Neonatal 6-Hydroxydopamine Treatment and the Development of Renal Hypertension in the Rat

The onset and development of 2 kidney-2 clip renal hypertension was studied in chronically sympathectomized rats treated with 6-hydroxy-dopamine (6-OHDA) immediately after birth and with adrenal demedullation performed at the time of clipping. Blood pressure (BP) was lower in 6-OHDA treated animals than in untreated controls and the rate of hypertension development was similar in both groups. Urinary excretion of norepinephrine (NE) was significantly decreased during the 15th week and normal by the end of the 20th week. The cardiac NE content reached negligible levels while the mesenteric arteries retained 50% of its content. In the central nervous system (CNS) the 6-OHDA treatment induced a significant increase in NE concentration in the brain stem and medulla oblongata and a significant decrease in cerebellum. Hypertension produced a significant decrease in NE content in the brain stem while 6-OHDA treatment in hypertensive rats resulted in a generalized NE depletion in all the CNS areas. Results have shown that 6-OHDA treatment does not produce a complete and generally distributed sympathectomy; treatment reduces the level of BP but does not change the slope in BP increase.     

Central Neural Mechanism Contributing to Attenuation of Angiotensin II-Induced Hypertension in Rats on Dietary Calcium Supplementation

The effect of dietary calcium (Ca) supplementation on blood pressure (BP) and the central nervous system (CNS) mechanism underlying this effect were studied in angiotensin II (Ang II)-induced hypertensive rats. The effects of dietary Ca (0.5, 2, 4%) on systolic blood pressure (SBP), ionized Ca concentration (Ca⁺⁺) in cerebrospinal fluid (CSF) and central norepinephrine (NE) turnover were investigated in male Wistar rats receiving subcutaneous infusion of Ang II (100 ng/min). Central NE turnover was studied by measuring 3-methoxy-4-hydroxyphenylglycol (MHPG) concentration in CSF with multiple electrode liquid chromatography. Ang II significantly increased SBP, and dietary Ca dose-dependently attenuated the increase. SBP inversely correlated with Ca⁺⁺ and MHPG in CSF. Intracerebroventricular injection of CaCl₂ more markedly reduced BP in Ang II-treated rats than that in control rats. These results suggest that modulation of central NE turnover possibly caused by the increase in CNS Ca⁺⁺ is involved in the anti-hypertensive mechanism of dietary Ca supplementation in Ang II-induced hypertensive rats.     

The Brain Renin—Angiotensin System and the Development of Doc - Salt Hypertension

The effect of captopril, given in the drinking fluid, on the development of DOC-salt hypertension was analyzed. Although captopril did not prevent an increase in blood pressure (BP) elicited by DOC-salt, captopril did diminish BP in both DOC-salt and control animals. From the first week of treatment DOC-salt rats increased their fluid intake (FI). At the end of the experiment, captopril reduced this increment (655% to 357%). At the same time plasma angiotensinogen was diminished (-35%; P < 0.001) and cerebrospinal fluid (CSF) substrate concentration increased (+33%; P < 0.02) in DOC-salt rats, captopril did not modify these changes. In control rats captopril did not alter FI, depleted plasma angiotensinogen, (-73%; P < 0.001), did not change the central prohormone and increased plasma renin activity (PRA) (+260%; P < 0.001).

In conclusion: CSF angiotensinogen concentration changes as previously found in CNS while a clear dissociation between plasma and CSF angiotensinogen was found in DOC-salt rats. In these animals the hypertension was not clearly affected by captopril treatment. However the effect of the converting enzyme inhibitor suggests that the central renin-angiotensin system could participate in the increase in FI.     

