Cerebrospinal Fluid Angiotensin-converting Enzyme Research Articles

Spinal cord sarcoidosis in Japan: utility of cerebrospinal fluid examination and nerve conduction study for diagnosis and prognosis prediction.

Spinal cord sarcoidosis (SCS) is rare, and its diagnosis is challenging. We examined clinical, laboratory, and imaging features in patients with SCS to obtain useful clues for diagnosis and prognosis. Eleven consecutive patients (four males, seven females) at a single Japanese institution were investigated. Median age at onset was 66years old. The most frequent site affected, other than the nervous system, was the respiratory system. While histological confirmation of non-caseating granulomas was often found there, no patient had respiratory symptoms. Peripheral nerve involvement was detected in 64% of patients. Soluble IL-2 receptor (sIL-2R) levels in serum and cerebrospinal fluid (CSF) were elevated in 64% and 45% of patients, respectively, and this finding was more common than elevation of angiotensin-converting enzyme (ACE). 18F-fluorodeoxyglucose (FDG) positron emission tomography showed abnormally high uptake in spinal lesions of all examined patients. Although corticosteroids were administrated to all patients, and immuno-suppressants were prescribed to six (55%), the modified Rankin Scale was unchanged or worsened in four (36%) patients during the follow-up period. Neurological exacerbation of myelopathy was seen in four (36%) patients. Complete response rate was only seen in 9%. High levels of cell count, protein, ACE, and sIL-2R in CSF were significantly more frequent in patients with a marked improvement after immunotherapy than in the other patients. These results suggest that high serum and CSF sIL-2R, high uptake of FDG, and peripheral nerve involvement are indicative of SCS. Given that SCS is commonly intractable, CSF abnormalities may predict efficacy of immunotherapies.

CSF TO ACE THE DIAGNOSIS

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Sarcoidosis is a granulomatous disorder characterized by noncaseating granulomas affecting involved organs. Although the majority of sarcoidosis is diagnosed as pulmonary sarcoidosis incidentally on chest imaging, extrapulmonary sarcoidosis is the presenting symptom for approximately 30% of all cases, with 5-10% affecting the nervous system. Angiotensin Converting Enzyme can be produced by granulomas, with 55% of cases demonstrating positive ACE levels within cerebrospinal fluid. CASE PRESENTATION: A 28 year old man with no past medical history presented with bilateral lower extremity weakness and numbness, gradually worsening over four weeks, starting in the pelvic area causing urinary urgency and painful defecation with distal spread. Over the few days prior to admission his family had also noticed dysarthria. Physical exam was notable for anisocoria, dysarthria, ataxic gait, diminished lower extremity reflexes, and saddle anesthesia. Serum was unremarkable except a sed rate of 39 and a positive ANA. Lumbar puncture showed an elevated white count of 43 cells/uL, predominantly lymphocytes, and an elevated protein at 336mg/dL. CSF ACE level was elevated (7.0 units/L). An MRI of the brain and spine showed diffuse nodular leptomeningeal enhancement of the entire spinal cord and brain. A CT of chest abdomen and pelvis was obtained which demonstrated innumerable pulmonary nodules and masses in a perilymphatic distribution with upper lobe predominance and subcarinal, pelvic and abdominal lymphadenopathy. Endobronchial biopsies of right mainstem bronchus nodularity and EBUS guided transbronchial needle aspiration of the subcarinal lymph node revealed granulomatous inflammation. He was treated with IV pulsed Solumedrol for 3 days with improvement in his neurologic symptoms. He was discharged on prednisone 1 mg/kg and methotrexate 15 mg weekly. Repeat MRI 5 days post treatment showed improvement of leptomeningeal enhancement. DISCUSSION: In this case, we observed a young man who developed neurologic symptoms as his first sign of sarcoidosis. Neurosarcoidosis can effect any portion of the peripheral or central nervous system. Cranial mononeuropathy, cognitive deficits, radiculopathy, and aseptic meningitis are common manifestations, wherever a granuloma can obstruct a nerve. A helpful diagnostic cue is angiotensin I-converting enzyme within the CSF itself, as granulomas synthesize this enzyme which can diffuse into various fluid compartments. The mainstay of treatment for any neurologic symptom is to treat the underlying sarcoidosis with steroids, as was done on our patient. CONCLUSIONS: In a younger patient with a pulmonary nodules and masses with associated neurologic complaints, neurosarcoidosis is a unique diagnosis that physicians should consider on their differential, while excluding malignancy. Angiotensin Converting Enzyme in CSF can be a helpful diagnostic cue. Reference #1: "Neurosarcoidosis” by Burns, Arch Neurol. 2003 Aug;60(8):1166-8. Reference #2: "Clinical characteristics of patients in a case control study of sarcoidosis” by Baughman, Teirstein, Et Al. Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1885-9. Reference #3: "Cerebrospinal fluid angiotensin-converting enzyme for diagnosis of central nervous system sarcoidosis.” By Khoury, Wellik, Et Al. Neurologist. 2009 Mar;15(2):108-11. https://doi.org/10.1097/NRL.0b013e31819bcf84. DISCLOSURES: No relevant relationships by Elena Burke, source=Web Response no disclosure on file for Christine Fleury; No relevant relationships by Kellen Mulhern, source=Web Response

