Neural pathways from the lamina terminalis influencing cardiovascular and body fluid homeostasis

1. The lamina terminalis, a region of the brain with a high concentration of angiotensin AT1 receptors, consists of three distinct nuclei, the median preoptic nucleus, the subfornical organ and organum vasculosum of the lamina terminalis (OVLT). These latter two regions lack a blood-brain and detect changes in plasma angiotensin (Ang) II concentration and osmolality. 2. Efferent neural pathways from the lamina terminalis to the hypothalamic paraventricular and supraoptic nuclei mediate vasopressin secretion in response to plasma hypertonicity and increased circulating levels of AngII. 3. Studies using the neurotropic virus pseudorabies, which undergoes retrograde transynaptic neuronal transport following injection into peripheral sites, show that neurons in the lamina terminalis have efferent polysynaptic neural connections to the peripheral sympathetic nervous system. Some of these neurons have been shown to have polysynaptic connections to the kidney and to express AT1 receptor mRNA. We propose that circulating AngII acts at AT1 receptors in the subfornical organ and OVLT to influence the sympathetic nervous system. It is likely that the neural pathway subserving this influence involves a synapse in the hypothalamic paraventricular nucleus. 4. The lamina terminalis may exert an inhibitory osmoregulatory influence on renin secretion by the kidney. This osmoregulatory influence may be mediated by inhibition of renal sympathetic nerve activity and appears to involve a central angiotensinergic synapse. 5. The lamina terminalis exerts an osmoregulatory influence on renal sodium excretion that is independent of the renal nerves and is probably hormonally mediated.     

ROLE OF THE HYPOTHALAMIC PARAVENTRICULAR NUCLEUS IN CARDIOVASCULAR REGULATION

1. The paraventricular hypothalamic nucleus (PVH) is a complex structure with both neuroendocrine and autonomic functions. It is a major source of vasopressin and the primary source of corticotropin-releasing factor. In addition, parvicellular PVH neurons have reciprocal connections with brain-stem autonomic centres and directly innervate sympathetic preganglionic neurons. Evidence is reviewed which indicates that in conscious rats PVH activation increases blood pressure, heart rate, renal nerve activity and plasma renin activity. 2. In conscious rats, a non-hypotensive haemorrhage (13 mL/kg blood loss over 24 min) results in increased numbers of Fos-immunoreactive cell nuclei within both magnocellular and parvicellular PVH neurons, including the ventral medial parvicellular regions known to contain neuronal projections to brainstem autonomic centres and spinal cord sympathetic preganglionic neurons. 3. Cell-selective ibotenate lesions of the parvicellular PVH significantly blunt the corticosterone response but do not alter blood pressure, heart rate or plasma renin concentration response to non-hypotensive or hypotensive haemorrhage. This and earlier studies indicate that, while the PVH is necessary for the corticosterone response and contributes to increased vasopressin release during blood loss, it does not play an important role in the sympathetic nervous system and renin-angiotensin responses to hypovolaemia and hypotension. 4. There is evidence to indicate that the parvicellular PVH serves as a necessary relay for cardiovascular and renin responses to certain behavioural stressors. We propose that cardiovascular information relayed to parvicellular PVH autonomic regions may be used to modulate behavioural, rather than homeostatic, effects on haemodynamics and renin release.     

Differential regulation of brown adipose and splanchnic sympathetic outflows in rat: roles of raphe and rostral ventrolateral medulla neurons

