Traumatic brain injury results in a concomitant increase in neocortical expression of vasopressin and its V1a receptor.

Arginine vasopressin (AVP) has been shown to promote the disruption of the blood-brain barrier (BBB) and the formation of edema in various animal models of brain injury. However, the source(s) of this AVP have not been identified. Since the cerebral cortex was considerably affected in some of these brain injury models, we sought to determine if AVP was produced in the cerebral cortex, and, if so, whether or not this cortical AVP expression was up regulated after injury. In the present study, a controlled cortical impact model of traumatic brain injury (TBI) in rats was used, and the temporal changes in expression of AVP and its V(1a) receptor were analyzed by real-time reverse-transcriptase polymerase chain reaction. The expression of AVP and its V(1a) receptor in the ipsilateral cortex adjacent to the lesion area was significantly up regulated between 4 h and 1 day post-TBI. The maximum increase in mRNA for AVP (4.3-fold) and its receptor (2.6-fold) in the ipsilateral vs. contralateral cortex was observed at 6 h post-TBI. Compared to sham-injured rats, no statistically significant changes in expression of AVP or its receptor were found in the contralateral cortex. These results suggest that the cerebral cortex is an important source of AVP in the injured brain, and the parallel increase in the expression of AVP and its cognate receptor may act to augment the actions of AVP related to promoting the disruption of the BBB and the formation of post-traumatic edema.

Early neutrophilic expression of vascular endothelial growth factor after traumatic brain injury.

The formation of edema after traumatic brain injury (TBI) is in part associated with the disruption of the blood-brain barrier. However, the molecular and cellular mechanisms underlying these phenomena have not been fully understood. One possible factor involved in edema formation is vascular endothelial growth factor (VEGF). This growth factor has previously been demonstrated to increase the blood-brain barrier permeability to the low molecular weight markers and macromolecules. In this study, we analyzed the temporal changes in VEGF expression after TBI in rats. In the intact brain, VEGF was expressed at relatively low levels and was found in the cells located close to the cerebrospinal fluid space. These were the astrocytes located under the ependyma and the pia-glial lining, as well as the epithelial cells of the choroid plexus. In addition, several groups of neurons, including those located in the frontoparietal cortex and in all hippocampal regions, were VEGF-positive. The pattern of VEGF-immunopositive staining of neurons and choroidal epithelium suggested that in these cells, VEGF binds to the cell membrane-associated heparan sulfate proteoglycans. Following TBI, there was an early (within 4 h post-injury) increase in VEGF expression in the traumatized parenchyma associated with neutrophilic invasion. The ipsilateral choroid plexus appeared to play a role in facilitating the migration of neutrophils from blood into the cerebrospinal fluid space, from where many of these cells infiltrated the brain parenchyma. VEGF-immunopositive staining of neutrophils resembled haloes and was found ipsilaterally within the frontoparietal cortex and around the velum interpositum, a part of the subarachnoid space. These haloes likely represent the deposition of neutrophil-derived VEGF within the extracellular matrix, from where this growth factor may be gradually released during an early post-traumatic period. The maximum number of VEGF-secreting neutrophils was observed between 8 h and 1 day after TBI. In addition, from 4 h post-TBI, there was a progressive increase in the number of VEGF-immunoreactive astrocytes in the ipsilateral frontoparietal cortex. The maximum number of astrocytes expressing VEGF was observed 4 days after TBI, and then the levels of astroglial VEGF expression declined gradually. Early invasion of brain parenchyma by VEGF-secreting neutrophils together with a delayed increase in astrocytic synthesis of this growth factor correlate with the biphasic opening of the blood-brain barrier and formation of edema previously observed after TBI. Therefore, these findings suggest that VEGF plays an important role in promoting the formation of post-traumatic brain edema.

Expression of two membrane fusion proteins, synaptosome-associated protein of 25 kDa and vesicle-associated membrane protein, in choroid plexus epithelium.

