Standard restitution, effective refractory period (ERP), electrical alternans and VFT were measured at baseline and during SS and VS separately. Results: The restitution curve was shifted downwards and made steeper with SS whilst VS caused an upward shift and a flattening of the curve. The maximum slope of restitution was increased from 1.30 ± 0.10 at baseline to 1.86 ± 0.17 (by 45 ± 12%, P < 0.01) with SS and decreased to 0.69 ± 0.10 (by 51 ± 6%, P < 0.001) with VS. ERP was decreased from 127.3 ± 2.5 ms to 111.8 ± 1.8 ms with SS (by 12 ± 2%, P < 0.001) and increased to 144.0 ± 2.2 ms with VS (by 13 ± 2%, P < 0.001). VFT was decreased from 4.7 ± 0.6 mA to 1.9 ± 0.5 mA with SS (by 64 ± 5%, P < 0.001) and increased to 8.7 ± 1.1 mA with VS (by 89 ± 14%, P < 0.0005). There was a significant inverse relationship between the maximum slope of restitution and VFT (r = −0.63, P < 0.0001). When compared with baseline, SS caused electrical alternans at longer pacing cycle lengths (139.0 ± 8.4 vs. 123.0 ± 7.8 ms, P < 0.01) with greater degree of alternans (32.5 ± 9.9 vs. 15.4 ± 3.2%, P < 0.05). It also caused a wider range of cycle lengths where alternans occurred (53.0 ± 6.2 vs. 41.0 ± 7.0 ms, P < 0.05) whilst vagus nerve stimulation shortened this range (33.0 ± 7.3 ms, P < 0.001). Conclusions: Sympathetic stimulation increased maximum slope of restitution and electrical alternans but decreased ERP and VF threshold whilst vagus nerve stimulation had opposite effects. The interaction between action potential duration and beat-to-beat interval may play an important role in the autonomic modulation of VF initiation.

Experimental Physiology, Mar 1, 2000

Autonomic Neuroscience Basic Clinical, Apr 1, 2009

A significant proportion of the spinally projecting neurones in the paraventricular nucleus are i... more A significant proportion of the spinally projecting neurones in the paraventricular nucleus are immunoreactive for oxytocin. Some of these oxytocin neurones terminate on sympathetic preganglionic neurones in the upper thoracic spinal cord, a region from which cardiac sympathetic neurones originate. No studies have so far identified a cardiac action of the supraspinal oxytocin neurones. The present study was designed to test the hypothesis that these oxytocin neurones excite spinal cardiac sympathetic neurones. This was done by measuring heart rate changes in response to intrathecal oxytocin and a selective agonist, and to stimulation of paraventricular neurones before and during blockade of spinal sites with selective antagonists. Rats were anaesthetised with chloralose and urethane (50 mg and 650 mg/kg) and recordings were made of heart rate and blood pressure. Drugs in a volume of 10 µl were applied to the upper thoracic spinal cord via a catheter placed intrathecally with its tip at T2. The paraventricular nucleus was explored with a glass micropipette, placed stereotaxically, and filled with D,L-homocysteic acid (DLH, 200 mM) for exciting neurones and pontamine sky blue for marking the position. Oxytocin (0.002 mM) applied to the spinal cord elicited increases in heart rate (26 ± 5 beats per minute). This was mimicked by a highly selective oxytocin agonist. These heart rate increases were blocked selectively by two different oxytocin antagonists but unaffected by a V 1a vasopressin antagonist. Excitation of sites in dorsal and medial parvocellular sub-nuclei of the paraventricular nucleus elicited increases in heart rate (36 ± 3 bpm) which were significantly reduced by oxytocin antagonists but not affected by V 1a antagonist. Also these induced increases in heart rate were unaffected by vagotomy or i.v. atropine but were abolished by i.v. esmolol. It is concluded that there is a population of paraventricular-spinal oxytocin neurones that excite cardiac sympathetic preganglionic neurones controlling heart rate.

