Dose-related potent brain stimulation by the neuropeptide endothelin-1 after intraventricular administration in conscious rats.

Injection of the neuropeptide, endothelin-1 (ET, range of 3-9 pmol), into a lateral ventricle (ICV) of rats produced barrel rolling and other convulsions including ataxia, forelimb and facial clonus, nystagmus, and tonic extension of the tail and hindlimbs. Using the quantitative autoradiographic [14C]deoxyglucose method, we resolved the focal hypermetabolic correlates of the convulsive activity in numerous brain regions. The present study tested whether the effects of ET were dose dependent by assessing 13 behavioral, 9 physiological, and brain metabolic responses in six individual structures of rats treated separately with ICV ET in doses between 1.5 and 18 pmol. Barrel-rolling convulsions, having a threshold for onset at 3 pmol, displayed increased incidence and severity, and a shorter latency to onset, with the higher ET doses. Within 10-20 min, ET evoked dose-dependent increases in mean arterial pressure and plasma glucose levels, and a significant reduction in arterial PCO2. Among brain structures, the periventricular caudate nucleus near the injection site had an elevated rate of glucose metabolism (+60%) at a 3 pmol threshold. The substantia nigra pars reticulata, medial terminal nucleus of the accessory optic tract, rostral lamella of the inferior olivary nucleus, cerebellar paramedian lobule, and cerebellar copula pyramis, all of which have moderate to dense populations of ET-1 receptors and are related by anatomical connections, displayed significant metabolic stimulation by 9 pmol ET (+47 to +122%). The behavioral, physiological, and focal hypermetabolic effects of the central ET appear to be time coordinated, interrelated, and dose dependent. Identification of the threshold dose for central actions of ET at 3 pmol ICV reveals this peptide as the most potent neuroactive substance yet described in vivo.

FR139317, a specific ETA-receptor antagonist, inhibits cerebral activation by intraventricular endothelin-1 in conscious rats.

A comprehensive series of time-related behavioral, physiological and cerebral metabolic studies was conducted using conscious Sprague-Dawley rats to discern the anti-endothelin (ET) properties of the specific ETA receptor antagonist, FR139317. Endothelin-1 (9 pmol given by injection into one lateral ventricle, i.c.v.) produced convulsions, acute arterial hypertension, arterial hyperglycemia, and hyperventilation. Brain structures close to the i.c.v. site of injection, such as the caudate nucleus, lateral septal nucleus, corpus callosum and hippocampal CA3 medial lamellae, as well as 14 other individual structures, displayed moderate-to-intense levels of metabolic activation after endothelin. Data were assessed quantitatively by means of the autoradiographic [14C]deoxyglucose technique combined with image analysis. Neural circuits in the efferent projection paths of the stimulated forebrain structures, such as the midbrain oculomotor complex, amygdaloid nuclei, substantia nigra pars reticulata and caudal subicular subregions of the hippocampal formation, were stimulated focally by endothelin. Specific medullary nuclei and cerebellar cortical subregions displayed high rates of glucose metabolism following endothelin injection at the time of maximum behavioral and physiological stimulation. I.c.v. treatment with > or = 14 nmol FR139317 before endothelin significantly inhibited the effects produced by the peptide. At the highest dose of FR139317 (28 nmol), there was only mild behavioral stimulation following endothelin injection, and hypermetabolic responses in the brain were abolished except in two specific areas of the cerebellar cortex (approx 40% increases in metabolic activity in the copula pyramis and paramedian lobule). The results indicate that the cerebral stimulatory effects of i.c.v. endothelin are mediated by the A type of endothelin receptor. By itself, i.c.v. FR139317 had no effects on the parameters assessed. Further evaluation of FR139317 is warranted as a possible therapeutic agent for neuropathologies suspected of deriving from central neural or vascular stimulation by endothelin, such as aneurysmal vasospasm, ischemia, excitotoxicity, and peptide-mediated epilepsies.

Neurotoxicity in conscious rats following intraventricular SNAP, a nitric oxide donor.