Androgens alter brain catecholamine content and blood pressure in the testicular feminized male rat

Androgens interact with catecholamines in the central nervous system (CNS) to regulate many physiological processes including blood pressure (BP). To test the hypothesis that testosterone (T) and 5a-dihydrotestosterone (DHT) modulate CNS catecholamines and BP through androgen receptor (AR)-dependent and independent mechanisms, we used the testicular feminized male (Tfm) rat. Females that carry the AR mutation (Tfm mutation) on the X chromosome were bred with spontaneously hypertensive rat (SHR) males. The normal AR male and Tfm offspring were divided into groups: control, castrated, castrated, and T or (DHT) replacement. In both AR normal and Tfm males, BP was reduced by castration, but T restored BP in both groups. In the amygdale, castration decreased dopamine (DA) in both strains and both T and DHT restored it. In the bed nucleus of the stria terminalis castration increased DA which was further increased by DHT and reduced to normal by T in both strains. In the frontal cortex, castration reduced DA content in both strains but only T restored it to normal in SHR but not in Tfm. Brain norepinephrine (NE) content showed a significant strain effect for the preoptic area (POA), but no treatment effect. Although castration did not change NE in the amygdala or POA in either strain, both T and DHT increased NE in the Tfm castrates. Blood pressure was influenced by T manipulation and correlated most significantly with DA content in the amygdala, frontal cortex, and stria terminalis. These data demonstrate an action of androgen on brain catecholamines and BP, which is independent of the classic androgen receptor.     

Meningoencephalitis caused by Histoplasma capsulatum: occurrence in a renal transplant recipient and a review of the literature.

A case of meningoencephalitis caused by histoplasmosis in a renal transplant patient is described. The diagnosis was made postmortem. The clinicopathological features of 39 additional cases of central nervous system (CNS) invasion by histoplasmosis were reviewed. In the great majority of instances (92.1%), CNS involvement occurred in the disseminated form of the disease. Diagnosis was proved by culturing the fungus from bone marrow, blood, lymph nodes, or liver. Neurological symptoms and signs and cerebrospinal fluid (CSF) changes did not occur until extensive brain damage had resulted. Difficulty in culturing the organism in the (CSF) caused a further delay in making an early diagnosis of CNS involvement. The use of meningeal and brain biopsy specimens in conjunction with the electroencephalogram (EEG) may help in making an earlier diagnosis of CNS involvement.     

Lactate and glucose concentrations in brain interstitial fluid, cerebrospinal fluid, and serum during experimental pneumococcal meningitis.

Metabolic abnormalities during bacterial meningitis include hypoglycorrhachia and cerebrospinal fluid (CSF) lactate accumulation. The mechanisms by which these alterations occur within the central nervous system (CNS) are still incompletely delineated. To determine the evolution of these changes and establish the locus of abnormal metabolism during meningitis, glucose and lactate concentrations in brain interstitial fluid, CSF, and serum were measured simultaneously and sequentially during experimental pneumococcal meningitis in rabbits. Interstitial fluid samples were obtained from the frontal cortex and hippocampus by using in situ brain microdialysis, and serum and CSF were directly sampled. There was an increase of CSF lactate concentration, accompanied by increased local production of lactate in the brain, and a decrease of CSF-to-serum glucose ratio that was paralleled by a decrease in cortical glucose concentration. Brain microdialysate lactate concentration was not affected by either systemic lactic acidosis or artificially elevated CSF lactate concentration. These data support the hypothesis that the brain is a locus for anaerobic glycolysis during meningitis, resulting in increased lactate production and perhaps contributing to decreased tissue glucose concentration.     

Measurement of lactic acid in cerebrospinal fluid of patients with infections of the central nervous system

The concentration of lactic acid in cerebrospinal fluid (CSF) was determined by gas-liquid chromatography in 205 samples of CSF from 97 patients with or without infections of the central nervous system. Patients without infection or those with nonbacterial (presumably viral) meningitis consistently had low concentrations of lactic acid in CSF (i.e., less than or equal to 35 mg/100 ml), whereas patients with bacterial or tuberculosis meningitis consistently had concentrations of lactic acid in CSF of greater than 35 mg/100 ml. There was no overlap in concentrations of lactic acid between these two groups. Further, lactic acid concentrations in CSF from patients partially treated for meningitis were generally greater than 35 mg/100 ml through the third day of therapy and, thereafter, progressively declined to less than 20 mg/100 ml by the seventh to 10th day of therapy. Relapse of bacterial infection was consistently documented by a recurrence of an increased concentration of lactic acid in CSF. Preliminary experience with determination of the concentration of lactic acid in CSF suggests that it may be useful in distinguishing bacterial (with or without positive cultures) and tuberculous meningitis from meningitis due to nonbacterial causes.     