1. The medullary premotor neurons determining the sympathetic outflow regulating cardiac function and vasoconstriction are located in the rostral ventrolateral medulla (RVLM). The present study sought evidence for an alternative location for the sympathetic premotor neurons determining the sympathetic nerve activity (SNA) controlling brown adipose tissue (BAT) metabolism and thermogenesis. 2. The tonic discharge on sympathetic nerves is determined by the inputs to functionally specific sympathetic preganglionic neurons from supraspinal populations of premotor neurons. Under normothermic conditions, BAT SNA was nearly silent, while splanchnic (SPL) SNA, controlling mesenteric vasoconstriction, exhibited sustained large-amplitude bursts. 3. The rostral raphe pallidus (RPa) contains potential sympathetic premotor neurons that project to the region of sympathetic preganglionic neurons in the thoracic spinal cord. Disinhibition of neurons in RPa elicited a dramatic increase in BAT SNA, with only a small rise in SPL SNA. 4. Splanchnic SNA was strongly influenced by the baroreceptor reflex, as indicated by a high coherence with the arterial pressure wave, a significant amplitude modulation over the time-course of the cardiac cycle and a marked inhibition of SPL SNA during a sustained increase in arterial pressure. When activated, the bursts in BAT SNA exhibited no correlation with arterial pressure and were not affected by increases in arterial pressure. 5. Because these characteristics and reflex responses in sympathetic outflow have been shown to arise from the on-going or altered discharge of sympathetic premotor neurons, the marked differences between SPL and BAT SNA provide strong evidence supporting the hypothesis that vasoconstriction and thermogenesis (metabolism) are controlled by distinct populations of sympathetic premotor neurons, the former in the RVLM and the latter, potentially, in the RPa.     

Neural pathways underlying lactate-induced panic.

Panic disorder is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as 0.5 M sodium lactate infusions. Although studied for four decades, the mechanism of lactate sensitivity in panic disorder has not been understood. The dorsomedial hypothalamus/perifornical region (DMH/PeF) coordinates rapid mobilization of behavioral, autonomic, respiratory and endocrine responses to stress, and rats with disrupted GABA inhibition in the DMH/PeF exhibit panic-like responses to lactate, similar to panic disorder patients. Utilizing a variety of anatomical and pharmacological methods, we provide evidence that lactate, via osmosensitive periventricular pathways, activates neurons in the compromised DMH/PeF, which relays this signal to forebrain limbic structures such as the bed nucleus of the stria terminalis to mediate anxiety responses, and specific brainstem sympathetic and parasympathetic pathways to mediate the respiratory and cardiovascular components of the panic-like response. Acutely restoring local GABAergic tone in the DMH/PeF blocked lactate-induced panic-like responses. Autonomic panic-like responses appear to be a result of DMH/PeF-mediated mobilization of sympathetic responses (verified with atenolol) and resetting of the parasympathetically mediated baroreflex. Based on our findings, DMH/PeF efferent targets such as the C1 adrenergic neurons, paraventricular hypothalamus, and the central amygdala are implicated in sympathetic mobilization; the nucleus of the solitary tract is implicated in baroreflex resetting; and the parabrachial nucleus is implicated in respiratory responses. These results elucidate neural circuits underlying lactate-induced panic-like responses and the involvement of both sympathetic and parasympathetic systems.     

Circumventricular Organs: Gateways to the Brain Axonal Projections From The Organum Vasculosum Lamina Terminalis To The Supraoptic Nucleus: Functional Analysis And Presynaptic Modulation

1. The rat organum vasculosum lamina terminalis (OVLT) contains GABA‐ and glutamate‐releasing neurons that project directly to magnocellular neurosecretory cells (MNC) in the supraoptic nucleus. 2. Changes in osmolality over the OVLT in hypothalamic explants cause proportional changes in firing in MNC through corresponding changes in the frequency of spontaneous glutamatergic excitatory post‐synaptic potentials without affecting GABAergic inhibitory post‐synaptic potentials. 3. Exogenously applied atrial natriuretic peptide inhibits the osmotic control of MNC by causing a decrease in the amount of glutamate released provoked by action potentials originating from OVLT neurons.     

Translation of salt retention to central activation of the sympathetic nervous system in hypertension

1. Increased dietary salt increases blood pressure in many hypertensive individuals, producing salt-sensitive hypertension (SSH). The cause is unknown, but a major component appears to be activation of the sympathetic nervous system. The purpose of this short review is to present one hypothesis to explain how increased dietary salt increases sympathetic activity in SSH. 2. It is proposed that increased salt intake causes salt retention and raises plasma sodium chloride (NaCl) concentrations, which activate sodium/osmoreceptors to trigger sympathoexcitation. Moreover, we suggest that small and often undetectable increases in osmolality can drive significant sympathoexcitation, because the gain of the relationship between osmolality and increased sympathetic activity is enhanced. Multiple factors may contribute to this facilitation, including inappropriately elevated levels of angiotensin II or aldosterone, changes in gene expression or synaptic plasticity and increased sodium concentrations in cerebrospinal fluid. 3. Future studies are required to delineate the brain sites and mechanisms of action and interaction of osmolality and these amplification factors to elicit sustained sympathoexcitation in SSH.     