In addition to being the major site of cerebrospinal fluid formation, the choroid plexus epithelium emerges as an important source of polypeptides in the brain. Physiologically regulated release of some polypeptides synthesized by the choroid plexus has been shown. The molecular mechanisms underlying this polypeptide secretion have not been characterized, however. In the present study, synaptosome-associated protein of 25 kDa and vesicle-associated membrane protein, two membrane fusion proteins playing a critical role in exocytosis in neurons and endocrine cells, were found to be expressed in the choroid plexus epithelium. It was also shown that in choroidal epithelium, synaptosome-associated protein of 25 kDa and vesicle-associated membrane protein stably interact. Two members of the vesicle-associated membrane protein family, vesicle-associated membrane protein-1 and vesicle-associated membrane protein-2, were expressed in the rat choroid plexus at the messenger RNA and protein level. However, their newly discovered isoforms, vesicle-associated membrane protein-1b and vesicle-associated membrane protein-2b, produced by alternative RNA splicing, were not detected in choroidal tissue. Immunohistochemistry demonstrated that vesicle-associated membrane protein is confined to the cytoplasm of choroidal epithelium, whereas synaptosome-associated protein of 25 kDa is associated with plasma membranes, albeit with a varied cellular distribution among species studied. Specifically, in the rat choroid plexus, synaptosome-associated protein of 25 kDa was localized to the basolateral membrane domain of choroidal epithelium and was expressed in small groups of cells. In comparison, in ovine and human choroidal tissues, apical staining for synaptosome-associated protein of 25 kDa was found in the majority of epithelial cells. These species-related differences in cellular synaptosome-associated protein of 25 kDa distribution suggested that the synaptosome-associated protein of 25 kDa homologue, synaptosome-associated protein of 23 kDa, is also expressed in the rat choroid plexus, which was confirmed by reverse-transcriptase polymerase chain reaction. Our findings suggest that synaptosome-associated protein of 25 kDa and vesicle-associated membrane protein are involved in secretion of polypeptides from the choroid plexus epithelium. The presence of synaptosome-associated protein of 25 kDa and its homologue as well as multiple isoforms of vesicle-associated membrane protein in choroidal epithelium may play a role in the apical versus basolateral targeting of secretory vesicles.

Choroid plexus: target for polypeptides and site of their synthesis.

Choroid plexus (CP) is an important target organ for polypeptides. The fenestrated phenotype of choroidal endothelium facilitates the penetration of blood-borne polypeptides across the capillary walls. Thus, both circulating and cerebrospinal fluid (CSF)-borne polypeptides can reach their receptors on choroidal epithelium. Several polypeptides have been demonstrated to regulate CSF formation by controlling blood flow to choroid plexus and/or the activity of ion transport in choroidal epithelium. However, many ligand-receptor interactions occurring in the CP are not involved in the regulation of fluid secretion. Increasing evidence suggests that the choroidal epithelium plays an important role in hormonal signaling via a receptor-mediated transport into the brain (e.g., leptin) and helps to clear certain CSF-borne polypeptides (e.g., soluble amyloid beta-protein). Thus, impaired choroidal transport or insufficient clearance of polypeptides may contribute to pathogenesis of systemic or central nervous system (CNS) disorders, such as obesity or Alzheimer's disease. CP epithelium is not only a target but is also a source of neuropeptides, growth factors, and cytokines in the CNS. These polypeptides following their release into the CSF may exert distal, endocrine-like effects on target cells in the brain due to bulk flow of this fluid. Distinct temporal patterns of choroidal expression of several polypeptides are observed during brain development and in various CNS disorders, including traumatic brain injury and ischemia. Therefore, it is proposed that the CP plays an integral role not only in normal brain functioning, but also in the recovery from the injury. This review attempts to critically analyze the available data to support the above hypothesis.

Altered formation and bulk absorption of cerebrospinal fluid in FGF-2-induced hydrocephalus.

