Neuroendocrine self-control: dendritic release of vasopressin.
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Animals↗
Biomedical subjects
Robin M McAllen
Publications and source records attributed to Robin M McAllen.
The cold path to BAT.
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Adipose Tissue, Brown↗
Reflex activation of rat fusimotor neurons by body surface cooling, and its dependence on the medullary raphe.
The nature of muscle efferent fibre activation during whole body cooling was investigated in urethane-anaesthetized rats. Multiunit efferent activity to the gastrocnemius muscle was detected when the trunk skin was cooled by a water-perfused jacket to below 36.0 +/- 0.7 degrees C. That efferent activity was not blocked by hexamethonium (50 mg kg(-1), i.v.) and was not associated with movement or electromyographic activity. Cold-induced efferent activity enhanced the discharge of afferent filaments from the isotonically stretched gastrocnemius muscle, demonstrating that it was fusimotor. Fusimotor neurons were activated by falls in trunk skin temperature, but that activity ceased when the skin was rewarmed, regardless of how low core temperature had fallen. While low core temperature alone was ineffective, a high core temperature could inhibit the fusimotor response to skin cooling. Fusimotor activation by skin cooling was often accompanied by desynchronization of the frontal electroencephalogram (EEG), but was not a simple consequence of cortical arousal, in that warming the scrotum desynchronized the EEG without activating fusimotor fibres. Inhibition of neurons in the rostral medullary raphé by microinjections of glycine (0.5 m, 120-180 nl) reduced the fusimotor response to skin cooling by 95 +/- 3%, but did not prevent the EEG response. These results are interpreted as showing a novel thermoregulatory reflex that is triggered by cold exposure. It may underlie the increased muscle tone that precedes overt shivering, and could also serve to amplify shivering. Like several other cold-defence responses, this reflex depends upon neurons in the rostral medullary raphé.
Action Potentials↗
Human medullary responses to cooling and rewarming the skin: a functional MRI study.
A fall in skin temperature precipitates a repertoire of thermoregulatory responses that reduce the likelihood of a decrease in core temperature. Studies in animals suggest that medullary raphé neurons are essential for cold-defense, mediating both the cutaneous vasoconstrictor and thermogenic responses to ambient cooling; however, the involvement of raphé neurons in human thermoregulation has not been investigated. This study used functional MRI with an anatomically guided region of interest (ROI) approach to characterize changes in the blood oxygen level-dependent (BOLD) signal within the human medulla of nine normal subjects during non-noxious cooling and rewarming of the skin by a water-perfused body suit. An ROI covering 4.9 +/- 0.3 mm(2) in the ventral midline of the medulla immediately caudal to the pons (the rostral medullary raphé) showed an increase in BOLD signal of 3.9% (P < 0.01) during periods of skin cooling, compared with other times. Overall, that signal showed a strong inverse correlation (R = 0.48, P < 0.001) with skin temperature. A larger ROI covering the internal medullary cross section at the same level (area, 126 +/- 15 mm(2)) showed no significant change in mean BOLD signal with cooling (+0.2%, P > 0.05). These findings demonstrate that human rostral medullary raphé neurons are selectively activated in response to a thermoregulatory challenge and point to the location of thermoregulatory neurons homologous to those of the raphé pallidus nucleus in rodents.
Adult↗
Differential control of cardiac functions by the brain.
1. The idea is introduced that cardiac rate, contractility or atrioventricular (A-V) conduction spread may be controlled independently by the brain. Limited data from reflex studies are cited to support this view. 2. Evidence is presented that individual autonomic post- and preganglionic neurons have quite specific actions on the heart. Premotor and other central neurons can have preferential actions on heart rate, contractility or A-V conduction. 3. The functional implications of selective cardiac control are discussed.
Animals↗
Comparison between two rat sympathetic pathways activated in cold defense.