A solution containing S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO.-releasing compound, was microinjected in doses of 0.25-2 mumol into a lateral ventricle of conscious rats. SNAP produced dose-dependent convulsions similar to those associated with limbic stimulation, such as tonic extension of the hindlimbs and tail, and dystonia of the forepaws. At 2 mumol, SNAP evoked hyperventilation (arterial hypocapnia), arterial hyperglycemia and caused necrotic lesions of periventricular gray (e.g. lateral septal nucleus) and white matter structures. In the caudate nucleus and lateral septal nucleus ipsilateral to injection, SNAP elicited a bipolar metabolic pattern of low glucose metabolism proximal to the ventricle with higher values occurring more distally. In control studies, we proved that the residue of SNAP decomposition, N-acetylpenicillamine disulfide injected intraventricularly (2 mumol), was without physiological, behavioral, or histological effects. Ventricular pretreatment with methylene blue (2 nmol), a putative inhibitor of guanylate cyclase and superoxide generator, suppressed several of the behavioral manifestations of 1 mumol SNAP, such as the forepaw dystonia, squinting, and facial clonus, but was ineffective on the physiological and histological variables affected by the 2 mumol SNAP dose. Another NO. donor, sodium nitroprusside (2 mumol), produced fewer behavioral and cytotoxic effects over a 55-min observation period, but caused more intense and widely distributed metabolic stimulation, especially in commissural and projection white matter tracts. The results are the basis for a conscious rat model using intraventricular injection of nitrocompounds to examine the physiological, behavioral, metabolic and cytotoxic properties of NO. in the brain.

NMDA-mediated metabolic activation of the cerebellar cortex in behaving rats by the neuropeptide endothelin-1.

Generalized barrel-rolling convulsions and focal hypermetabolic responses in the cerebellar cortex of conscious rats to lateral ventricular injection of the neuropeptide, endothelin-1 (ET; 9 pmol), were diminished or eliminated by i.c.v. pretreatment with the glutamatergic NMDA receptor antagonist, MK-801 (44 nmol). Using the quantitative autoradiographic [14C]deoxyglucose technique, we assessed rates of glucose metabolism in individual structures anatomically connecting forebrain nuclei within a polysynaptic network linked to the cerebellar cortex. Cerebellar cortical afferent sources from specific subnuclei of the inferior olivary complex, cuneate nucleus, and medial vestibular nucleus, all of which were hypermetabolic following injection of ET alone, were also inhibited by MK-801. The findings indicate that a convulsive i.c.v. dose of ET elicits an NMDA-related stimulatory effect, whose origin is probably at the periventricular caudate nucleus, that activates rates of glucose metabolism in several afferent sources and subregions of the cerebellar cortex involved in the regulation of equilibrium, posture, and the visuovestibular system.

Sensory circumventricular organs and brain homeostatic pathways.

Circumventricular organs (CVOs), small structures bordering the ventricular spaces in the midline of the brain, have common morphological and endocrine-like characteristics that distinguish them from the rest of the nervous system. Among their unique features are cellular contacts with two fluid phases--blood and cerebrospinal fluid--and neural connections with strategic nuclei establishing circuitry for communications throughout the neuraxis. A variety of additional morphological and functional characteristics of the CVOs implicates this group of structures in a wide array of homeostatic processes. For three of the circumventricular organs--the subfornical organ (SFO), the organum vasculosum of the lamina terminalis (OVLT), and the area postrema (AP)--recent findings demonstrate these structures as targets for blood-borne information reaching the brain. We propose that these three sensory CVOs interact with other nuclei in the maintenance of several homeostatic processes by way of neural and humoral links. We emphasize the collective role of brain CVOs in the maintenance of body fluid homeostasis as a model for the functional integration of these fascinating "windows of the brain" within central neurohumoral systems.

Topography of short portal vessels in the rat pituitary gland: a scanning electron-microscopic and morphometric study of corrosion cast replicas.