Upregulation of certain growth factors in the central nervous system can alter brain fluid dynamics. Hydrocephalus was produced in adult Sprague-Dawley rats by infusing recombinant basic fibroblast growth factor (FGF-2) at 1 microg/day into a lateral ventricle for 2, 3, 5, or 10-12 days. Lateral and third ventricular enlargement progressively increased from 2 to 10 days. Ventriculomegaly was also induced by a 75% reduced dose of FGF-2. At 10-12 days, there was a 29% attenuation in cerebrospinal fluid (CSF) formation rate, from 2. 5 to 1.8 microliter/min (P < 0.01). Choroid plexus, the main site of CSF secretion, had an augmented number of dark epithelial cells, which have previously been associated with decreased choroidal fluid formation. The twofold elevated resistance to CSF absorption, i.e., 0.8 to 1.7 mmHg. min(-1). microliter(-1), was attributable, at least in part, to enhanced fibrosis and collagen deposits in the arachnoid villi, a major site for CSF absorption. Normal CSF pressure (2-3 mmHg) was consistent with a patent cerebral aqueduct and reduced CSF formation rate. The FGF-2-induced ventriculomegaly is interpreted as an ex vacuuo hydrocephalus brought about by an altered neuropil and interstitium of the brain.

Angiotensin II regulates choroid plexus blood flow by interacting with the sympathetic nervous system and nitric oxide.

Blood flow to the rat choroid plexus has minimal variability when plasma angiotensin II (AII) concentration is changed within a broad range of levels. We tested the hypothesis that a complex interplay of the vasoconstrictor and vasodilator AII actions in choroidal tissue results in small net changes in choroidal blood flow. Blood flow was measured with 123I- or 125I-N-isopropyl-p-iodoamphetamine. AII was infused intravenously (i.v.) at 30 (moderate dose) and 300 ng kg-1 min-1 (high dose), which respectively decreased (15%) and did not change choroidal blood flow. To determine whether AII regulates choroidal blood flow by interacting with the sympathetic nervous system, rats were given phentolamine (1 mg kg-1, i.v.). This alpha-adrenoceptor antagonist by itself did not alter blood flow; however, it attenuated the blood flow-lowering effect of moderate AII dose. Phentolamine also unmasked the vasodilator AII actions at high peptide concentration. beta-Adrenoceptor blockade, with propranolol (1 mg kg-1, i.v.), reduced blood flow (18-20%) and increased vascular resistance (23-26%). During beta-adrenoceptor blockade, a further decrease in blood flow (15-21%) and increase in vascular resistance (23%) was noted when high AII dose was administered. The direct vasoconstrictor effect of AII at moderate dose on choroidal vasculature was examined in rats subjected to chronic bilateral superior cervical ganglionectomy. In these animals, AII decreased blood flow (24%) and increased vascular resistance (24%). To find out whether the hemodynamic AII actions in choroidal tissue are mediated by nitric oxide (NO), Nomega-nitro-l-arginine methyl ester (l-NAME) was used. l-NAME (0.1 mg kg-1, i.v.) by itself did not alter blood flow; however, in l-NAME-treated rats high AII dose lowered blood flow (25-32%) and increased vascular resistance (30-43%). We conclude that the vasoconstrictor AII actions involve a direct peptide effect on the choroidal vascular bed, and the AII-mediated potentiation of sympathetic activity, which results in the activation of alpha-adrenoceptors. The AII-mediated stimulation of sympathetic nerves also results in the beta-adrenoceptor-dependent relaxation of choroidal blood vessels. In addition, choroidal vasodilatory actions of AII are NO-mediated.

AVP V1 receptor-mediated decrease in Cl- efflux and increase in dark cell number in choroid plexus epithelium.