The association of angiotensin-converting enzyme with biomarkers for Alzheimer's disease.

IntroductionLower angiotensin-converting enzyme (ACE) activity could increase the risk of Alzheimer’s disease (AD) as ACE functions to degrade amyloid-β (Aβ). Therefore, we investigated whether ACE protein and activity levels in cerebrospinal fluid (CSF) and serum were associated with CSF Aβ, total tau (tau) and tau phosphorylated at threonine 181 (ptau).MethodsWe included 118 subjects from our memory clinic-based Amsterdam Dementia Cohort (mean age 66 ± 8 years) with subjective memory complaints (n = 40) or AD (n = 78), who did not use antihypertensive drugs. We measured ACE protein levels (ng/ml) and activity (RFU) in CSF and serum, and amyloid β1–42, tau and ptau (pg/ml) in CSF.ResultsCross-sectional regression analyses showed that ACE protein level and activity in CSF and serum were lower in patients with AD compared to controls. Lower CSF ACE protein level, and to a lesser extent serum ACE protein level and CSF ACE activity, were associated with lower CSF Aβ, indicating more brain Aβ pathology; adjusted regression coefficients (B) (95% CI) per SD increase were 0.09 (0.04; 0.15), 0.06 (0.00; 0.12) and 0.05 (0.00; 0.11), respectively. Further, lower CSF ACE protein level was associated with lower CSF tau and ptau levels; adjusted B’s (95% CI) per SD increase were 0.15 (0.06; 0.25) and 0.17 (0.10; 0.25), respectively.ConclusionsThese results strengthen the hypothesis that ACE degrades Aβ. This could suggest that lowering ACE levels by for example ACE-inhibitors might have adverse consequences for patients with, or at risk for AD.

Neurosarcoidosis: Two case reports with multiple cranial nerve involvement and review of the literature

Involvement of the central nervous system is registered in a relatively small number of patients with sarcoidosis. In this article we present two cases with various neurological symptoms that fulfill criteria for neurosarcoidosis (NS). In addition, we review the literature on NS with special attention to isolated cranial nerve involvement. First patient: Neurological examination identified multiple cranial neuropathy, moderate right-sided hemiparesis, polyradiculoneuritis of the lower limbs and positive meningeal signs. Laboratory tests showed serum and cerebrospinal fluid (CSF) inflammatory abnormalities, with increased values of the angiotensin-converting enzyme (ACE). CSF analysis also showed presence of 9 oligoclonal IgG bands. Brain and spine magnetic resonance imaging (MRI) revealed diffuse meningopathy, and focal granulomatous lesion in the body of the L5 vertebra. Lung sarcoidosis was confirmed by additional diagnostic procedures. The patient was treated with Methylprednisolone and a tapering course of oral Prednisone, which reduced the pain in the back and legs and improved the strength of the right leg. However, the other neurological deficiencies remained. After confirming lung sarcoidosis, the patient received Methotrexate in addition to Prednisone but during the following 2 years the patient's condition progressively worsened and ended in death. Second patient: Neurological findings showed weakness of the right n. oculomotorius and the right n. trochlearis, as well as the right-side face weakness. We found raised level of the ACE in serum and CSF. Thorax high-definition computed tomography (HDCTT) showed ribbon-like domains of discrete changes in the pulmonary parenchyma. MRI of the brain showed multiple white matter lesions. This patient also received Methylprednisolone followed by Prednisone, and after two months, ocular motility normalized. The diagnosis of NS is always a challenge. For this rerason definitive diagnosis requires the exclusion of other causes of neuropathy. Multiple cranial neuropathies should always arouse suspicion of NS.