We applied scanning electron microscopy combined with imaging and morphometric techniques to analyze the dorsal topography and morphology of short portal vessels linking the capillary beds of the pituitary neural and anterior lobes in adult male albino rats. The pituitary microvasculature was replicated by intracarotid injection of Batson's No. 17 compound producing plastic casts that were advantageous for comprehensive morphometric analyses using an imaging device. The analysis revealed the existence of two types of portal vessels having quantitatively different morphological properties. The bilateral venular plexus of 3-4 vessels located at the base of the infundibular stalk (each venule measuring 300 microns in length and 32 microns in diameter) appears to be the major part of the short portal system in the dorsum of the rat pituitary gland. Narrower capillary-like shunt vessels (6.8 microns in diameter), of about the same length as the venules, were situated throughout other subregions of the intermediate lobe cleft. The short portal vessels of both types made direct anastomoses with the capillary networks in the neural and anterior lobes. The neural lobe capillaries were twice as numerous (1324 per mm2), and only half as wide (6.2 microns), as the sinusoidal capillaries in the anterior lobe (density of 637 per mm2; diameter of 13.7 microns). The topographical position of the portal venular system suggests that the caudolateral subregions of the pituitary neural and anterior lobes have a functional relationship dependent on rapid interlobe transfer of neurohumoral factors such as hormones via the portal blood. This process appears to be supplemented throughout the rest of the cleft between the two lobes by a small number of capillary shunts that supply the epithelial cell lobules of the intermediate lobe in situ. The findings collectively indicate that this portal system provides a constant stream of neurohumoral information that is shared moment-by-moment between the pituitary neural and anterior lobes.

Calcium-mediated metabolic stimulation of neuroendocrine structures by intraventricular endothelin-1 in conscious rats.

We examined the hypothesis that the vascular- and brain-derived peptide, endothelin-1 (ET), would affect cerebral neuroendocrine structures when administered via the peripheral circulation or via a lateral cerebral ventricle (i.c.v.). ET was infused intravenously (14 nmol/min) or injected i.c.v. (9 pmol) in conscious rats in which local cerebral glucose metabolism was assessed by the quantitative autoradiographic [14C]deoxyglucose technique. Whereas intravenously infused ET was previously demonstrated to selectively stimulate metabolic activity in the pituitary intermediate and anterior lobes of conscious rats, it was without effect in 20 individual structures or subnuclei involved in neuroendocrine functions, including several circumventricular organs. Intraventricular ET, however, caused hypermetabolic responses in 9 neuroendocrine structures, including the pineal gland, subfornical organ, median eminence, the hypothalamic paraventricular and supraoptic nuclei, and other hypothalamic and preoptic structures. The metabolic stimulation resulting from central ET was abolished or attenuated regionally by i.c.v. pretreatment with the calcium L-channel inhibitor, nimodipine. The findings indicate that i.c.v. ET elicits a calcium-mediated hypermetabolic effect on several neuroendocrine structures in the forebrain involved in the regulation of fluid homeostasis, the cardiovascular system, and body temperature.

Potent metabolic stimulation of septal gray and cerebral white matter in vivo by intraventricular endothelin and nitric oxide.

Endothelin-1 (ET) and sodium nitroprusside (SNP, which liberates nitric oxide, NO) were given alone or together into a lateral cerebral ventricle (icv) of anesthetized rats to assess their potential interaction on cerebral rates of glucose metabolism (autoradiographic [14C]deoxyglucose technique). ET (9 pmol) produced hypermetabolic effects ipsilaterally in the septal nuclei and periventricular white matter. NO lesioned the septum, which displayed neuronal damage and diminished metabolic activity, and evoked potent increases in glucose metabolism bilaterally in commissural and projection white matter tracts. Together, ET and NO had synergistic hypermetabolic effects in the hippocampal fimbria, but were antagonistic on the metabolic rate of the lateral septal nucleus and choroid plexus. The results reveal an extraordinary sensitivity in the metabolic rate of septal gray matter to ET and of white matter fibers to NO in vivo. Icv administration offers a useful approach for examination of the metabolic and toxicological properties of the novel neurotransmitter substances ET and NO on septal neurons, myelinated fibers, and choroidal epithelia.

Metabolic and neuroanatomical correlates of barrel-rolling and oculoclonic convulsions induced by intraventricular endothelin-1: a novel peptidergic signaling mechanism in visuovestibular and oculomotor regulation?