The cerebrospinal fluid (CSF)-generating choroid plexus (CP) has many V1 binding sites for arginine vasopressin (AVP). AVP decreases CSF formation rate and choroidal blood flow, but little is known about how AVP alters ion transport across the blood-CSF barrier. Adult rat lateral ventricle CP was loaded with 36Cl-, exposed to AVP for 20 min, and then placed in isotope-free artificial CSF to measure release of 36Cl-. Effect of AVP at 10(-12) to 10(-7) M on the Cl- efflux rate coefficient (in s-1) was quantified. Maximal inhibition (by 20%) of Cl- extrusion at 10(-9) M AVP was prevented by the V1 receptor antagonist [beta-mercapto-beta, beta-cyclopentamethyleneproprionyl1,O-Me-Tyr2,Arg8]vasopressin. AVP also increased by more than twofold the number of dark and possibly dehydrated but otherwise morphologically normal choroid epithelial cells in adult CP. The V1 receptor antagonist prevented this AVP-induced increment in dark cell frequency. In infant rats (1 wk) with incomplete CSF secretory ability, 10(-9) M AVP altered neither Cl- efflux nor dark cell frequency. The ability of AVP to elicit functional and structural changes in adult, but not infant, CP epithelium is discussed in regard to ion transport, CSF secretion, intracranial pressure, and hydrocephalus.

Cerebrospinal fluid formation and absorption in dehydrated sheep.

Cerebrospinal fluid (CSF) plays an important role in the brain's adaptive response to acute osmotic disturbances. In the present experiments, the effect of 48-h dehydration on CSF formation and absorption rates was studied in conscious adult sheep. Animals had cannulas chronically implanted into the lateral cerebral ventricles and cisterna magna to enable the ventriculocisternal perfusion. A 48-h water deprivation altered neither CSF production nor resistance to CSF absorption. However, in the water-depleted sheep, intraventricular pressure tended to be lower than that found under control conditions. This likely resulted from decreased extracellular fluid volume and a subsequent drop in central venous pressure occurring in dehydrated animals. In conclusion, our findings provide evidence for the maintenance of CSF production during mild dehydration, which may play a role in the regulation of fluid balance in the brain during chronic hyperosmotic stress.

Vasopressin mediates the inhibitory effect of central angiotensin II on cerebrospinal fluid formation.

Angiotensin II infused at low doses into the cerebral ventricles decreases cerebrospinal fluid (CSF) production. Since central angiotensin II also activates the sympathetic nervous system and promotes vasopressin release, the roles of these two factors in mediating the inhibitory effect of angiotensin II on CSF formation were studied. CSF production was measured in rats by the ventriculocisternal perfusion method. During central angiotensin II infusion (5 pg min(-1)), the following adrenoceptor antagonists were administered intravenously (i.v.): phentolamine (alpha1/alpha2, 2 mg/kg per h), prazosin (alpha1, 1 mg/kg per h), and propranolol (beta, 1 mg/kg per h). None of these agents affected the inhibitory effect of angiotensin II on CSF formation. In comparison, in animals administered i.v., the vasopressin V1 receptor antagonist, d(CH2)5Tyr(Me)Arg-vasopressin (10 microg/kg per h), the angiotensin II-induced decrease in CSF production was abolished. Our observations indicate, therefore, that vasopressin mediates the inhibitory effect of central angiotensin II on CSF formation.

Vasopressin gene expression in rat choroid plexus.

Vasopressin (VP) levels in cerebrospinal fluid (CSF) change in response to physiological stimuli and under various pathological conditions. The sources of CSF VP have yet to be clarified, however. In the present study, we provide evidence indicating that VP is synthesized in the choroid plexus, the primary site of CSF formation. All experiments were performed on adult male Sprague-Dawley rats. The presence of VP mRNA in choroid plexus epithelium was demonstrated by in situ hybridization histochemistry using the 35S-labeled riboprobe that was complementary to cDNA fragment of rat VP encoding the C-terminus part of proVP. In situ hybridization findings were confirmed by reverse transcriptase-polymerase chain reaction analysis. Immunohistochemistry for VP-associated neurophysin (VP-NP), a polypeptide component of proVP, revealed subapical accumulation of VP-NP-immunopositive product in choroidal epithelial cells. Immunoprecipitation and immunoblotting of choroidal protein extracts with anti-VP-NP antibody demonstrated the presence of a approximately 10-kD polypeptide that was also detected in hypothalamus. We hypothesize that the choroid plexus-derived VP exerts autocrine and/or paracrine effects on tissues near the CSF system.