Treatment of refractory neurosarcoidosis with TNF‐inhibitors: what lies ahead?

We read with interest the case series on the treatment of refractory neurosarcoidosis with infliximab. We were interested to know whether the serum and cerebrospinal fluid angiotensin converting enzyme or other makers of sarcoidosis might have been ascertained (such as increased cerebrospinal fluid CD4/CD8 lymphocyte ratios, lysozyme and b2-microglobulin), as these can have a role in monitoring disease activity, and in supporting a diagnosis if a patient (e.g. Case 1) declines biopsy. Likewise, a gallium or positron-emission tomography scan may indicate accessible disease worthy of biopsy, for example, salivary glands or lymph nodes. Sarcoidosis refractory to glucocorticosteroids is an important and difficult area, and although there have not been any randomised controlled treatment trials for isolated neurosarcoidosis, there is now a large body of evidence from placebo-controlled studies that anti-TNF-a agents have a relatively modest effect in modulating this disease, which is disappointing given the logical choice of TNF antagonists in sarcoidosis. Nonetheless, individual trials of therapy may be worthwhile as in the refractory cases reported, if monitored carefully, and the therapy discontinued quickly if ineffective, particularly with the awareness that tuberculosis might be unmasked as being the true diagnosis, rather than sarcoidosis. We also note that Pereira et al. tested azathioprine in two of their patients although did not assess anti-malarials. Azathioprine, as well as chloroquine and hydroxychloroquine have also been reported as being useful in a few small case series of neurosarcoidosis, but no clinical trial data exist. Hopefully, better agents that target CD4+ type 1 helper T-cell (TH1) immunity and associated sarcoid inflammatory pathways will become available as the immunology of this fascinating disease becomes apparent.

Cerebrospinal Fluid Angiotensin-Converting Enzyme for Diagnosis of Central Nervous System Sarcoidosis

Sarcoidosis is a multisystem granulomatous disease that may involve the central nervous system (CNS) in many ways, leading to diagnostic difficulties. An accurate diagnostic laboratory test would enhance the evaluation and management of these patients. To determine the diagnostic accuracy of cerebrospinal fluid angiotensin-converting enzyme (ACE) for CNS neurosarcoidosis. The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the field of neuroimmunology. Two primary articles were selected for review. Cerebrospinal fluid ACE assay is insensitive (24%-55%) but may be reasonably specific (94%-95%) for CNS neurosarcoidosis. However, existing data are derived from studies with significant methodological and reporting limitations. The diagnostic accuracy of cerebrospinal fluid ACE for CNS neurosarcoidosis is not clearly established and the test cannot replace tissue diagnosis. Despite its insensitivity, some clinicians might consider the specificity of cerebrospinal fluid ACE, based on existing data, high enough to warrant inclusion in the diagnostic evaluation of patients in whom CNS neurosarcoidosis is being considered. A well-designed prospective diagnostic study seems warranted.

Neurosarcoidosis: clinical presentations and course in 50 patients.

Fifty consecutive patients with neurosarcoidosis were evaluated retrospectively. Sarcoidosis presented first with neurologic signs in 24 patients (48%), but systemic symptoms developed later in all but five. Main neurologic involvements were central nervous system lesions in 33 patients (66%), cranial nerve paresis in 12 (24%), and peripheral nerve lesions in five patients (10%). Seventeen patients (34%) had more than one type of neurologic involvement. Routine cerebrospinal fluid (CSF) parameters showed unspecific abnormalities in 35 patients (70%). CSF angiotensin converting enzyme was elevated in 18 of 31 patients (58%). Brain computerized tomography was abnormal in 13 of 32 patients (41%). Visual and brainstem evoked potentials were abnormal in ten (43%) and eight (35%) of 23 patients, respectively, suggesting subclinical lesions in 13 patients. Neurologic signs improved in 24 patients (48%), were stable in 11 (22%), and progressed in 15 patients (30%). Six patients died. Cranial nerve lesions improved most often. Course of neurologic involvements was similar in acute or subacute and chronic sarcoidosis. The effect of steroid treatment was inconsistent.