The neuroactive peptide endothelin-1 has receptors distributed abundantly among subdivisions and nuclei of the visuovestibular and oculomotor systems. In previous work, we and others described the convulsive manifestations resulting from central injection of this neuropeptide, including nystagmus, oculoclonus, exophthalmos, tonic hindlimb extension, and a generalized repetitive motor disturbance called barrel-rolling. We applied the quantitative, autoradiographic [14C]deoxyglucose method to examine the hypothesis that visuovestibular and oculomotor structures would become metabolically stimulated when endothelin was introduced into the brain via the ventricular system in conscious rats. Since previous work had demonstrated that hypermetabolic responses to endothelin in other neural systems were inhibited by an antagonist of neuronal calcium L-type channels, nimodipine, we further tested whether the increased function of vestibulooculomotor nuclei whose metabolic activity was sensitive to endothelin could be altered following nimodipine pretreatment via the ventricle. A single unilateral injection of endothelin (9 pmol in 3 microliters saline) into a lateral ventricle provoked significantly increased rates of glucose metabolism in 22 of 39 individual anatomical structures of the visuovestibular and oculomotor systems. Among those affected were the superficial stratum of the caudal superior colliculus (+25%), the optic tract bilaterally (+35 to 43%), the oculomotor cranial nerve nuclei (III, IV, VI; range of +21 to 47%), and the medial terminal nucleus of the accessory optic tract which harbors dense fields of endothelin binding sites (bilateral increase of +70 to 96%). Several other nuclei involved in the proprioceptive and visuovestibular disturbance caused by endothelin displayed increased metabolic activity, including the cuneate, gracile, sensory trigeminal, and prepositus hypoglossal nuclei, the vestibular subnuclear system, and the cerebellar flocculus. Identification of hypermetabolic responsivity to endothelin in these structures provides further information on the anatomical substrates mediating the behavioral phenomenology of endothelin-induced motor convulsions which involve the paroxysmal participation of the extraocular muscles and motor control systems producing barrel-rolling convulsions. Nimodipine pretreatment inhibited both the convulsive activity and the cerebral hypermetabolic responses to intraventricular endothelin. The results indicate that the neural systems sensitive to intraventricular endothelin become functionally active via a calcium-mediated process that may involve the neuropeptide as an intrinsic signaling molecule.

A new experimental model of epilepsy based on the intraventricular injection of endothelin.

Injection of endothelin-1 (ET-1, 9 pmol) into a lateral cerebral ventricle (LCV) of rats produces barrel-rolling and other convulsive signs that resemble those of generalized seizures in some types of epilepsy. Using the quantitative autoradiographic [14C]deoxyglucose technique, we documented that the neuroanatomical metabolic correlates of the ET-1-induced convulsions in rats are high rates of glucose utilization by structures near the site of LCV injection and throughout a diverse circuit of anatomically related brain regions. We speculate that this circuitry connects the caudate nucleus (putative site of initial stimulation in the forebrain) to the paramedian lobule and vermis of the caudal cerebellar cortex in the hindbrain. We evaluated the behavioral, physiological, and hypermetabolic responses to central ET-1 in the presence of three agents with anticonvulsant properties, providing clues about the cellular mechanisms of this convulsive and hypermetabolic state. Intraventricular MK-801 [a noncompetitive antagonist of glutamic acid N-methyl-D-aspartate (NMDA) receptors], nimodipine (an antagonist of dihydropyridine-sensitive, voltage-gated calcium L-channels), or methylene blue (an inhibitor of guanylate cyclase, the enzyme on which nitric oxide acts) each produced significant attenuation of the behavioral and cerebral metabolic activation. The results introduce several quantitative parameters for an experimental model of employing intraventricular ET-1 in rats to study mechanisms of peptidergic convulsive disorders and the efficacies of promising anticonvulsant compounds in the treatment of epilepsy.

Theoretical conformational analyses of endothelin-1 in vacuum, aqueous, and lipid environments.