Expression of the BRL-3A insulin-like growth factor binding protein (rBP-30) in the rat central nervous system

The expression of the BRL 3A insulin-like growth factor binding protein (rBP-30) was characterized in rat brain, hypothalamus, and pituitary tissue and cultured neuronal and astroglial cells. The 27K BP expressed by BRL 3A cells (rBP-30) was found to also be expressed in conditioned media from newborn rat astrocytes and fetal neurons, but not in the medium from the neuroblastoma cell line, B104. Moreover, a polyclonal antibody, anti HEC1, specifically immunoprecipitated the BRL 3A BP from the same conditioned media, as well as from rat cerebrospinal and amniotic fluid and from conditioned medium of cells isolated from the neurointermediate lobe of adult rat pituitary. The same antibody also immunoprecipitated hBP-31 from human CSF. Northern blot analyses showed that rBP-30 mRNA was expressed in adult rat brain and pituitary, fetal brain and liver, and in fetal neurons and newborn astrocytes maintained in culture. We conclude that the BRL 3A BP (rBP-30) is the major insulin-like growth factor binding protein in the rat CNS and may be the rat analog of hBP-31, the predominant BP in human CSF.     

Hypercortisolemia inhibits yohimbine-induced release of norepinephrine in the posterolateral hypothalamus of conscious rats.

Chronic hypercortisolemia attenuates yohimbine (YOH)-induced increments in plasma levels of the sympathetic neurotransmitter norepinephrine (NE). The present study used in vivo microdialysis to study the effects of hypercortisolemia on YOH-induced release of NE in the brain. Cortisol (25 mg/kg.day) or saline was infused sc into rats for 7 days via an osmotic minipump. Microdialysate and plasma concentrations of NE and its metabolites dihydroxyphenylglycol and methoxyhydroxyphenylglycol were measured before and after YOH (1 mg/kg, iv) administration in conscious animals, with microdialysate and plasma collections beginning 20-24 h after probe implantation. Chronic cortisol treatment resulted in attenuated NE, dihydroxyphenylglycol, and methoxyhydroxyphenylglycol responses in both microdialysate and plasma. The results indicate that YOH increases central neural as well as peripheral release, reuptake, turnover, and metabolism of NE and that hypercortisolemia suppresses these responses.     

大鼠重症肌无力中枢受损时白细胞介素-1的变化

目的 探讨重症肌无力（ＭＧ）患者中枢神经系统损害与白细胞介素（ＩＬ）－１之间的关系。方法 将ＭＧ患者中提取的ＩｇＧ注入大鼠脑室系统,建立大鼠中枢神经系统受损模型,然后观察模型大鼠脑、胸腺,血清ＩＬ－１水平的变化。结果 脑室内注入ＩｇＧ后第１周起,脑,胸腺及血清中ＩＬ－１水平升高,其中脑组织上升最为明显,第２周未达高峰,而在胸腺及血中上升则相对缓慢,第３周未时仍在缓慢上升。结论 大鼠中枢神经系统损受     

Brain-selective overexpression of angiotensin (AT1) receptors causes enhanced cardiovascular sensitivity in transgenic mice

To examine the physiological importance of brain angiotensin II type 1 (AT1) receptors, we developed a novel transgenic mouse model with rat AT1a receptors targeted selectively to neurons of the central nervous system (CNS). A transgene consisting of 2.8 kb of the rat neuron-specific enolase (NSE) 5' flanking region fused to a cDNA encoding the full open-reading frame of the rat AT1a receptor was constructed and transgenic mice (NSE-AT1a) were generated. Two of six transgenic founder lines exhibited brain-selective expression of the transgene at either moderate or high levels. Immunohistochemistry revealed widespread distribution of AT1 receptors in neurons throughout the CNS. This neuron-targeted overexpression of AT1a receptors resulted in enhanced cardiovascular responsiveness to intracerebroventricular (ICV) angiotensin II (Ang II) injection but not to other central pressor agents, demonstrating functional overexpression of the transgene in NSE-AT1a mice. Interestingly, baseline blood pressure (BP) was not elevated in either transgenic line. However, blockade of central AT1 receptors with ICV losartan caused significant falls in basal BP in NSE-AT1a mice but had no effect in nontransgenic controls. These results suggest that whereas there is an enhanced contribution of central AT1 receptors to the maintenance of baseline BP in NSE-AT1a mice, particularly effective baroreflex buffering prevents hypertension in this model. Used both independently, and in conjunction with mice harboring gene-targeted deletions of AT1a receptors, this new model will permit quantitative and relevant investigations of the role of central AT1a receptors in cardiovascular homeostasis in health and disease.     