A link between sICAM-1, ACE and parietal blood flow in the aging brain

A connection between Alzheimer's disease (AD) and endothelium pathology has been inferred from measured decreases in both blood flow and metabolism in the parietal and temporal cortex. However, it is not known whether these alterations are seen in normal aging. We performed regional cerebral blood flow (rCBF) measurements in 22 AD patients and in 44 non-demented subjects during a simple test of information processing speed. Cerebrospinal fluid (CSF) levels of angiotensin-converting enzyme (ACE) and the soluble form of intercellular adhesion molecule-1 (sICAM-1) were analyzed in non-demented subjects. We found correlations between sICAM-1 and ACE ( p = 0.004), and sICAM (but not ACE) and CSF/plasma albumin ratio ( p < 0.0001). Higher concentrations of sICAM-1 (>893 ng/L) and ACE (>5.22 μg/L) were exclusively associated with lower parietal blood flow ( p < 0.001). The rCBF patterns in the AD and non-demented subjects with biomarker levels above median showed similar reductions in the temporoparietal areas. Our findings provide evidence that elevated CSF sICAM-1 and ACE are associated with lower perfusion levels in the parietal cortex of cognitively intact elderly.

Cerebrospinal fluid angiotensin-converting enzyme (ACE) correlates with length of illness in schizophrenia

The aim of the study was to evaluate a possible progression with time of cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) levels in treated schizophrenia patients. CSF ACE was determined in duplicate by a sensitive inhibitor-binding assay (IBA) from morning CSF samples of 56 acute and chronic in-patients with schizophrenic psychoses diagnosed according to DSM-IV. CSF ACE correlated significantly with length of schizophrenic psychosis ( r=0.39, p=0.003). There was also a positive significant correlation between CSF ACE and duration of current psychotic episode ( r=0.39, p=0.003) as well as duration of current hospitalization ( r=0.66, p<0.001). These significances were maintained even when patients who were not treated with antipsychotics at the time of sampling were excluded. The correlations also remained significant when controlling for current neuroleptic dose in chlorpromazine equivalents. Serum ACE did not correlate with any clinical variable. No significant correlations between serum or CSF ACE and age, diagnostic subgroup, gender, serum ACE, CSF to serum albumin ratios, or neuroleptic dose in chlorpromazine equivalents were detected. The elevation of CSF ACE seemed to be confined to a subgroup of chronic patients with few positive symptoms. Elevated CSF ACE may reflect an increased solubilization of ACE from cell membranes in the central nervous system or constitute an increased expression of the ACE gene in response to some stimuli. This may be a function of treatment or a result of the deteriorating schizophrenic process.

Determination of Angiotensin-Converting Enzyme Levels in Cerebrospinal Fluid Is Not a Useful Test for the Diagnosis of Neurosarcoidosis