FOREBRAIN PATHWAYS MEDIATING STRESS-INDUCED RENIN SECRETION

1. All stressors tested so far increase plasma renin levels; among these are exposure to foot-shock, immobilization, forced swimming, head-up tilt, exercise, hypotension haemorrhage and conditioned fear. 2. In old rats (22 months old), conditioned fear stress fails to increase plasma renin concentrations to the same level as in young rats (7 months old). 3. Destruction of cells in the paraventricular hypothalamic nucleus (PVH), either electrolytically or with the cell-selective neurotoxin ibotenic acid, prevents the effect of conditioned fear stress, but not of immobilization, on plasma renin concentration. 4. Ibotenic acid-induced lesions in the central amygdaloid nucleus inhibit conditioned fear stress-induced increases in plasma renin concentrations, but do not reduce the renin response to immobilization. Lesions in lateral amygdaloid nuclei do not reduce the renin response to stressors. 5. Although lesions in the bed nucleus of the stria terminalis (BNST) reduce the adrenocortical response to conditioned fear stress, they do not reduce the effect of stress on plasma renin concentration. 6. Destruction of catecholaminergic terminals in the PVH prevents the effect of conditioned fear stress on plasma renin concentration. 7. Electrolytic lesions in the dorsal raphe nucleus, which is a major site of origin of ascending serotonergic pathways, also inhibit the effect of conditioned fear stress on plasma renin concentration. 8. Activation of serotonin_1A (5HT_1A) receptors with the anti-anxiety drugs buspirone and ipsapirone reduces the firing rate of serotonergic neurons in the dorsal raphe nucleus in the midbrain and decreases the effect of stress on plasma renin concentrations. In contrast, the benzodiazepine anxiolytic drugs, chlordiazepoxide and midazolam, are ineffective in inhibiting the renin response to stress. 9. Chemical sympathectomy combined with adrenal medullectomy does not prevent the effect of conditioned fear stress on plasma renin concentration, suggesting that the sympathetic system is not the sole mediator of the message from the brain to the kidneys. 10. Combined, these observations suggest that aversive information from the cortex is transmitted via the amygdala to catecholaminergic cells in the medulla and to serotonergic cells in the dorsal raphe that stimulate the PVH to increase the release of renin.     

Estradiol alters the chemosensitive cardiac afferent reflex in female rats by augmenting sympathoinhibition and attenuating sympathoexcitation

The chemosensitive cardiac vagal and sympathetic afferent reflexes are implicated in driving pathophysiological changes in sympathetic nerve activity (SNA) in cardiovascular disease states. This study investigated the impact of sex and ovarian hormones on the chemosensitive cardiac afferent reflex. Experiments were performed in anaesthetized, sinoaortic baroreceptor denervated male, female and ovariectomized female (OVX) Wistar rats with either intact cardiac innervation or bilateral vagotomy. To investigate the chemosensitive cardiac afferent reflexes renal SNA, heart rate (HR) and arterial pressure (AP) were recorded before and following application of capsaicin onto the epicardial surface of the left ventricle. Compared to males, ovary‐intact females displayed similar cardiac afferent reflex mediated changes in renal SNA albeit with a reduced maximum sympathetic reflex driven increase in renal SNA. In females, ovariectomy significantly attenuated the cardiac vagal afferent reflex mediated inhibition of renal SNA (renal SNA decreased 2 ± 17% in OVX versus ?50 ± 4% in ovary‐intact females, P < 0.05) and augmented cardiac sympathetic afferent reflex mediated sympathoexcitation (renal SNA increased 91 ± 11% in OVX vs 62 ± 9% in ovary‐intact females, P < 0.05) so that overall increases in reflex driven sympathoexcitation were significantly enhanced. Chronic estradiol replacement, but not progesterone replacement, begun at time of ovariectomy restored cardiac afferent reflex responses to be similar as ovary‐intact females. Vagal denervation eliminated all group differences. The current findings show ovariectomy in female rats, mimicking menopause in women, results in greater chemosensitive cardiac afferent reflex driven sympathoexcitation and does so, at least partly, via the loss of estradiols actions on the cardiac vagal afferent reflex pathway.     