Evidence for activation of brain atrial natriuretic factor during acute plasma volume expansion in sheep.

Atrial Natriuretic Factor (ANF) has been demonstrated within the central nervous system (CNS), where it has been implicated in the regulation of blood pressure, fluid and electrolyte balance. To explore the effect of acute plasma vol expansion on the activation of CNS ANF, changes in ANF levels of CSF drawn from the cisterna magna of anesthetized sheep were measured. Intravenous infusions of Dextran (10 ml/kg body wt, n = 7) or control (total vol 7.5 ml Dextran, n = 7) were administered over 30 min. Compared to control experiments, plasma vol expansion resulted in a 3-fold increase of central venous pressure (P = 0.002), a 25% increase in mean arterial pressure (P = 0.011), and a 20% reduction in packed red cell volume (P = 0.024). Accompanying these hemodynamic changes, plasma ANF concentrations doubled (17.0 +/- 3.0-41.0 +/- 7.8 pmol/liter at 60 min vs. 20.0 +/- 4.7-19.3 +/- 3.6 pmol/liter in controls) and remained elevated for 4 h, whereas CSF ANF concentrations showed a transient 3-fold increase (2.1 +/- 0.3-6.6 +/- 1.9 pmol/liter at 120 min vs. 2.5 +/- 0.5-3.8 +/- 0.7 pmol/liter in controls). The maximum increments of both plasma and CSF ANF were statistically significant (P = 0.002 and 0.03, respectively). Basal CSF levels were approximately 1/10 those in plasma, and no correlation was seen in either basal plasma and CSF levels, or the maximum increments of plasma and CSF ANF concentrations. In vol-expanded sheep, plasma cyclic GMP concentrations tended to increase, although not significantly different from controls, while CSF cyclic GMP was similar to controls throughout the experiments. The entry of ANF to cisterna magna CSF was studied in five additional anesthetized sheep. Infusion iv of ileu rat ANP (50 ng/kg.min over 60 min) raised plasma ANF levels 30-fold, but CSF ANF concentrations did not change. These experiments show that plasma vol expansion in sheep, in addition to stimulating cardiac ANF secretion, induces an increase in CSF ANF, which cannot be accounted for by transfer of ANF from blood into CSF.     

Comparative measurements of glucose, beta-hydroxybutyrate, acetoacetate, and insulin in blood and cerebrospinal fluid during starvation

The possibility that altered central nervous system (CNS) metabolism is reflected by changes in the constituents of the cerebrospinal fluid (CSF) was investigated. From eight obese subjects undergoing total starvation for weight reduction, overnight and 21-day fasting specimens of venous blood and lumbar CSF were obtained nearly simultaneously to determine the concentrations of glucose, beta-hydroxybutyrate (β-OHB), acetoacetate (AcAc), and immunoreactive insulin (IRI). After 21 days of starvation, the glucose concentration fell in both blood and CSF. The decrease in blood glucose was greater than the decline in CSF glucose, resulting in a diminished blood-CSF difference. Concentrations of β-OHB and AcAc in blood and CSF were elevated after prolonged fasting, but blood levels exceeded those in CSF, producing an increased blood-CSF ketone body difference. After an overnight and 21-day fast, the IRI levels in CSF were about one-half of the serum levels. These data suggest that metabolic alterations in CNS metabolism during prolonged starvation are reflected in substrate concentrations observed in CSF, and demonstrate that insulin is presented in the CSF of man.     