Endothelin-1 (ET-1) is a flexible molecule capable of existing in multiple shapes (conformations) depending on the surrounding molecular solvation. The conformational diversity of ET-1 was studied in three solvation spheres (gas phase, aqueous, and membrane lipid) with the new evolving biotechnology of computational biomolecular simulation. Simulations were performed using a combination of molecular mechanics, molecular dynamics, and semiempirical quantum mechanics calculations in a RISC architecture large-scale computing environment. Marked differences between the gas phase "folded" conformation and the membrane lipid "extended" conformation were identified.

Acute endoneurial ischemia induced by epineurial endothelin in the rat sciatic nerve.

Endothelin (ET) is a potent vasoconstrictor peptide that may have pathophysiological roles in the microcirculation of the peripheral nervous system. We examined the local action of epineurial ET-1 on sciatic endoneurial blood flow using serial hydrogen clearance measurements in anesthetized, paralyzed, and ventilated Sprague-Dawley rats. In separate rats, we made serial measurements of sciatic motor multifiber conduction before and then after application of epineurial ET (saline on contralateral nerve) 2 and 24 h and 4 and 7 days later. Epineurial bathing solutions of ET increased microvascular resistance and reduced local endoneurial blood flow in a dose-responsive fashion with a half-maximum effective concentration of 10(-8) M. Maximum vasoconstriction at 10(-6) M ET was associated with a fall in endoneurial blood flow from 18.7 (pre-ET) to 7.2 ml x 100 g-1 x min-1. Epineurial norepinephrine (10(-7) to 10(-10) M) also resulted in vasoconstriction, but of lesser degree. Pretreatment with intraperitoneal nimodipine, a dihydropyridine Ca2+ channel antagonist, but not phentolamine, prevented the vasoconstrictive action of ET. Three of eight animals developed temporary but complete axonal conduction block at the site of ET administration (10(-5) M) and four others had partial conduction block. Contralateral saline-treated sciatic fibers were unaffected. Local ET action on extrinsic epineurial microvessels results in reversible ischemia of the underlying endoneurium that may be associated with conduction block. ET's action is more potent than norepinephrine and appears dependent on L-type voltage-gated Ca2+ channels.

Intraventricular endothelin-1 uncouples the blood flow: metabolism relationship in periventricular structures of the rat brain: involvement of L-type calcium channels.

Endothelin-1 (ET) produces contraction of cerebral resistance vessels in vitro and in situ, but also is neuroactive causing increases in tissue energy metabolism as measured by [14C]deoxyglucose autoradiography in the intact rat brain. ET may, therefore, disengage the normally tight linkage between cerebral blood flow and tissue metabolism. Using anatomically rigorous autoradiographic and imaging techniques to measure focal blood flow in anesthetized, ventilated rats, we found that intraventricular injection of 9 pmol of ET reduced rates of perfusion by an average of 29% (compared to a saline-injected condition) in 6 individual periventricular structures bordering the injected lateral ventricle. A significant vasoconstrictor effect (41% decrease in blood flow) also occurred in the ipsilateral choroid plexus after ET injection, despite its increased rate of glucose metabolism. We employed a hydrogen clearance method to monitor rates of blood flow serially within the periventricular margin of the caudate nucleus after intraventricular injection of the dihydropyridine calcium-channel antagonist, nimodipine (72 nmol), or 9 pmol ET, alone and in sequence. Nimodipine increased caudate blood flow (by 47%) and prevented the vasoconstriction produced by ET. The results indicate that ET causes vasoconstriction in penventricular brain structures and choroid plexus even in the presence of substantial increases in glucose metabolism. The simultaneous stimulation by intraventricular ET of tissue hypermetabolic and vascular constrictor mechanisms, leading to a net reduction of periventricular blood flow, is mediated, at least in part, by dihydropyridine-sensitive calcium L-channels.

Efferent microvascular responses to electrical stimulation of the area postrema in rats.