To the Editor: Recently, we questioned the clinical utility of determining the level of angiotensin-converting enzyme (ACE) in cerebrospinal fluid (CSF) for the diagnosis of neurosarcoidosis. The diagnosis of sarcoidosis, a multisystem granulomatous disorder of unknown etiology, is typically based on clinical signs and symptoms supported by radiographic findings and the presence of noncaseating epithelioid granulomas in more than one organ. Elevated serum levels of ACE, hypercalciuria, and hypercalcemia provide supportive, but not diagnostic, evidence of sarcoidosis. Approximately 5% of patients with sarcoidosis have neurologic involvement. When neurologic symptoms occur in the absence of other organ system abnormalities, the diagnosis of neurosarcoidosis is especially problematic. Measurement of CSF levels of ACE has been advocated as a means of distinguishing between neurosarcoidosis and other nonsarcoid neurologic disease processes. Although several scientific publications have supported the use of CSF ACE levels for the diagnosis of neurosarcoidosis, many of them are letters to the editor with little or no supporting data.1Rubinstein I Hoffstein V Angiotensin-converting enzyme m neurosarcoidosis (letter].Arch Neural. 1987; 44: 249-250Crossref PubMed Scopus (7) Google Scholar, 2Chan Seem CP Norfolk G Spokes EG CSF angiotensin-converting enzyme in neurosarcoidosis 1 letter).Lancet. 1985; 1: 456-457Abstract PubMed Scopus (39) Google Scholar, 3Ahmed S Angiotensin-converting enzyme and neurosarcoidosis llettej].Chest. 1991; 99: 1054Crossref Scopus (4) Google Scholar, 4Rubinstein I Central nervous system sarcoidosis |letterJ.J Neurosurg. 1986; 65: 265PubMed Google Scholar In the largest study reported in the literature, CSF ACE levels were determined in 32 patients with sarcoidosis, including 20 with a diagnosis of neurosarcoidosis. This study reported elevated CSF ACE levels in 55% of patients with neurosarcoidosis, in 5% of patients with sarcoidosis not involving the central nervous system,5Oksaner V Fynrquist F Somer H Qronhagen-Rlska C Angiotensin converting enzyme in cerebrospinal fluid: a new assay.Neurology. 1985; 35: 1220-1223Crossref PubMed Google Scholar and in 13% of patients with other neurologic diseases.6Oksanen V New cerebrospinal fluid, neurophysiological and neuroradiological examinations in the diagnosis and follow-up of neurosarcoidosis.Sarcoidosis. 1987; 4: 105-110PubMed Google Scholar Despite this apparent lack of sensitivity and specificity, the authors concluded that the CSF level of ACE seems useful in the diagnosis of neurosarcoidosis. In an attempt to establish whether determination of CSF ACE levels should be a part of our laboratory test repertoire, we conducted a retrospective chart review of 110 Mayo Clinic patients in whom the CSF level of ACE was measured to rule out neurosarcoidosis. Although CSF ACE levels were higher in patients with neurosarcoidosis than in patients without this diagnosis, considerable overlap in the CSF ACE levels between the two groups (Table 1) limited the usefulness of the test for individual patients. The sensitivity and specificity of the test were 24% and 95%, respectively. In 5 of 9 patients (56%) with an elevated CSF ACE level, neurosarcoidosis was not diagnosed; 13 of 17 patients (76%) diagnosed with neurosarcoidosis had a normal CSF ACE level, and 5 of 93 patients (5%) without neurosarcoidosis had an elevated CSF ACE level. Five of the 17 patients in whom neurosarcoidosis was diagnosed were receiving prednisone at the time the ACE levels were measured. Although this factor limits the conclusions of our review, we believe it also limits the clinical utility of CSF ACE determinations because the question of neurologic involvement often arises in patients who are receiving prednisone therapy for sarcoidosis.Table 1Cerebrospinal Fluid Levels of Angiotensin-Converting Enzyme in 110 Mayo Clinic Patients With Suspected NeurosarcoidoslsCSF ACE level (U/L)*ACE = angiotensin-converting enzyme; CSF = cerebrospinal fluid.†Reference range, 0 to 61.Diagnosis of neurosarcoidosi sNo. of patientsMeanMedianRangeYes170.530.410.05–2.01No930.250.250.01–l.28* ACE = angiotensin-converting enzyme; CSF = cerebrospinal fluid.† Reference range, 0 to 61. Open table in a new tab We believe that there is insufficient evidence to support the routine use of CSF ACE levels for the diagnosis of neurosarcoidosis. In accordance with our position that tests that do not provide clinically useful information represent an unnecessary contribution to the overall cost of medical care, we have discontinued performing this test in our laboratory. We believe that additional efforts are needed to develop other diagnostic modalities for the diagnosis of neurosarcoidosis and that further use of CSF ACE levels should be done in the context of prospective studies. CorrectionMayo Clinic ProceedingsVol. 75Issue 3PreviewIn the Letter to the Editor by Dale and O'Brien entitled “Determination of Angiotensin-Converting Enzyme Levels in Cerebrospinal Fluid Is Not a Useful Test for the Diagnosis of Neurosarcoidosis,” published in the May 1999 issue of Mayo Clinic Proceedings (Mayo Clin Proc. 1999;74:535), an error occurred in the dagger footnote to Table 1. The footnote should read as follows: “Reference range, 0 to 0.61 [not 61].” Full-Text PDF

