Robin M. McAllen

The brain renin-angiotensin system: location and physiological roles

Angiotensinogen, the precursor molecule for angiotensins I, II and III, and the enzymes renin, angiotensin-converting enzyme (ACE), and aminopeptidases A and N may all be synthesised within the brain. Angiotensin (Ang) AT(1), AT(2) and AT(4) receptors are also plentiful in the brain. AT(1) receptors are found in several brain regions, such as the hypothalamic paraventricular and supraoptic nuclei, the lamina terminalis, lateral parabrachial nucleus, ventrolateral medulla and nucleus of the solitary tract (NTS), which are known to have roles in the regulation of the cardiovascular system and/or body fluid and electrolyte balance. Immunohistochemical and neuropharmacological studies suggest that angiotensinergic neural pathways utilise Ang II and/or Ang III as a neurotransmitter or neuromodulator in the aforementioned brain regions. Angiotensinogen is synthesised predominantly in astrocytes, but the processes by which Ang II is generated or incorporated in neurons for utilisation as a neurotransmitter is unknown. Centrally administered AT(1) receptor antagonists or angiotensinogen antisense oligonucleotides inhibit sympathetic activity and reduce arterial blood pressure in certain physiological or pathophysiological conditions, as well as disrupting water drinking and sodium appetite, vasopressin secretion, sodium excretion, renin release and thermoregulation. The AT(4) receptor is identical to insulin-regulated aminopeptidase (IRAP) and plays a role in memory mechanisms. In conclusion, angiotensinergic neural pathways and angiotensin peptides are important in neural function and may have important homeostatic roles, particularly related to cardiovascular function, osmoregulation and thermoregulation.

The sensory circumventricular organs of the mammalian brain.

The brains three sensory circumventricular organs, the subfornical organ, organum vasculosum of the lamina terminalis and the area postrema lack a blood brain barrier and are the only regions in the brain in which neurons are exposed to the chemical environment of the systemic circulation. Therefore they are ideally placed to monitor the changes in osmotic, ionic and hormonal composition of the blood. This book describes their. General structure and relationship to the cerebral ventricles Regional subdivisions Vasculature and barrier properties Neurons, glia and ependymal cells Receptors, neurotransmitters, neuropeptides and enzymes Neuroanatomical connections Functions.

Vasopressin secretion: osmotic and hormonal regulation by the lamina terminalis.

The lamina terminalis, located in the anterior wall of the third ventricle, is comprised of the subfornical organ, median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT). The subfornical organ and OVLT are two of the brains circumventricular organs that lack the blood–brain barrier, and are therefore exposed to the ionic and hormonal environment of the systemic circulation. Previous investigations in sheep and rats show that this region of the brain has a crucial role in osmoregulatory vasopressin secretion and thirst. The effects of lesions of the lamina terminalis, studies of immediate–early gene expression and electrophysiological data show that all three regions of the lamina terminalis are involved in osmoregulation. There is considerable evidence that physiological osmoreceptors subserving vasopressin release are located in the dorsal cap region of the OVLT and possibly also around the periphery of the subfornical organ and in the MnPO. The circulating peptide hormones angiotensin II and relaxin also have access to peptide specific receptors (AT1 and LGR7 receptors, respectively) in the subfornical organ and OVLT, and both angiotensin II and relaxin act on the subfornical organ to stimulate water drinking in the rat. Studies that combined neuroanatomical tracing and detection of c‐fos expression in response to angiotensin II or relaxin suggest that both of these circulating peptides act on neurones within the dorsal cap of the OVLT and the periphery of the subfornical organ to stimulate vasopressin release.

The location of cardiac vagal preganglionic motoneurones in the medulla of the cat.

1. Electrophysiological techniques have been used to locate the origin of preganglionic vagal motoneurones supplying the heart of the cat. 2. The right cardiac vagal branches were identified anatomically and their ability to slow the heart was assessed by electrical stimulation. Control experiments revealed that contamination of cardiac branches by bronchomotor and oesophageal efferent fibres was likely to be small. 3. Fifty‐seven neurones in the medulla were activated antidromically on stimulating the cardiac branches at up to 5 times the threshold for cardiac slowing. They had axons with conduction velocities between 3 and 15 m/sec, corresponding to B fibres. 4. None of these were located in the region of the dorsal motor nucleus of the vagus, in spite of repeated sampling there, but all were located in the region of the nucleus ambigus. Histological examination of marked neurones (forty‐six of the fifty‐seven neurones) revealed that they were associated with its principal column, rostral to the obex. 5. Sampling motoneurones of the dorsal motor nucleus revealed that most sent axons down the thoracic vagus below the cardiac branches. Only three of thirty‐three could be activated antidromically by high intensity stimulation of the cardiac branches, but on the basis of their thresholds and conduction velocities, it is argued that they were unlikely to be cardio‐inhibitory neurones. 6. It is concluded that preganglionic cardio‐inhibitory neurones arise not in the dorsal motor nucleus, but in the principal column of the nucleus ambiguus.