LACK OF SYMPATHETIC AUGMENTATION IN RESPONSE TO INTRAVENOUS LOAD OF GLUCOSE IN RABBITS

1. We investigated a link between sympathetic nervous function and carbohydrate metabolism by measuring renal sympathetic nerve activity in response to intravenous load of glucose in alpha-chloralose-urethane anaesthetized rabbits. 2. Intravenous infusion of a 25% glucose solution (0.5 g/kg) over 3 min caused a transient increase in arterial blood pressure and a decrease in renal sympathetic nerve activity. Thereafter, these parameters were restored and remained around preload levels while plasma glucose and insulin concentrations were still elevated. 3. Equimolar mannitol solution produced similar patterns of change in blood pressure and nerve activity without an elevation of plasma glucose and insulin levels. 4. The transient changes in blood pressure and renal nerve activity could be attributed to acute hypervolaemia indicated by similar changes in plasma osmolality and haematocrits in the two groups of treatment. 5. The present study did not support a close relationship between carbohydrate metabolism and the sympathetic nervous system regulating cardiovascular function.     

Physiological actions of angiotensin II mediated by AT1 AND AT2 receptors in the brain

1. Autoradiographic binding studies have shown that the AT(1) receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT(1) receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord. 2. While there are differences between species, AT(2) receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat. 3. Circulating AngII acts on AT(1) receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking. 4. Centrally administered AngII may act on AT(1) receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion. 5. Recent evidence shows that centrally administered AT(1) antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses. 6. Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT(1) receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.     

Glutamate receptors in the raphe pallidus mediate brown adipose tissue thermogenesis evoked by activation of dorsomedial hypothalamic neurons

Disinhibition of DMH neurons with the GABAA receptor antagonist, bicuculline, increases heart rate (HR) and augments both brown adipose tissue sympathetic nerve activity (BAT SNA) and renal SNA (RSNA) contributing to the evoked increases in BAT thermogenesis and arterial pressure (AP). We determined the role of glutamate receptor activation in the rostral raphe pallidus (RPa) in mediating the sympathoexcitatory responses in HR, BAT SNA and RSNA following disinhibition of DMH neurons in urethane/chloralose anesthetized, artificially ventilated rats. Microinjections of either the selective NMDA receptor agonist, NMDA, or the selective non-NMDA receptor agonist, kainic acid (KA), into the RPa produced increases in BAT SNA (peak: + 502% and + 408% of control, respectively) and BAT temperature (peak: + 0.6 degrees C and + 1.0 degrees C) accompanied by rises in HR (peak: + 38 and + 63 bpm), RSNA (peak: + 57% and + 58% of control) and MAP (peak: + 12 and 15 mmHg). These responses were reversed by subsequent microinjection into RPa of the respective selective glutamate receptor antagonists, AP5 and CNQX. Microinjections of the non-selective glutamate receptor antagonist, kynurenic acid (Kyn), the NMDA receptor antagonist, AP5, or the non-NMDA receptor antagonist, CNQX, were effective in reversing the increases in BAT SNA (for Kyn, from peak of + 419% of control to + 9% of control) and BAT temperature, but not those in HR, MAP or RSNA (for Kyn, from peak of + 143% of control to + 124% of control) evoked by unilateral microinjection of bicuculline into the DMH. These results indicate that both NMDA and non-NMDA glutamate receptors in the RPa play a significant role in mediating the excitatory synaptic transmission producing the activation of BAT thermogenesis following disinhibition of DMH neurons. Glutamate receptors in the RPa may not be important for transmitting cardiovascular responses induced by activation of the DMH neurons.     