Effectiveness of Chloroquine and Hydroxychloroquine in Treating Selected Patients With Sarcoidosis With Neurological Involvement

To assess the efficacy of chloroquine (Aralen) phosphate and hydroxychloroquine (Plaquenil) sulfate in the treatment of patients with neurosarcoidosis who either do not respond to corticosteroid therapy or develop unacceptable side effects. Retrospective study. Sarcoidosis clinic at a university teaching hospital. Twelve patients with biopsy-proved sarcoidosis, 6 women and 6 men ranging from 20 to 49 years of age, with neurological involvement. Chloroquine phosphate, 250 mg twice daily, or hydroxychloroquine sulfate, 200 mg twice daily, was administered for a period of 6 to 21 months. Patients had regular clinical evaluation, determination of serum and cerebrospinal fluid angiotensin-converting enzyme level, computed tomography or magnetic resonance imaging, chest radiography, lung function testing, and slit-lamp examination of the eyes. Chloroquine or hydroxychloroquine either stabilized symptoms or controlled neurological symptoms in 10 of 12 patients. Two patients failed to respond. Cerebrospinal fluid abnormalities, including lymphocytosis, were seen in 3 patients. Magnetic resonance imaging with gadolinium was most helpful in supporting the diagnosis of sarcoidosis and monitoring the course of the disease. Chloroquine and hydroxychloroquine are effective in controlling neurological sarcoidosis in those patients who fail to respond to corticosteroids or develop severe side effects. Ocular toxic effects from chloroquine or hydroxychloroquine were not observed.

A longitudinal study of cerebrospinal fluid angiotensin-converting enzyme in neuroleptic-treated schizophrenia

1. 1. The aim of the study was to replicate our earlier finding of elevated cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) in neuroleptic-treated schizophrenia and to elucidate the correlations between CSF ACE, neuroleptic treatment, and psychotic symptoms in a longitudinal study. 2. 2. Levels of ACE were measured in CSF and serum from 9 acutely psychotic schizophrenic patients at two separate points of time; within a few days of admission and at follow-up after 3–4 weeks. CSF ACE was also determined from 9 healthy controls. 3. 3. The schizophrenic patients showed non-significantly higher levels of CSF ACE than the controls. Although a significant clinical improvement was observed and the neuroleptic medication was reduced during the follow-up period, there were no significant differences in serum or CSF ACE between the two observation points in the schizophrenia group.

Elevated plasma vasopressin and normal cerebrospinal fluid angiotensin-converting enzyme in chronic pain disorder

The study was performed proceeding from the hypothesis that pain proneness in chronic pain disorder (CPD) is a result of alterations in central mechanisms regulating pain sensations. To elucidate the function of the central renin-angiotensin system, the levels of angiotensin-converting enzyme (ACE) and arginine vasopressin (AVP) in cerebrospinal fluid (CSF) and peripheral blood were measured in 15 CPD patients and 19 healthy controls. Plasma AVP levels (p = .01) as well as the serum osmolality (p = .01) were significantly higher in the CPD group. No significant differences in CSF ACE levels were found. AVP is a stress-related peptide, but central antinociceptive effects have also been reported. Elevated plasma AVP levels possibly may constitute a response to chronic stress.

Higher cerebrospinal fluid angiotensin-converting enzyme levels in neuroleptic-treated than in drug-free schizophrenics

Higher cerebrospinal fluid angiotensin-converting enzyme levels in neuroleptic-treated than in drug-free schizophrenics