Exp Physiol, 2010

The effects of direct autonomic nerve stimulation on the heart may be quite different to those of... more The effects of direct autonomic nerve stimulation on the heart may be quite different to those of perfusion with pharmacological neuromodulating agents. This study was designed to investigate the effect of autonomic nerve stimulation on intracellular calcium fluorescence using fura-2 AM in the isolated Langendorff-perfused rabbit heart preparation with intact dual autonomic innervation. The effects of autonomic nerve stimulation on cardiac force and calcium transients were more obvious during intrinsic sinus rhythm. High-frequency (15 Hz, n = 5) right vagus nerve stimulation (VS) decreased heart rate from 142.7 ± 2.6 to 75.5 ± 10.2 beats min -1 and left ventricular pressure from 36.4 ± 3.2 to 25.9 ± 1.9 mmHg, whilst simultaneously decreasing the diastolic and systolic level of the calcium transient. Direct sympathetic nerve stimulation (7 Hz, n = 8) increased heart rate (from 144.7 ± 10.5 to 213.2 ± 4.9 beats min -1 ) and left ventricular pressure (from 37.5 ± 3.6 to 43.7 ± 2.8 mmHg), whilst simultaneously increasing the diastolic and systolic level of the calcium transient. During constant ventricular pacing, the highfrequency right vagus nerve stimulation did not have any direct effect on ventricular force or the calcium transient (n = 8), but was effective in reducing the effect of direct sympathetic nerve stimulation.

Exp Physiol, 2004

It is now well accepted that the sympathetic nervous system responds to specific afferent stimuli... more 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.

Clinical Science, 1999

Evidence from animal studies suggests that beta-blockers can act within the central nervous syste... more Evidence from animal studies suggests that beta-blockers can act within the central nervous system to increase cardiac vagal motoneuron activity. We have attempted to determine whether such an effect is evident in healthy humans, by examining the effects of lipophilic and hydrophilic agents on heart rate variability and cardiac vagal reflexes. A total of 20 healthy volunteers took part in the study. Autonomic studies were performed after 72 h of treatment with placebo, atenolol or metoprolol in a blinded cross-over design. ECG recordings were taken at rest and during mental and orthostatic stress. Heart rate variability was measured in the time and frequency domains. The effects on heart rate of two opposing cardiac vagal reflexes were examined. Trigeminal stimulation causing vagal stimulation, and isometric forearm muscle contraction (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;muscle heart reflex&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;) causing vagal inhibition, were performed alone and simultaneously. At rest, during mental stress and during trigeminal stimulation, beta-blocker therapy was associated with significantly increased high-frequency beat-to-beat heart rate variability when compared with placebo. There were no significant differences in effects on heart rate or heart rate variability between atenolol and metoprolol. Analysis of the muscle heart reflex, alone and with simultaneous trigeminal stimulation, showed that the magnitude of the R-R interval response was significantly greater after beta-blocker therapy compared with placebo, but the effects of atenolol and metoprolol were equivalent. beta-Blocker therapy increased cardiac vagal activity, as shown by measures of high-frequency heart rate variability and reflex studies. Lipophilic and hydrophilic beta-blockers appeared to be equally efficacious in increasing the cardiac vagal modulation of heart rate.

Background. Lung transplantation activity is frustrated by donor lung availability. We sought to ... more Background. Lung transplantation activity is frustrated by donor lung availability. We sought to examine the effect of active donor management and hormone administration on pulmonary function and yield in cadaveric heart-beating potential lung donors.

Neuroscience, 1997

The rostroventrolateral medulla is a key site for the regulation of vasomotor tone. Sympathoexcit... more The rostroventrolateral medulla is a key site for the regulation of vasomotor tone. Sympathoexcitatory neurons project from this region to contact sympathetic preganglionic neurons located in the intermediolateral nucleus of the thoracic and lumbar spinal cord. Functional studies show that stimulation of specific sites in the ventral medulla lead to selective activation of different vascular effectors. The present study was designed to determine the anatomical basis for this selectivity in vasomotor control. Anterograde and retrograde tracing methods were utilized to determine if the descending rostral ventrolateral projection is topographically organized such that neurons in particular locations within the nucleus project preferentially and contact a specific group of sympathetic preganglionic neurons. For this purpose spinally-projecting neurons at 15 sites from three separate rostrocaudal locations within the rostroventrolateral medulla in nine rats were anterogradely labelled with biotin dextran amine. The spinal cord was examined for axon terminals having close apposition to two groups of sympathetic preganglionic neurons, those projecting to the superior cervical ganglion and those to the adrenal medulla which were retrogradely labelled with cholera B chain-conjugated horseradish peroxidase. Areas of close apposition between retrogradely-labelled dendrites, cell bodies and anterogradely-labelled axons were found. Axons descending from the more rostral part of the rostroventrolateral medulla produced the highest density of close appositions to sympathetic preganglionic neurons in both target-specific populations. Caudal rostroventrolateral medulla injection sites gave rise to a less dense distribution of axons and terminals around the spinal sympathetic nuclei.This study has demonstrated that spinally-projecting neurons in the rostroventrolateral medulla are both topographically and viscerotopically organized. It is suggested that such an arrangement provides the means for selective and differential control of autonomic effectors and in particular those involved in cardiovascular regulation.