INTEGRATIVE ROLE OF THE LAMINA TERMINALIS IN THE REGULATION OF CARDIOVASCULAR AND BODY FLUID HOMEOSTASIS

1. Cardiovascular and body fluid homeostasis depends upon the activation and co-ordination of reflexes and behavioural responses. In order to accomplish this, the brain receives and processes both neural and chemical input. Once in the brain, information from sources signalling the status of the cardiovascular system and body fluid balance travels, and is integrated, throughout a widely distributed neural network. Recent studies using neuroanatomical and functional techniques have identified several key areas within this neural network. One major processing node is comprised of structures located along the lamina terminalis. 2. Structures associated with the lamina terminalis include the median preoptic nucleus (MePO) and two sensory circumventricular organs (SCVO), the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT). Current evidence indicates that blood-borne signals, such as angiotensin II (AngII), reach SCVO (e.g. SFO) where they are transduced. This information is then carried via neural pathways to brain nuclei (e.g. MePO) where it is integrated with other inputs, such as those derived from systemic arterial blood pressure and volume receptors. 3. Because of their receptive and integrative functions, lamina terminalis structures are essential for the normal control of hormone release (e.g. vasopressin), sympathetic activation and behaviours (thirst and salt appetite), which collectively contribute to maintenance of cardiovascular and body fluid homeostasis.     

ANTEROVENTRAL WALL OF THE THIRD VENTRICLE AND DORSAL LAMINA TERMINALIS: HEADQUARTERS FOR CONTROL OF BODY FLUID HOMEOSTASIS?

1. The subfornical organ, median preoptic nucleus and the organum vasculosum of the lamina terminalis (OVLT) are a series of structures situated in the anterior wall of the third ventricle and form the lamina terminalis. The OVLT and ventral part of the median preoptic nucleus are part of a region known as the anteroventral third ventricle region.
2. Data from many laboratories, using techniques ranging from lesions, electrophysiology, neuropharmacology, Fos expression, immunohistochemistry and receptor localization, indicate that the tissue in the lamina terminalis plays a major role in many aspects of body fluid and electrolyte balance.
3. The subfornical organ and OVLT lack the blood-brain barrier and detect alterations in plasma tonicity and the concentrations of circulating hormones such as angiotensin II and possibly atrial natriuretic peptide and relaxin.
4. This information is then integrated within the lamina terminalis (probably in the median preoptic nucleus) with neural signals from other brain regions. The neural output from the lamina terminalis is distributed to a number of effector sites including the paraventricular (both parvo- and magno-cellular parts) and supraoptic nuclei and influences vasopressin secretion, water drinking, salt intake, renin secretion, renal sodium excretion and cardiovascular regulation.     

Plasma catecholamines and neuropeptide-Y as indices of sympathetic nerve activity in normotensive and stroke-prone spontaneously hypertensive rats

The suitability of plasma catecholamines (CAs) and neuropeptide-Y (NPY) as biochemical indices of sympathetic nerve activity (SNA) has been investigated, and these parameters have been compared between adult normotensive (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Plasma norepinephrine (NE), epinephrine (E) and NPY were measured in venous and arterial blood samples taken from conscious, unrestrained rats. Under resting conditions, both CAs were significantly higher in SHRSP than in WKY; plasma E in particular was raised threefold. SHRSP had higher plasma levels of NPY in arterial blood but not in venous blood. Acute hydralazine-induced hypotension caused a slight rise in NPY and striking increases of CAs, which were accentuated in SHRSP. Ganglion blockade with pentolinium reversed these increases but the differences in basal plasma CA levels between strains still persisted. Barbiturate anaesthesia had little effect on plasma levels of NPY or NE, but plasma E levels were depressed, particularly in SHRSP, so that the strain difference in plasma E taken from venous blood was no longer apparent. The results indicate that plasma levels of CAs but not NPY are useful indices of SNA in conscious rats. Comparisons between WKY and SHRSP after drug treatment demonstrate a major contribution by the adrenal medulla to plasma CA levels in SHRSP which, under resting conditions, may not be sympathetically evoked.     