Angiotensin(1–7) in the spontaneously hypertensive rat

We profiled the concentrations of angiotensin I (Ang I), angiotensin II (Ang II), and angiotensin(1–7) [Ang(1–7)] by the combination of radioimmunoassay and high performance liquid chromatography in the blood of 14-week-old male Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) drinking either tap water or a solution containing ceranapril (30 mg/kg) or lisinopril (20 mg/kg) for 14 days. Differences in the chemical and pharmacokinetic properties of the two converting enzyme inhibitors ruled out class-related effects. Plasma renin activity, angiotensin converting enzyme (ACE) activity, and plasma levels of Ang I and Ang II were the same in vehicle-treated WKY and SHR. In contrast, plasma levels of both Ang(1–7) and vasopressin in SHR were 3.7-fold and 2.6-fold higher, respectively ( p<0.05). Angiotensin converting enzyme inhibition reduced the blood pressure of WKY and SHR, and augmented their intake of water and output of urine. These changes were associated with increases in renin activity and plasma levels of Ang I and Ang(1–7). In both WKY and SHR, lisinopril had a greater effect in inhibiting plasma and cerebrospinal fluid ACE, reducing levels of plasma angiotensinogen, and increasing the concentrations of authentic Ang II. The principal finding of this study is that plasma Ang(1–7) is the sole component of the circulating angiotensin system that is elevated in the established phase of genetic hypertension. The finding that chronic inhibition of ACE augments circulating levels of Ang(1–7) evidenced the existence of functional pathways for the alternate processing of Ang I.

Elevated angiotensin-converting enzyme (kininase II) in the cerebrospinal fluid of neuroleptic-treated schizophrenic patients

Disturbances of water homeostasis have frequently been reported in schizophrenia. Water homeostasis is regulated by arginine vasopressin (AVP), the renin-angiotensin system and natriuretic hormones. The aim of this study was to determine the activity of the central renin-angiotensin system in schizophrenia by measuring levels of angiotensin-converting enzyme (ACE) in the cerebrospinal fluid (CSF) and blood in 14 in-patients with schizophrenia on neuroleptic medication and in 9 healthy volunteers. The levels of CSF ACE were significantly higher in the schizophrenia group. There were no correlations between CSF ACE and gender, age, age at first episode, duration of illness, term of hospitalization or neuroleptic dosage. No correlations between CSF ACE and serum ACE were found in either group. The authors suggest an activated central renin-angiotensin system in schizophrenia at least during antipsychotic drug treatment, which may cause ‘psychogenic’ polydipsia in some patients. ACE and the brain renin-angiotensin system may also play a role in the regulation of neuron growth and differentiation in schizophrenia.

Cerebrovascular reactivity to angiotensin and angiotensin-converting enzyme activity in cerebrospinal fluid

The purpose of the present study was to test the vasomotor effect of angiotensin I (A I) and angiotensin II (A II) in feline cerebral arteries and to examine the presence of angiotensin converting enzyme (ACE) activity in the vessel wall and cerebrospinal fluid (CSF). A II (10 −8–10 −5) induced concentration-dependent contractions of feline pial arteries (resting diameter, 98–286 μm) in situ with a maximum of 34% at 10 −4 M A II. A I produced dose-related contractions being approximately 20 times less potent that A II. The action of A I was significantly attenuated by the ACE inhibitor captopril (10 −5 M). These findings demonstrate the presence of ACE activity in the vessel wall and/or its surroundings. ACE activity was also found in feline CSF sampled from the cisterna carebello-medullaris. Bradykinin (BK) was broken down and A I converted to A II by CSF, both effects being inhibited by captopril. This was demonstrated using bioassay and high-performance liquid chromatography. Considering the present and previous studies we conclude that the presence of ACE in the vessel wall and CSF is necessary for the conversion of A I to A II. Although ACE in CSF is able to degrade BK it appears not to be important for the metabolism of BK acting from the perivascular side of pial arteries in situ.

Acute oral captopril inhibits angiotensin converting enzyme activity in human cerebrospinal fluid.

Angiotensin converting enzyme (ACE) activity in human plasma and cerebrospinal fluid (CSF), was measured by a fluorimetric method, following an acute oral dose (75 mg) of captopril. A decrease of approximately 60% in enzyme activity was observed in CSF, suggesting that the drug penetrates the blood/brain barrier (BBB) in sufficient amounts to inhibit the ACE in CSF. The activity of CSF enkephalinase, an enzyme present in human brain and inhibited in vitro by an elevated concentration of captopril, was, however, unaffected by the acute drug administration. It is proposed that the antihypertensive effect of captopril in humans may be due, at least in part, to the inhibition of ACE contained within brain structures.