The presence of arginine vasopressin and its mRNA in rat choroid plexus epithelium.

Arginine vasopressin (AVP) plays an important role in the regulation of secretory function and hemodynamics of choroid plexus, the primary site of cerebrospinal fluid (CSF) production. In the present study, localization of AVP and its transcripts in choroid plexus of adult male Sprague-Dawley rats was studied by immunohistochemistry and in situ hybridization histochemistry, respectively. For immunohistochemical analysis, AVP-specific polyclonal rabbit antibody was employed. Plasmid, pGrVP, containing a 232-bp fragment of rat AVP cDNA encoding the C-terminus of proAVP, was used as a probe to detect AVP mRNA. AVP-immunoreactive product was predominantly localized close to the apical (CSF-facing) membrane of choroidal epithelium while AVP transcripts were distributed throughout the cytoplasm of the cells. Our findings indicate that AVP is synthesized in choroid plexus epithelium, which suggests autocrine and/or paracrine actions of this peptide in choroidal tissue.

Immunohistochemical localization of nitric oxide synthase in rat anterior choroidal artery, stromal blood microvessels, and choroid plexus epithelial cells.

Nitric oxide (NO) has recently been shown to regulate blood flow to choroid plexus, a specialized brain structure responsible for production of most of cerebrospinal fluid. In the present study, we used a specific polyclonal rabbit antibody against the neuronal isoform of NO synthase (NOS), a synthetic enzyme for NO, to determine the localization of NOS in the choroid plexus of adult male Sprague-Dawley rats. NOS-containing nerve fibers were found in the anterior choroidal artery and its branches, and in stromal blood microvessels. Chronic denervation experiments indicated that these nerve fibers originate predominantly from the sphenopalatine ganglion. NOS-immunopositive staining was also detected in the cytoplasm of choroidal epithelial cells. NADPH-diaphorase, a histochemical marker for NOS, was found to colocalize with NOS-immunoreactive product in both nerve fibers and choroidal epithelium. Both neuronal and epithelium-derived NO may regulate secretory function and hemodynamics of choroidal tissue.

NADPH-diaphorase histochemistry of rat choroid plexus blood vessels and epithelium.

Choroid plexus is the major source of cerebrospinal fluid. The hemodynamics and secretory function of this tissue are controlled by multiple endocrine and neural mechanisms. Nitric oxide (NO) has been demonstrated to play an important role in regulating choroidal blood flow. In the present study, performed on adult male Sprague-Dawley rats, we employed a NADPH-diaphorase (NADPH-d) histochemical method to localize nitrergic innervation of choroidal blood vessels. This approach was based on previous observations that NADPH-d colocalizes with NO synthase, a synthetic enzyme for NO, in the central and peripheral nervous systems. NADPH-d-positive nerve fibers were found to accompany both large arteries and veins and blood microvessels (possibly arterioles) located in choroidal stroma. NADPH-d reaction product was also localized to the vascular endothelial lining and choroidal epithelial cells. All the above sources of NO may play important roles in the regulation of secretory and hemodynamic functions of the choroid plexus.

The role of angiotensin II in the regulation of blood flow to choroid plexuses and cerebrospinal fluid formation in the rat.