Cardiovascular alterations by chronic intermittent hypoxia: importance of carotid body chemoreflexes

1. Humans experiencing intermittent hypoxia (IH) owing to recurrent apnoea syndromes exhibit serious cardiovascular morbidity, including high blood pressure, increased sympathetic nerve activity, cardiac arrhythmia and myocardial infarction. Although apnoeas are accompanied by a simultaneous decrease in arterial O(2) (hypoxia) and an increase in CO(2) (hypercapnia), studies on experimental animals suggest that hypoxia, rather than hypercapnia, is the primary stimulus for developing hypertension and enhanced sympathetic nerve activity. Enhanced hypoxic-sensing ability of the carotid bodies and the ensuing reflex activation of the sympathetic nervous system have been suggested to play a critical role in cardiorespiratory alterations resulting from recurrent apnoeas. 2. The purpose of the present review is to highlight recent studies demonstrating the effects of IH on carotid body sensory activity and its consequences on sympathetic activation in a rodent model of chronic IH. Adult rats exposed to chronic IH (15 s of 5% O(2) followed by 5 min of 21% O(2), nine episodes per h, 8 h/day for 10 days) exhibited selective enhancement of carotid body sensory response to hypoxia. In addition, chronic IH induced a novel form of sensory plasticity in the carotid body, manifested as sensory long-term facilitation (LTF). Functional changes in the carotid body occurred in the absence of morphological changes in the chemoreceptor tissue. 3. Acute hypoxia increased expiratory modulated splanchnic nerve activity (SNA) and acute IH-induced LTF in SNA. Hypoxia-induced SNA activation was prevented by bilateral sectioning of the sinus nerves. Rats exposed to chronic IH exhibited enhanced hypoxia-induced sympathetic activation and augmented LTF of the SNA. Bilateral sectioning of the sinus nerves abolished these responses, suggesting chronic IH-induced alterations in carotid body sensitivity contribute to LTF in SNA and the subsequent cardiovascular alterations.     

The baroreflex and beyond: control of sympathetic vasomotor tone by GABAergic neurons in the ventrolateral medulla

1. Barosensitive, bulbospinal neurons in the rostral ventrolateral medulla (RVLM), which provide the major tonic excitatory drive to sympathetic vasomotor neurons, are prominently inhibited by GABA. 2. A major source of the GABAergic inhibition to presympathetic RVLM neurons arises from an area immediately caudal to the RVLM, known as the caudal ventrolateral medulla (CVLM). 3. Arterial baroreceptor afferents projecting to the nucleus tractus solitarius (NTS) provide a major tonic excitatory input to GABAergic CVLM neurons. These CVLM cells are a critical component for baroreflex-mediated changes in presympathetic RVLM neuronal activity, sympathetic nerve activity (SNA) and arterial pressure (AP). 4. Some GABAergic CVLM neurons are tonically activated by inputs independent of arterial baroreceptors or the NTS, providing a GABAergic-mediated inhibition of the presympathetic RVLM neurons that is autonomous of baroreceptor inputs. 5. GABAergic CVLM neurons appear to play two distinct, yet important, roles in the regulation of sympathetic vasomotor tone and AP. They dampen immediate changes in AP via the baroreflex and tonically inhibit the activity of the presympathetic RVLM neurons by baroreceptor-independent mechanisms. This baroreceptor-independent, GABAergic inhibition of presympathetic RVLM neurons may play an important role in determining the long-term level of sympathetic vasomotor tone and AP.     