Imatinib mesylate has limited activity against the central nervous system involvement of Philadelphia chromosome-positive acute lymphoblastic leukaemia due to poor penetration into cerebrospinal fluid

A 32-year-old woman with relapsed Philadelphia chromosome-positive acute lymphoblastic leukaemia was treated with imatinib mesylate (formerly STI571), a selective inhibitor of BCR/ABL tyrosine kinase. Although the initial marrow response was good and stably maintained, she subsequently relapsed with extensive infiltration of leukaemic cells into the central nervous system (CNS). After controlling her CNS disease with additional intrathecal chemotherapy, we measured the concentration of imatinib in cerebrospinal fluid (CSF) and blood simultaneously. The concentration of imatinib in CSF was about 92-fold lower than that in blood. These results suggest that imatinib poorly penetrates the blood-brain barrier and has limited activity against CNS leukaemia.     

Cerebrospinal fluid asparagine depletion during pegylated asparaginase therapy in children with acute lymphoblastic leukaemia

L‐asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Cerebrospinal fluid (CSF) asparagine depletion is considered a marker of asparaginase effect in the central nervous system (CNS) and may play a role in CNS‐directed anti‐leukaemia therapy. The objective of this study was to describe CSF asparagine depletion during 30 weeks of pegylated asparaginase therapy, 1000 iu/m² i.m. every second week, and to correlate CSF asparagine concentration with serum L‐asparaginase enzyme activity. Danish children (1–17 years) with ALL, treated according to the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol, standard and intermediate risk, were included. CSF samples were obtained throughout L‐asparaginase treatment at every scheduled lumbar puncture. A total of 128 samples from 31 patients were available for analysis. Median CSF asparagine concentration decreased from a pre‐treatment level of 5·3 μmol/l to median levels ≤1·5 μmol/l. However, only 4/31 patients (five samples) had CSF asparagine concentrations below the limit of detection (0·1 μmol/l). In 11 patients, 24 paired same day serum and CSF samples were obtained. A decrease in CSF asparagine corresponded to serum enzyme activities above 50 iu/l. Higher serum enzyme activities were not followed by more extensive depletion. In conclusion, pegylated asparaginase 1000 iu/m² i.m. every second week effectively reduced CSF asparagine levels.     

Yohimbine increases cerebrospinal fluid and plasma norepinephrine but not arginine vasopressin in humans

Previous studies have demonstrated alpha 2-inhibitory regulation of central nervous system (CNS) noradrenergic and arginine vasopressinergic systems. We tested the hypothesis that alpha 2-inhibition of CNS noradrenergic and vasopressinergic systems is tonic in nature by measuring the response of cerebrospinal fluid (CSF) norepinephrine (NE) and arginine vasopressin (AVP) to the alpha 2-antagonist yohimbine in 7 young normal male human subjects. We also evaluated the tonic nature of alpha 2-inhibition of the sympathetic nervous system (SNS) and of AVP release into plasma by measuring the response of plasma NE and plasma AVP to yohimbine. CSF NE was significantly higher following yohimbine as compared to placebo. In contrast CSF AVP did not differ between yohimbine and placebo conditions. Similarly, plasma NE was significantly higher following yohimbine as compared to placebo, while plasma AVP was unchanged. These results support a tonic alpha 2-inhibitory regulatory mechanism for both CNS noradrenergic systems and sympathetic outflow. Such tonic alpha 2-inhibition could not be demonstrated for regulation of AVP levels in CSF or plasma in humans.     

Cerebrospinal fluid ferritin in patients with leukaemia and malignant lymphoma

To evaluate whether cerebrospinal fluid (CSF) ferritin could be of diagnostic value in haematological malignancies with central nervous system (CNS) involvement, the ferritin concentration was measured in 21 patients with acute leukaemia and lymphoma. Of the 17 patients without CNS involvement, 16 had CSF ferritin values in the normal range (2-7 micrograms/l); 1 patient had an elevated value, probably due to blood contamination in connection with a very high serum ferritin level. 4 patients had tumour invasion of the CNS indicated by the presence of blastic cells in the CSF; CSF ferritin levels in these patients were likewise in the normal range. There was no difference between CSF ferritin values in patients with and without CNS involvement. With the present assay, measurement of CSF ferritin appears to be irrelevant in the evaluation of CNS invasion in haematological malignancies.     