The effect of peripherally administered angiotensin II (AII) on blood flow to choroid plexuses was examined in pentobarbital-anesthetized rats. The indicator fractionation method with 123I- or 125I-N-isopropyl-p-iodoamphetamine as the marker was employed to measure blood flow. Basal blood flow to choroid plexus of the lateral cerebral ventricle (LVCP) (3.19 +/- 0.23 ml g-1 min-1) was lower than that to choroid plexuses of the third (3VCP) and fourth (4VCP) ventricles (3.90 +/- 0.38 and 3.95 +/- 0.36 ml g-1 min-1, respectively). The effect of AII on choroidal blood flow varied depending on peptide dose and anatomical location of the choroidal tissue. AII infused intravenously at rates of 30 and 50 ng kg-1 min-1 decreased blood flow to both LVCP and 4VCP by 12-20%. Both lower (10 ng kg-1 min-1) and higher (100 and 300 ng kg-1 min-1) AII doses did not alter blood flow to LVCP and 4VCP. Blood flow to the 3VCP was not affected by any dose of the peptide used. In comparison, blood flow to cerebral cortex increased by 33% during intravenous AII infusion at a rate of 300 ng kg-1 min-1. The choroidal blood flow-lowering effect of moderate AII doses was abolished by both AT1 (losartan) and AT2 (PD 123319) receptor subtype antagonists (3 mg kg-1 i.v.). To determine whether the hemodynamic changes observed in choroid plexuses with moderate AII doses influence CSF formation, the ventriculocisternal perfusion was performed in rats (under the experimental conditions described) with Blue Dextran 2000 as the indicator.(ABSTRACT TRUNCATED AT 250 WORDS)

AT1 receptor subtype mediates the inhibitory effect of central angiotensin II on cerebrospinal fluid formation in the rat.

The effect of central administration of angiotensin II (AII) on cerebrospinal fluid (CSF) formation was studied in pentobarbital-anesthetized, artificially-ventilated rats. CSF production was measured by the ventriculocisternal perfusion method with Blue Dextran 2000 as the indicator. Baseline value of CSF production was 3.35 +/- 0.08 microliters/min. Intracerebroventricular (i.c.v.) infusion of AII at rates of 0.5 and 5 pg/min significantly lowered (P < 0.01) CSF formation by 23% and 16%, respectively. In comparison, high peptide doses (50 and 500 pg/min) did not alter this parameter. The inhibitory effect of low AII doses on CSF formation was blocked by the i.c.v. AT1 receptor subtype antagonists, losartan and SK&F 108566 (2.4 and 2.7 ng/min, respectively), but not by the AT2 receptor subtype-specific agent, PD 123319 (3.8 ng/min). Peptide AII antagonists, [Sar1,Ile8]AII (5 ng/min), which binds to both AT1 and AT2 receptors, had a similar effect to those of AT1-specific blockers. It is concluded that AII, by controlling CSF formation, may influence the water and electrolyte balance in the brain.

Postnatal developmental changes in blood flow to choroid plexuses and cerebral cortex of the rat.

Postnatal developmental changes in blood flow to choroid plexuses of the lateral (LVCP) and fourth (4VCP) ventricles and cerebral cortex were studied in pentobarbital-anesthetized rats at 2, 3, 5, and 7-8 wk. Blood flow was measured by indicator fractionation with N-isopropyl-p-[125I]iodoamphetamine as the marker. Blood flow to the LVCP and 4VCP was 2.5 +/- 0.1 and 2.7 +/- 0.1 ml.g-1.min-1, respectively, and did not change between the 2nd and 3rd wk. However, it increased by 34% between the 3rd and 5th wk. From the age of 5 wk on, 4VCP was characterized by higher blood flow rates than LVCP. Cerebral cortical blood flow gradually increased between the 2nd and 5th wk. There was no difference in cortical blood flow between 5-wk-old and adult animals. The changes in choroidal blood flow likely represent a continuing adjustment of the choroidal vascular system to steadily increasing secretory capabilities of the maturing choroidal epithelium.

The role of angiotensin II in regulation of cerebrospinal fluid formation in rabbits.