A case of transient diabetes insipidus associated with poisoning by a herbicide containing glufosinate

BACKGROUND: The herbicide BASTA (AgrEvo, Germany), containing glufosinate ammonium (20%) and an anionic surfactant, polyoxyethylene alkylether sulfate (33%), is widely used. In acute oral BASTA poisoning, patients develop a variety of clinical signs, including disturbed consciousness, convulsions, and apnea. These effects are suspected to be due to the effects of glufosinate on the central nervous system. CASE REPORT: A 60-year-old man ingested 500 mL of BASTA herbicide in a suicide attempt. He developed not only unconsciousness, respiratory distress, and convulsions but also an increase in urine output (7885 mL/d), elevated serum sodium (167 mEq/L), elevated plasma osmolality (332 mOsm/kg), and a decrease in both urine osmolality (200 mOsm/kg) and urine specific gravity (1.003), which suggested the development of diabetes insipidus. The plasma level of antidiuretic hormone remained within the normal range (1.3 pg/mL), despite high plasma osmolality. The administration of desmopressin was successful in normalizing urine volume, specific gravity, and osmolality. Serum sodium corrected gradually within 48 hours. The possible mechanisms causing the diabetes insipidus are discussed.     

Differential effects of central and peripheral desipramine on sympathoadrenal function and heart rate in conscious rabbits.

The effects of the tricyclic antidepressant, desipramine, on the baroreflex regulation of renal sympathetic nerve activity (SNA) and heart rate (HR), the nasopharyngeal reflex, plasma epinephrine and blood pressure (BP) were studied in conscious rabbits. Renal SNA and HR were recorded during slow ramp changes in mean arterial pressure (MAP) and during inhalation of cigarette smoke. Intracisternal (i.c.) and intravenous (i.v.) drug administration were compared, using doses which produced similar total central nervous system (CNS) concentrations. After a brief sympathoexcitation, i.c. desipramine inhibited renal SNA and MAP and increased plasma adrenaline and HR. The renal sympathetic baroreflex was substantially attenuated, with reflex range and gain reduced by 46 and 31%, respectively, but the cardiac baroreflex and nasopharyngeal reflex were affected minimally. Sixty-four percent of the desipramine remaining in the brain was concentrated in the medulla oblongata and spinalis; levels in cortex, thalamus, midbrain, lower spinal cord, and peripheral tissues were minimal. Treatment with i.v. desipramine decreased renal SNA and increased HR without altering MAP or epinephrine release. There was a slight attenuation of the nasopharyngeal reflex, a slight baroreceptor-independent reduction in renal SNA at most MAP levels, and an augmentation of the cardiac baroreflex. The drug was uniformly distributed throughout the CNS; only 20% of the centrally accumulated dose was in the medulla. Thus, i.c. desipramine produces a differentiated pattern of sympathoadrenal effects, probably by increasing norepinephrine (NE) concentrations at several sites within the medulla. The effects of i.v. desipramine were different, owing to poorer access to the medulla and the consequences of peripheral neuronal uptake blockade, which may include a modest inhibition at the sympathetic ganglia and an excitation at cardiac and vasoconstrictor neuroeffector junctions.     

Circumventricular Organs: Gateways to the Brain Multisynaptic Neuronal Pathways From The Submandibular And Sublingual Glands To The Lamina Terminalis In The Rat: A Model For The Role Of The Lamina Terminalis In The Control Of Osmo- And Thermoregulatory Behaviour

1. The putative regulatory role of the lamina terminalis in the central control of salivation was investigated in the rat using the viral‐tracing technique and Fos‐immunohistochemistry. 2. Neurons situated in the lamina terminalis, such as the vascular organ of the lamina terminalis (OVLT), median preoptic nucleus (MnPO) and subfornical organ (SFO), were retrogradely labelled after pseudorabies virus injections into the submandibular or sublingual gland. 3. Viral tracing combined with glandular denervation showed that lamina terminalis structures sent efferents, in particular, to the parasympathetic side of submandibular gland innervation. 4. Saliva lost under heat stress has severe implications for the body fluid economy of rats and a key to the understanding of the central regulation of heat‐induced salivation may be the integrative role of the lamina terminalis processing thermoregulatory and osmoregulatory information.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN II MEDIATED BY AT1 AND AT2 RECEPTORS IN THE BRAIN

• 1 Autoradiographic binding studies have shown that the AT₁ receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT₁ receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord.
• 2 While there are differences between species, AT₂ receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.
• 3 Circulating AngII acts on AT₁ receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.
• 4 Centrally administered AngII may act on AT₁ receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.
• 5 Recent evidence shows that centrally administered AT₁ antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.
• 6 Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT₁ receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.