In cold defense and fever, activity increases in sympathetic nerves supplying both tail vessels and interscapular brown adipose tissue (iBAT). These mediate cutaneous vasoconstrictor and thermogenic responses, respectively, and both depend upon neurons in the rostral medullary raphé. To examine the commonality of brain circuits driving these two outflows, sympathetic nerve activity (SNA) was recorded simultaneously from sympathetic fibers in the ventral tail artery (tail SNA) and the nerve to iBAT (iBAT SNA) in urethane-anesthetized rats. From a warm baseline, cold-defense responses were evoked by intermittently circulating cold water through a water jacket around the animal's shaved trunk. Repeated episodes of trunk skin cooling decreased core (rectal) temperature. The threshold skin temperature to activate iBAT SNA was 37.3 +/- 0.5 degrees C (n = 7), significantly lower than that to activate tail SNA (40.1 +/- 0.4 degrees C; P < 0.01, n = 7). A fall in core temperature always strongly activated tail SNA (threshold 38.3 +/- 0.2 degrees C, n = 7), but its effect on iBAT SNA was absent (2 of 7 rats) or weak (threshold 36.9 +/- 0.1 degrees C, n = 5). The relative sensitivity to core vs. skin cooling (K-ratio) was significantly greater for tail SNA than for iBAT SNA. Spectral analysis of paired recordings showed significant coherence between tail SNA and iBAT SNA only at 1.0 +/- 0.1 Hz. The coherence was due entirely to the modulation of both signals by the ventilatory cycle because it disappeared when the coherence spectrum was partialized with respect to airway pressure. These findings indicate that independent central pathways drive cutaneous vasoconstrictor and thermogenic sympathetic pathways during cold defense.
Adipose Tissue, Brown↗
Misidentification of cardiac vagal pre-ganglionic neurons after injections of retrograde tracer into the pericardial space in the rat.
We evaluated whether pericardial injections of the retrograde tracers cholera toxin subunit B (CTb) or Fast Blue (FB) reliably labelled cardiac vagal pre-ganglionic neurons. Injections of CTb into the pericardial space of the rat labelled neurons in both the external and compact formations of the nucleus ambiguus. Most labelled neurons were found in the compact formation of the nucleus ambiguus, and the majority of these, and only these, expressed immunoreactivity for calcitonin gene-related peptide. This distribution of labelled neurons and their immunohistochemical properties is characteristic of oesophageal motoneurons. Examination of the oesophagus following intra-pericardial CTb applications revealed strong labelling of motor end plates within the skeletal muscle of the thoracic but not the abdominal oesophagus. When a second retrograde tracer, FB, was injected into the abdominal oesophagus, labelled somata were found adjacent to CTb-labelled neurons in the compact formation of the nucleus ambiguus. No co-localisation of tracers was found, but identical proportions of calcitonin gene-related peptide (CGRP) immunoreactivity were observed in both groups of neurons. FB injected into the pericardial space labelled intra-cardiac neurons but not brainstem neurons. We conclude that intra-pericardial, and perhaps sub-epicardial, injections of some retrograde tracers are likely to label a subset of oesophageal, as well as cardiac, vagal motor neurons in the brainstem.
Amidines↗
A subsidiary fever center in the medullary raphé?
In fever, as in normal thermoregulation, signals from the preoptic area drive both cutaneous vasoconstriction and thermogenesis by brown adipose tissue (BAT). Both of these responses are mediated by sympathetic nerves whose premotor neurons are located in the medullary raphé. EP3 receptors, key prostaglandin E2 (PGE2) receptors responsible for fever induction, are expressed in this same medullary raphé region. To investigate whether PGE2 in the medullary raphé might contribute to the febrile response, we tested whether direct injections of PGE2 into the medullary raphé could drive sympathetic nerve activity (SNA) to BAT and cutaneous (tail) vessels in anesthetized rats. Microinjections of glutamate (50 mM, 60-180 nl) into the medullary raphé activated both tail and BAT SNA, as did cooling the trunk skin. PGE2 injections (150-500 ng in 300-1,000 nl) into the medullary raphé had no effect on tail SNA, BAT SNA, body temperature, or heart rate. By contrast, 150 ng PGE2 injected into the preoptic area caused large increases in both tail and BAT SNA (+60 +/- 17 spikes/15 s and 1,591 +/- 150% of control, respectively), increased body temperature (+1.8 +/- 0.2 degrees C), blood pressure (+17 +/- 2 mmHg), and heart rate (+124 +/- 19 beats/min). These results suggest that despite expression of EP3 receptors, neurons in the medullary raphé are unable to drive febrile responses of tail and BAT SNA independently of the preoptic area. Rather, they appear merely to transmit signals for heat production and heat conservation originating from the preoptic area.
Adipose Tissue, Brown↗
Inhibition of rostral medullary raphé neurons prevents cold-induced activity in sympathetic nerves to rat tail and rabbit ear arteries.