Intravenous hypertonic saline induces Fos immunoreactivity in neurons throughout the lamina terminalis.

Expression of Fos, the protein product of c-fos, was studied immunohistochemically in the forebrain of rats infused intravenously with hypertonic solutions. Intravenous 1.5 or 0.75 mol/l NaCl or 1.2 mol/l sucrose in 0.15 mol/l NaCl, but not isotonic 0.15 mol/l NaCl, caused increased Fos expression in the hypothalamic paraventricular and supraoptic nuclei and throughout the lamina terminalis (organum vasculosum laminae terminalis, median preoptic nucleus and subfornical organ). These results show that neurons in the lamina terminalis are activated by physiological increases in plasma tonicity and support an involvement of the lamina terminalis in osmoregulation.

Effects of kainic acid applied to the ventral surface of the medulla oblongata on vasomotor tone, the baroreceptor reflex and hypothalamic autonomic responses

Application of an excitotoxic amino acid, kainic acid, to the ventral medullary surface just caudal to the trapezoid bodies (at Feldberg and Guertzensteins glycine-sensitive area) led to the following observations. (1) Blood pressure began to rise within 25 s and by 10 min rose to high levels (200-240 mm Hg). Blood pressure subsequently fell to levels at or approaching those of a spinal animal. (2) Sympathetic vasomotor activity became insensitive to baroreceptor inhibition shortly after the peak in blood pressure, and the cardioinhibitory action of the reflex was enhanced during this time. (3) The autonomic effects of hypothalamic stimulation were differentially affected--pupillary dilatation and retraction of the nictitating membranes were unaffected, while the increases in blood pressure and renal nerve activity were blocked. (4) Recovery from these effects was observed on two occasions, when the animals were infused with a pressor agent and allowed to survive beyond 6 h after the kainic acid application. These results support the view that vasomotor tone is dependent upon the activity of relatively superficial cells in the ventral medulla. We further suggest that baroreceptor inhibition of sympathetic vasomotor activity acts via these cells and that descending hypothalamic autonomic pathways are organized at this level in terms of separate end organs.

Two types of vagal preganglionic motoneurones projecting to the heart and lungs.

1. A study has been made of eighty‐four cells in the cats nucleus ambiguus whose axons projected to the cardiac (seventy‐four) and pulmonary (ten) branches of the right vagus. Their axonal conduction velocities were all in the range of B fibres (2·8‐15·5 m/sec).

The cholinergic anti-inflammatory pathway: A critical review

From a critical review of the evidence on the cholinergic anti-inflammatory pathway and its mode of action, the following conclusions were reached. (1) Both local and systemic inflammation may be suppressed by electrical stimulation of the peripheral cut end of either vagus. (2) The spleen mediates most of the systemic inflammatory response (measured by TNF-α production) to systemic endotoxin and is also the site where that response is suppressed by vagal stimulation. (3) The anti-inflammatory effect of vagal stimulation depends on the presence of noradrenaline-containing nerve terminals in the spleen. (4) There is no disynaptic connection from the vagus to the spleen via the splenic sympathetic nerve: vagal stimulation does not drive action potentials in the splenic nerve. (5) Acetylcholine-synthesizing T lymphocytes provide an essential non-neural link in the anti-inflammatory pathway from vagus to spleen. (6) Alpha-7 subunit-containing nicotinic receptors are essential for the vagal anti-inflammatory action: their critical location is uncertain, but is suggested here to be on splenic sympathetic nerve terminals. (7) The vagal anti-inflammatory pathway can be activated electrically or pharmacologically, but it is not the efferent arm of the inflammatory reflex response to endotoxemia.

The baroreceptor input to cardiac vagal motoneurones

1. A study has been made of twenty‐three cardiac vagal motoneurones (c.v.m.s) in the nucleus ambiguus of chloralose‐anaesthetized cats.

The sinus nerve and baroreceptor input to the medulla of the cat.

Electrical stimulation within the medulla of cats revealed that myelinated primary afferent fibres of the sinus nerve terminated within the immediate vicinity of the tractus solitarius and its nucleus. 2. The activity of neurones within this area was also evoked on sinus nerve stimulation, although few (17%) were activated within a latency compatible with monosynaptic excitation. Additional projections over polysynaptic pathways have been shown to the parahypoglossal area and to the area of the nucleus ambiguus. 3. These three areas were shown to contain neurones whose activity was enhanced by stimulation of the baroreceptor endings of the ipsilateral carotid sinus. 4. No evidence for a projection of sinus nerve afferents to the medial reticular formation (an area extending medially from the hypoglossal nucleus and nerve tract and including the paramedian reticular nucleus) was obtained in either antidromic or orthodromic studies. 5. The organization of the central pathway of the carotid sinus baroreceptor reflex is discussed in the light of these results.