The effect of central and peripheral administrations of angiotensin II (AII) on cerebrospinal fluid (CSF) formation was investigated in rabbits anesthetized with intravenous alpha-chloralose and urethane. CSF production was measured by the ventriculo-cisternal perfusion method with Blue dextran 2000 used as an indicator substance. AII infused intracerebroventricularly (i.c.v.) at rates of 5.5 and 55 pg min-1 significantly decreased CSF formation rate by 27% and 36%, respectively. This AII action could be completely blocked by simultaneously administered specific AII antagonist, [Sar1,Ala8]AII (saralasin), given i.c.v. at a rate of 5.5 ng min-1. Intracerebroventricular infusion of AII at a rate of 5.5 ng min-1 did not change CSF production. Saralasin, when given alone into the ventricular system (5.5 ng min-1), non-significantly increased CSF production by 12%. However, in 4 of the 6 animals studied, the rise in CSF production was statistically significant (by 23%). Intravenous infusion of AII at rates of 30 and 100 ng kg-1 min-1 was found not to change CSF formation rate. Also, i.c.v. administration of angiotensin I converting enzyme inhibitor, captopril (10 microliters min-1), did not influence CSF production. It is concluded that the centrally released AII can control CSF production. Our results suggest that under normal conditions, AII exerts a tonic inhibitory effect on CSF formation. In contrast, the blood-borne peptide seems not to influence this physiological process.

Atrial natriuretic peptide does not alter cerebrospinal fluid formation in sheep.

Because the choroid plexus has been shown to have a high density of atrial natriuretic peptide (ANP) binding sites, we investigated the effect of intracerebroventricular and intravenous administrations of ANP on cerebrospinal fluid (CSF) formation. CSF formation rate was measured in conscious sheep with a dye-dilution method using blue dextran 2000 as an indicator substance. During the experiment animals were partially restrained in a sling, and their ventricular systems were perfused with artificial CSF containing the indicator substance. ANP (alpha-human ANP) administered centrally at rates of 0.015-15 ng/min, resulting in CSF ANP concentrations ranging from physiological to pharmacological CSF hormone levels, was found not to influence CSF formation. Similarly, intravenous administration of ANP at a rate of 10 ng.kg-1.min-1 did not affect CSF formation, i.e., decreases in CSF formation rate in all experiments involving ANP administration were not significantly different from those observed in time control experiments. Our results suggest that ANP does not significantly affect CSF production in sheep. It is possible that the lack of effect of ANP on CSF formation is associated with the predominance in the choroid plexus of clearance receptors over biologically active receptors.

Effect of central administration of angiotensin II on cerebrospinal fluid formation in rabbits.

The effect of central administration of AII on CSF formation was studied in alpha-chloralose and urethane anesthetized rabbits using the ventriculocisternal perfusion method. AII infused i.c.v. at rates of 5.5 and 55 pg/min significantly decreased CSF production by 25% and 35%, respectively. In contrast, AII when given at 5.5 ng/min did not change CSF formation. It seems that drop in CSF production observed during central administration of AII at low doses is mediated by both increased vasopressin release and activation of the sympathetic nervous system. The lack of changes in CSF formation with the highest AII dose used is not clear at present and awaits further investigation. Specific AII antagonist, saralasin, was found to significantly increase CSF production in four of five animals studied. It is suggested that in normal conditions AII may exert a tonic inhibitory effect on CSF formation.

Effect of arginine vasopressin on blood vessels of the perfused choroid plexus of the sheep.

The perfused sheep choroid plexus was used to evaluate the response of the plexus blood vessels to systemically administered arginine vasopressin (AVP). AVP was found to decrease the diameter of the choroid plexus arterioles with a maximum change of 28 +/- 5% (mean +/- S.E.) at a plasma peptide concentration of 10(-7) M. This effect was blocked by the specific V1-vasopressinergic antagonist, d(CH2)5Tyr(Me)AVP. In contrast, venules were found not to show any appreciable response to AVP. Plasma AVP concentrations necessary to evoke a significant response of the choroid plexus arterioles are much higher than the highest plasma peptide levels observed in different physiological or pathophysiological situations. Some indirect evidence suggests, however, that AVP might be released within the choroid plexus from the vasopressinergic synaptic terminals, thus reaching a considerably high local concentration. It is possible then that the plexus vessels' tone could be controlled by the putative vasopressinergic neuronal fibers ending in the choroid plexus.