Sympathetically-mediated vasoconstriction of cutaneous vessels is critical for thermoregulation in the cold. We determined whether cold-induced sympathetic discharge depends on activity of neurons in the rostral medullary raphé. In urethane-anesthetized rats and rabbits, cooling the trunk skin by a water jacket reproducibly increased cutaneous sympathetic discharge recorded in the tail (rats) and the ear pinna (rabbits). When neurons in the rostral medullary raphé were inhibited by microinjection of glycine (30-100 nmol in 60-200 nl in rats), or muscimol (1 nmol in 100 nl in rabbits), cutaneous sympathetic activity was silenced and no longer responded to cooling (7+/-3 and 5+/-2% of pre-injection increase in rats and rabbits, respectively, P < 0.01). Our data demonstrate that activity of rostral medullary raphé neurons is important for the CNS mediation of cold-induced increases in sympathetic cutaneous vasomotor nerves.
Action Potentials↗
Stimulation of cardiac sympathetic nerve activity by central angiotensinergic mechanisms in conscious sheep.
Central actions of angiotensin play an important role in cardiovascular control and have been implicated in the pathogenesis of hypertension and heart failure. One feature of centrally or peripherally administered angiotensin is that the bradycardia in response to an acute pressor effect is blunted. It is unknown whether after central angiotensin this is due partly to increased cardiac sympathetic nerve activity (CSNA). We recorded CSNA and arterial pressure in conscious sheep, at least 3 days after electrode implantation. The effects of intracerebroventricular infusions of ANG II (3 nmol/h for 30 min) and artificial cerebrospinal fluid (CSF) (1 ml/h) were determined. The response to intracerebroventricular hypertonic saline (0.6 M NaCl in CSF at 1 ml/h) was examined as there is evidence that hypertonic saline acts via angiotensinergic pathways. Intracerebroventricular angiotensin increased CSNA by 23 +/- 7% (P < 0.001) and mean arterial pressure (MAP) by 7.6 +/- 1.2 mmHg (P < 0.001) but did not significantly change heart rate (n = 5). During intracerebroventricular ANG II the reflex relation between CSNA and diastolic blood pressure was significantly shifted to the right (P < 0.01). Intracerebroventricular hypertonic saline increased CSNA (+9.4 +/- 6.6%, P < 0.05) and MAP but did not alter heart rate. The responses to angiotensin and hypertonic saline were prevented by intracerebroventricular losartan (1 mg/h). In conclusion, in conscious sheep angiotensin acts within the brain to increase CSNA, despite increased MAP. The increase in CSNA may account partly for the lack of bradycardia in response to the increased arterial pressure. The responses to angiotensin and hypertonic saline were losartan sensitive, indicating they were mediated by angiotensin AT-1 receptors.
Angiotensin II↗
Preoptic thermoregulatory mechanisms in detail.
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Animals↗
ANP potentiates nonarterial baroreflex bradycardia: evidence from sinoaortic denervation in rats.
Previous findings indicate that atrial natriuretic peptide (ANP) enhances the reflex bradycardia arising from stimulation of cardiac mechanoreceptors and chemoreceptors, but not that from arterial baroreceptors. The present study tests this proposal by examining the effect of ANP on these reflexes in six chronically sinoaortic-denervated (SAD), and eight sham-operated (sham), conscious rats. Arterial baroreceptor-heart rate (HR) reflex function was examined by constructing full-range steady-state blood pressure (BP)-HR curves using alternating doses of pressor (methoxamine, 2-100 microg/kg) and depressor (nitroprusside, 1-50 microg/kg) agents. Nonarterial baroreceptor reflex function was assessed by the 'ramp' bradycardic response to the rapid BP rise after i.v. methoxamine (100 microg/kg bolus dose). The cardiopulmonary chemoreflex was evoked by i.v. injections of serotonin (1-20 microg/kg). These three tests were performed on each rat during infusions, in random order, of rat ANP (150 ng/kg/min i.v.) and saline vehicle. The ability of ANP to significantly enhance ramp reflex bradycardia was not diminished in SAD compared with sham rats (+54 +/- 12% vs. +42 +/- 15%, respectively). ANP also significantly enhanced cardiopulmonary chemoreflex bradycardia in both groups (+60 +/- 15% in SAD, +40 +/- 8% in sham). Neither the normal steady-state BP-HR response in sham rats nor the small residual response in SAD rats was enhanced by ANP (-1 +/- 7% in sham, -11 +/- 8% in SAD). We conclude that ANP enhances reflex bradycardias of nonarterial, probably cardiac mechanoreceptor, origin.