As part of its role to transduce blood-borne and afferent neural stimuli to the brain, the area postrema conducts efferent projections monosynaptically to individual nuclei of the medulla oblongata and pons. We hypothesized that electrical activation of the area postrema would mimic this transduction process and couple microvascular responses in efferent sites to local increases in tissue metabolism reported previously. We used quantitative autoradiographic techniques and image analysis to measure capillary transfer constants for [14C]alpha-aminoisobutyric acid (AIB, a small, neutral amino acid) and blood flow (iodo[14C]antipyrine) in individual brainstem structures of anesthetized rats. The area postrema was stimulated electrically by means of a monopolar microelectrode positioned stereotaxically 100 microns deep in the dorsocentral aspect of the organ. There were no significant effects of stimulation on [14C]AIB influx or blood flow in control hindbrain structures where postremal projections are sparse or absent--the spinal trigeminal nucleus, reticular formation, or cerebellar vermis. Stimulation of the area postrema produced equivalent increases in transcapillary influx of [14C]AIB and capillary blood flow in the nucleus of the solitary tract, dorsal motor nuclei of the vagus nerves, ventrolateral medullary C1 region, locus coeruleus, dorsal tegmental nuclei, and lateral parabrachial nuclei. Formation of ratios interrelating rates of [14C]AIB influx and blood flow with previously assessed values of tissue glucose metabolism indicated that these measures increased proportionately during postremal stimulation. Such proportional increases in capillary [14C]AIB transfer and blood flow during tissue activation by area postrema stimulation are consistent with interpretation that the increase in blood flow resulted from recruitment of unused surface area in the capillary networks of individual efferent nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional quantitative permeability of blood-brain barrier lesions in rats with chronic renal hypertension.

Blood-brain transfer constants for a small, neutral amino acid tracer, [14C]alpha-aminoisobutyric acid (AIB), were measured by quantitative autoradiography and image analysis in 15 individual brain structures of 2-kidney, 1-clip renal hypertensive rats (RHR) and age-matched normotensive controls (NR). Mean arterial pressures (MAP) for 4 month-old RHR and NR were 182 +/- 19 and 121 +/- 3 mmHg, respectively. Most brain structures in RHR had very low [14C]AIB transfer constants similar to those in NR (1-3 microliters.g-1.min-1), indicative of normal blood-brain barrier (BBB) function. Focal lesions, however, having transfer constants 2-7x normal and measuring less than 1.7 mm2 in area, appeared in RHR primarily in the cerebellar vermian and cerebral cortices. Chronic unilateral cervical sympathectomy did not influence the incidence or magnitude of BBB lesions in the denervated hemisphere of RHR. Acute arterial hypertension produced by systemic infusion of phenylephrine (elevation of MAP in RHR by 43%) increased the incidence and magnitude of lesions by 48% and 2-12x, respectively, although many brain regions in acutely hypertensive RHR retained normal permeability to [14C]AIB. The results demonstrate normal BBB permeability for much of the brain in chronic renal hypertension, with focal lesions having 7x or less the normal rate of blood-brain transfer for a small physiological probe.

Cerebral hypermetabolism produced by intraventricular endothelin-1 in rats: inhibition by nimodipine.

Injection of endothelin-1 (9 pmol) into the lateral cerebral ventricle of rats produced barrel-rotations, convulsions, tonic hindlimb extensions, facial clonus, and kinetic ataxia for up to 45 min. Quantitative metabolic autoradiographs produced from the [14C]deoxyglucose method and analyzed over 60 individual brain structures or subregions revealed intense hypermetabolism in periventricular tissues close to the injection site and in many of their efferent projection sites. Histological examination of these areas proved that this dose of endothelin was without toxic or ischemic effects on neurons or glial cells. Structures metabolically affected ipsilateral to injection were caudate nucleus (+164%), lateral septal nucleus (+270%), and two white matter tracts--corpus callosum (+236%) and hippocampal fimbria (+318%). Distant stimulated structures included cerebellar cortical layers, but not cerebellar nuclei or white matter. Increased rates of glucose metabolism among many other nuclei, particularly distinct subunits of the hippocampal formation and structures in contact with the ventricular system, signify that endothelin induced widespread metabolic stimulation over much of the neuraxis. Furthermore, although the 9 pmol concentration of endothelin produced convulsive movements and diverse metabolic stimulation, it did not evoke detectable electroencephalographic seizure activity assessed by intra- or extracerebral electroencephalography. Both the convulsions and hypermetabolic activation were inhibited by intraventricular pretreatment with the dihydropyridine calcium-channel antagonist, nimodipine. The results identify endothelin-1 as a calcium-mediated 'convulsive' peptide with selective stimulatory effects on cerebral glucose metabolism.