Clinical Science, 2001

The objective of the present study was to determine the autonomic effects of angiotensin II (AT 1... more The objective of the present study was to determine the autonomic effects of angiotensin II (AT 1 ) receptor blocker therapy in heart failure. In a randomized double-blind cross-over study, we compared the effects of candesartan and placebo on baroreflex sensitivity and on heart rate variability at rest, during stress and during 24 h monitoring. Acute effects were assessed 4 h after oral candesartan (8 mg) and chronic effects after 4 weeks of treatment (dose titrated to 16 mg daily). The study group comprised 21 patients with heart failure [mean (S.E.M.) ejection fraction 33 % (1 %)], in the absence of angiotensin-converting enzyme (ACE) inhibitor therapy. We found that acute candesartan was not different from placebo in its effects on blood pressure or mean RR interval. Chronic candesartan significantly reduced blood pressure [placebo, 137 (3)/82 (3) mmHg; candesartan, 121 (4)/75 (2) mmHg ; P 0.001; values are mean (S.E.M.)], but had no effect on mean RR interval [placebo, 857 (25) ms ; candesartan, 857 (21) ms]. Compared with placebo there were no significant effects of acute or chronic candesartan on heart rate variability in the time domain and no consistent effects in the frequency domain. Baroreflex sensitivity assessed by the phenylephrine bolus method was significantly increased after chronic candesartan [placebo, 3.5 (0.5) ms/mmHg; candesartan, 4.8 (0.7) ms/mmHg; P 0.05], although there were no changes in cross-spectral baroreflex sensitivity. Thus, in contrast with previous results with ACE inhibitors, angiotensin II receptor blockade in heart failure did not increase heart rate variability, and there was no consistent effect on baroreflex sensitivity.

The Faseb Journal, Apr 1, 2012

Pflugers Archiv European Journal of Physiology, Jul 1, 1999

The question of whether neurones in the paraventricular nucleus (PVN) of the hypothalamus have an... more The question of whether neurones in the paraventricular nucleus (PVN) of the hypothalamus have an influence on barosensitive vasomotor neurones of the caudal ventrolateral medulla (CVL) was addressed in this study using anaesthetised rats. Extracellular microelectrode recordings were made from 27 vasomotor neurones in the CVL, identified by their cardiac cycle-related probability of discharge, by the increase in activity in response to an increase in arterial blood pressure produced by i.v. phenylephrine and by the decrease in activity in response to a decrease in blood pressure produced by i.v. nitroprusside. Activation of neurones at different sites in the PVN with a microinjection of d,l-homocysteic acid (DLH) activated 12 CVL neurones and inhibited 6 CVL neurones. In four CVL units single-shock electrical stimulation at a PVN pressor site, first identified with DLH, elicited a synaptic action potential with a latency of 29+/-0.3 ms. It is concluded that PVN neurones can influence the CVL vasomotor neurones directly. This could be one means by which PVN-depressor and sympatho-inhibitory effects are produced.

Clin Exp Hypertension, 1995

Baroreceptor inhibition of a spinally evoked response in a renal nerve was studied following remo... more Baroreceptor inhibition of a spinally evoked response in a renal nerve was studied following removal of excitatory drive from the rostral ventrolateral medulla (RVLM), by microinjecting glycine into this region (RVLM block). Activation of arterial baroreceptors was still able to inhibit a spinally evoked response after RVLM block and this effect was abolished by intrathecal strychnine. Intrathecal bicuculline also was shown to reduce the magnitude of the baroreceptor inhibition but only when the RVLM was intact indicating that bicuculline was removing a facilitation. Both strychnine and bicuculline antagonised an NTS induced inhibition of activity in single sympathetic preganglionic neurones. It is concluded that arterial baroreceptor reflex regulation of vasomotor activity occurs at a spinal as well as a supraspinal site and GABA and glycine are the likely inhibitory mediators at both sites.