HLA-mismatched CD34-selected stem cell transplant complicated by HHV-6 reactivation in the central nervous system

We report here a patient who suffered from PCR- confirmed human herpesvirus type 6 (HHV-6) meningoencephalitis after allogeneic purified CD34+ cell transplantation from his HLA-mismatched sibling donor, even though he had been on intense prophylaxis with i.v. ganciclovir (GCV), acyclovir (ACV) and gamma-globulin containing a specific antibody against HHV-6. Serological evaluation disclosed that both the donor and recipient had IgG antibody against HHV-6 before transplantation. His blood WBC count started to transiently increase on day 10, and all blood components had decreased by day 20. He then developed a severe headache and high blood pressure, and sporadic abnormal neurological findings including nystagmus and delirium. An analysis of cerebrospinal fluid (CSF) revealed 8 cells/microl, a glucose level of 130 mg/dl and a protein level of 201 mg/dl (normal, 50 mg/dl) on day 26. At the time, HHV-6 was detected only in CSF by a PCR-based method and he was diagnosed as having meningoencephalitis due to the local reactivation of HHV-6. Although he failed to respond to high-dose therapy with ACV (60 mg/kg/day) and gamma-globulin, the DNA of this virus disappeared from the CNS upon treatment with GCV (30 mg/kg/day) combined with the intraventricular infusion of alpha-interferon. His clinical course was further complicated with meningoencephalitis due to staphylococcus epidermidis, and he died of tentorial herniation on day 79 without the recovery of blood components. This experience may indicate that intense prophylaxis to prevent reactivation of HHV-6 in the CNS is essential for the management of such profoundly immunosuppressed patients.     

Masked hypertension in young patients after successful aortic coarctation repair: impact on left ventricular geometry and function

Life expectancy is still reduced in aortic coarctation (AoC) patients despite a successful repair because of late arterial hypertension and atherosclerosis. Masked hypertension (MH) consists of an elevated daytime or awake ambulatory blood pressure (BP) in the presence of a normal BP on conventional measurement at the office. To assess the prevalence of MH among AoC normotensive young patients successfully treated and to evaluate the impact of MH on left ventricular (LV) geometry and function.We studied 76 AoC patients (mean age 14.5±5.7 years, male 64%). According to 24?h ambulatory BP monitoring (ABPM) our sample was divided in real normotensive patients (Group RN, n=40) and MH patients (Group MH, n=36). There was an increased pressure gradient in the aortic arch (15?mm?Hg±4 vs 13?mm?Hg±4.7, P<0.05), increased LV mass (51?g?m(-2.7)±13 vs 46 g?m(-2.7)±12, P<0.05), in MH AoC patients. Regional longitudinal deformation properties of the basal septal segment (-15%±2.4 vs -20%±5, P<0.01) and LV twist values (14°±1.6 vs 12°±1.9, P<0.0001) were reduced in the MH group. There is a high prevalence of MH in young patients with repaired AoC, which is associated with abnormal LV structure and function. Clinicians should consider 24?h ABPM measurements in apparently normotensive patients followed up for AoC repair.     

Angiotensin - Forming Enzyme Active at the Physiological PH in the Brain of Normal and Nephrectomized Rats

Enzymatic activity generating angiotensin at pH 5.5 and 7.2 has been detected in different areas of the central nervous system (CNS) of the rat. Control animals and those subjected to bilateral nephrectomy 48 h before the experiment (Nx) were analyzed. The different areas of the CNS were studied by the incubation of tissue homogenates in the presence (enzyme concentration) or not (enzyme activity) of an excess of added angiotensinogen. Concentration was determined by incubation at pH 7.2 and 5.5 while activity was evaluated only at pH 7.2. The enzymatic renin-like concentration at both pHs did not change after Nx thus showing they do not depend on plasma and vascular renin. On the other hand the activity of the enzyme showed a significant increase in the cerebral cortex and cerebellum after Nx suggesting an increased concentrations of renin substrate and/or different concentrations of inhibitors or activators of the enzymatic system in those areas.