Morphology and function of capillary networks in subregions of the rat tuber cinereum.

The differentiated cytology, cytochemistry, and functions within subdivisions of the tuber cinereum prompted this morphometric and physiological investigation of capillaries in the medium eminence and arcuate nucleus of albino rats. Morphometric studies established that the external zone of the median eminence had 3-5 times the number and surface area of true and sinusoidal capillaries than the internal or subependymal median eminence zones, or either of two subdivisions examined in the arcuate nucleus. Type-I true capillaries, around which Virchow-Robin spaces comprise 1% of arcuate tissue area, were situated proximally to the median eminence border. This finding is consistent with a premise that confluent pericapillary spaces enable infiltration of arcuate neurons by factors from capillary blood from the median eminence or Virchow-Robin spaces. Physiologically, the rate of penetration across the median eminence capillaries by blood-borne [14C]alpha-amino-isobutyric acid (a neutral amino acid used as a capillary permeability tracer) was 142 times greater than for capillaries in the distal arcuate nucleus within 12 s of tracer administration. A new finding was that the proximal arcuate nucleus had a permeability x surface area product of 69 microliters g-1 min-1, 34 times greater than that in more distal aspects of the tuber where blood-brain barrier properties exist. We also found that the microcirculatory transit time of a plasma space marker, [14C]sucrose, was considerably longer (1.2 s) in the median eminence and proximal arcuate nucleus than in the distal arcuate or ventromedial nucleus (0.4 s). By virtue of its high capillary permeability and extensive blood-tissue surface area, including the wide Virchow-Robin spaces, the median eminence external zone could be a gateway for flooding other tuberal compartments with blood-borne factors. This effect may be compounded by capillary bed specializations in the proximal arcuate nucleus where Type-I true capillaries, Type-III sinusoids, and pericapillary spaces are confluent with those in the median eminence. The results indicate that the proximal arcuate parenchyma could be exposed to circulating neuroactive substances on a moment-to-moment basis.

Circumventricular organ capillaries.

Most circumventricular organs (CVOs) have unusually dense and permeable capillary networks that facilitate secretion of or tissue penetration by circulating substances, unlike other nervous system structures wherein blood-brain barrier (BBB) properties of the capillary endothelium limit solute permeability. In this brief review, I shall discuss new facts from recent experiments, and draw on interpretations from previous studies, to illustrate how capillary systems vary both between and within some CVOs, how closely microvascular properties coincide topographically with the distribution and density of neuropil, transmitter substances and hormonal binding sites, and how physiological data can be combined with morphological descriptions of capillary beds to accent specialized processes of blood-brain solute exchange in individual CVOs. The emphasis of this paper is on exchange microvessels of the rat area postrema (AP), subfornical organ (SFO) and median eminence (ME) which are regions of dense binding for several hormones and contain appreciable numbers of neurons (AP and SFO) or neural terminations that may be part of the sensing apparatus for humoral messengers of homeostatic systems. The work is intended to highlight established concepts about the process of blood monitoring by CVOs, summarize new morphological and physiological characteristics of their capillaries, and provide clues to novel research that could foster further understanding of these curious sentinel and secretory organs of the brain.

Efferent metabolic effects of area postrema stimulation in renal hypertensive rats.

Electrical microstimulation of area postrema in anesthetized normotensive (NR) and renal hypertensive (RHR) rats produced increases of about 53% in rates of glucose metabolism in nucleus tractus solitarii and dorsal motor nucleus of the vagus nerves. However, in nucleus ambiguus, ventrolateral medullary C1 region, locus coeruleus, and lateral parabrachial nucleus, all of which are monosynaptically innervated by area postrema neurons, metabolic responsiveness to postremal stimulation was considerably attenuated in RHR (average increase of 16%) compared to the same structures in NR (average increase of 36%). Disturbances of brainstem neurotransmission or tissue reactivity to postremal pathway activation thus appear to be part of the central pathophysiology of chronic renal hypertension.