Neuroscience, Mar 18, 2008

Sympathetic preganglionic neurons (SPN) represent the final central neurons in the sympathetic pa... more Sympathetic preganglionic neurons (SPN) represent the final central neurons in the sympathetic pathways which regulate vasomotor tone; they therefore play a pivotal role in the re-distribution of cardiac output to different vascular beds in response to environmental challenges. While the consensus view is that activity in these neurons is due mainly to supraspinal inputs, the possibility that some activity may be generated intrinsically and modified by synaptic inputs cannot be excluded. Therefore, in order to distinguish between these two possibilities, the electrophysiological properties of cardiovascular-like SPN in the upper thoracic spinal cord of the anesthetized rat were examined and their response to activation of vasodepressor inputs was investigated. Intracellular recordings were made from 22 antidromically identified SPN of which 17 displayed irregular, but maintained, spontaneous activity; no evidence of bursting behavior or pacemaker-like activity was observed. Stimulation of the aortic depressor nerve or a vasodepressor site within the nucleus tractus solitarius (NTS) resulted in a membrane hyperpolarization, decrease in cell input resistance and long-lasting cessation of neuronal firing in SPN including a sub-population which had cardiac-modulated patterns of activity patterns. Recordings were also undertaken from 80 non-antidromically-activated neurons located in the vicinity of SPN; 23% of which fired in phase with the cardiac cycle, with this peak of activity occurring before similar increases in cardiac-modulated SPN. Stimulation of vasodepressor regions of the NTS evoked a membrane hyperpolarization and decrease in cell input resistance in cardiac-modulated but not non-modulated interneurons. These studies show that activity patterns in SPN in vivo are determined principally by synaptic inputs. They also demonstrate that spinal interneurons which exhibit cardiac-modulated patterns of activity are postsynaptically inhibited following activation of baroreceptor pathways. However, the question as to whether these inhibitory pathways and/or disfacilitation of tonic excitatory drive underlies the baroreceptor-mediated inhibition of SPN remains to be determined.

Experimental Brain Research, Mar 1, 1998

Vasopressin-containing nerve terminals are present in the spinal cord of several species. This st... more Vasopressin-containing nerve terminals are present in the spinal cord of several species. This study was designed to determine whether sympatho-adrenal preganglionic neurones (SPN) express vasopressin receptors (VPRs). SPN in the spinal cord were revealed by retrograde labelling of Fluorogold following its unilateral injection into the adrenal medulla of 12±20 day postnatal rats. VPRs were simultaneously visualised in the Fluorogold-labelled slices of spinal cord using a recently developed biotinylated vasopressin receptor antagonist [1-phenylacetyl,2-O-methyl-D-tyrosine,6-arginine,8-arginine,9-lysinamide(Ne-biotinamidocaproamide)]vasopressin, PhAcAL(Btn)VP. The VPR:PhAcAL(Btn)VP complexes were visualised either with Texas Red-conjugated avidin or with a Vectastain avidin:alkaline phosphatase detection kit. These dual-labelling experiments revealed VPRs to be present in the spinal grey matter and to be particularly dense in the intermediate grey matter and adjacent regions of the ventral horn. Many SPN were associated with receptor-specific labelling of PhAcAL(Btn)VP, thereby demonstrating that VPRs are expressed by these neurones. These VPRs were pharmacologically defined as the V 1a subtype. It is concluded that sympatho-adrenal preganglionic neurones express VPRs and that these are of the V 1a subtype. The distribution of VPRs is not, however, restricted to these SPN in the spinal cord.

Brain Research, Jul 10, 2001

Neurones in the paraventricular nucleus of the hypothalamus project to rostral ventrolateral medu... more Neurones in the paraventricular nucleus of the hypothalamus project to rostral ventrolateral medullary spinally projecting vasomotor neurones. We studied the excitatory action and the role of glutamate and vasopressin in this pathway in anaesthetised rats. A five barrel micropipette assembly was used for extracellular recording of neuronal activity and for microiontophoresis of drugs into the vicinity of identified medullary vasomotor neurones. Iontophoresis of L-glutamate or vasopressin into the vicinity of a vasomotor neurone increased activity, effects which were blocked by simultaneous iontophoretic application of a glutamate receptor antagonist, or a vasopressin V(1a) antagonist respectively. Paraventricular neurones were activated either by microinjecting D,L-homocysteic acid or by disinhibition by microinjecting bicuculline. The excitatory effects on vasomotor neurones, of paraventricular nucleus stimulation at some sites were prevented by simultaneous microiontophoretic application of kynurenic acid or at other sites by application of V(1a) antagonist. Neither antagonist altered the ongoing activity of the vasomotor neurones. Therefore, glutamate or vasopressin may act as excitatory neurotransmitters at synapses of paraventricular neurones on rostral ventrolateral medullary vasomotor neurones.