Animals↗
Role of the medullary raphé in thermoregulatory vasomotor control in rats.
To investigate the involvement of the medullary raphé in thermoregulatory vasomotor control, we chemically manipulated raphé neuronal activity while monitoring the tail vasomotor response to preoptic warming. For comparison, neuronal activity in the rostral ventrolateral medulla (RVLM) was manipulated in similar experiments. Injections of D,L-homocysteic acid (DLH; 0.5 mM, 0.3 microl) into a restricted region of the ventral medullary raphé suppressed the tail vasodilatation normally elicited by warming the preoptic area to 42 degrees C. DLH injection into the RVLM also suppressed the vasodilatation elicited by preoptic warming. Injection of bicuculline (0.5 mM, 0.3 microl) into the same raphé region suppressed the vasodilatation elicited by preoptic warming. Bicuculline injection into the RVLM did not suppress tail vasodilatation. These results suggest that neurones in both the medullary raphé and the RVLM are vasoconstrictor to the tail, but only those in the raphé receive inhibitory input from the preoptic area. That input might be direct and/or indirect (e.g. via the periaqueductal grey matter).
Animals↗
Aldosterone acts on the kidney, not the brain, to cause mineralocorticoid hypertension in sheep.
OBJECTIVE: To determine the extent to which mineralocortioid hypertension depends on a direct action of aldosterone on the kidney or on the brain. METHODS: Studies were performed in conscious sheep that were previously uninephrectomized, implanted with silastic cannulae in the renal artery of the remaining kidney, and had guide tubes implanted over the lateral cerebral ventricles. The effect of aldosterone, infused either intrarenally (i.r.; 2 microg/h) or intravenously (i.v.; 2 and 10 microg/h) for 10 days (n = 5), on arterial pressure and fluid and electrolyte balance was determined. The i.r. (2 microg/h) and i.v. (10 microg/h) doses were calculated to give similar intrarenal concentrations of aldosterone. In a further study, the effect of intracerebroventricular (i.c.v.) infusion of aldosterone (2 microg/h for 21 days) on arterial pressure was examined (n = 5). RESULTS: Infusion of aldosterone caused a progressive increase in mean arterial pressure from 83 +/- 3 mmHg to a maximum of 100 +/- 4 mmHg (P < 0.001) with 2 microg/h i.r. and from 84 +/- 3 mmHg to a maximum of 104 +/- 4 mmHg (P < 0.001) with 10 microg/h i.v., both by day 7. With both infusions there were similar increases in plasma [Na+] and decreases in plasma [K+] and total protein concentration (P < 0.05) between days 3 and 5; these were maintained throughout the infusion. There were no significant changes with i.v. aldosterone (2 microg/h). Long-term i.c.v. infusion of aldosterone (2 microg/h for 21 days) caused no change in arterial pressure. CONCLUSIONS: In conscious sheep the hypertensive response to aldosterone resulted from an action on the kidney, with no evidence for a direct action on the brain.
Aldosterone↗
A neglected 'accessory' vasomotor pathway: implications for blood pressure control.
1. Distinct from 'regular' sympathetic preganglionic neurons, there exists a population of 'accessory' preganglionic neurons. The latter are distinguishable by their unmyelinated axons and their different functional properties. They synapse on the same ganglion cells. 2. Ongoing sympathetic activity is driven by 'regular' preganglionic neurons. 3. 'Accessory' preganglionic neurons drive hexamethonium-resistant ganglionic transmission: part of this is muscarinic and part not (possibly peptidergic or nitrergic). 4. 'Accessory' preganglionic neurons supply cardiovascular (vasomotor, cardiac, adrenal), but apparently not other, sympathetic pathways. 5. 'Accessory' preganglionic neurons are activated by arterial chemoreceptors. 6. Brief activation of 'accessory' preganglionic neurons potentiates ongoing post-ganglionic activity for tens of minutes by an action at the ganglion. This is probably by enabling previously subthreshold excitatory post-synaptic potentials to trigger action potentials. 7. Evidence is presented that microinjections of GABA into the rostral ventrolateral medulla activate the 'accessory' pathway while inhibiting the 'regular' pathway. 8. A role for this 'accessory' pathway in the long-term control of blood pressure in health and disease is predicted, but still untested.
Animals↗