Hyperthermia and postmortem biochemical investigations.

The postmortem diagnosis of heat-related deaths presents certain difficulties. Firstly, preterminal or terminal body temperatures are often not available. Additionally, macroscopic and microscopic findings are nonspecific or inconclusive and depend on survival duration after exposure. The diagnosis of hyperthermia is therefore essentially based on scene investigation, the circumstances of death, and the reasonable exclusion of other causes of death. Immunohistochemistry and postmortem biochemical investigations have been performed by several authors in order to better circumstantiate the physiopathology of hyperthermia and provide further information to confirm or exclude a heat-related cause of death. Biochemical markers, such as electrolytes, hormones, blood proteins, enzymes, and neurotransmitters, have been analyzed in blood and other biological fluids to improve the diagnostic potential of autopsy, histology, and immunohistochemistry. The aim of this article is to present a review of the medicolegal literature pertaining to the postmortem biochemical investigations that are associated with heat-related deaths.

Natriuretic pro-peptides in idiopathic intracranial hypertension.

Idiopathic intracranial hypertension is a disorder of unknown pathogenesis. Natriuretic peptides may be involved in intracranial pressure regulation, but cerebrospinal fluid (CNS) and plasma concentrations in this disorder are unknown. We evaluated venous and intrathecal concentrations of ANP, BNP and CNP precursor peptides in 40 patients with idiopathic intracranial hypertension and in 20 controls. Natriuretic pro-peptides were quantitated using processing-independent assays. In CSF, no differences in peptide concentrations between patients and controls were found (proANP: 239 + or - 23 vs 231 + or - 22 pmol/L, proBNP: <2 pmol/L in all, proCNP: 1079 + or - 318 vs 1138 + or - 323 pmol/L). In plasma, proCNP was lower in IIH compared with controls (35.3 + or - 4.8 pmol/L vs 43.8 + or - 5.9 pmol/L, p<0.0001). Moreover, plasma proBNP was significantly lower in patients compared with controls (47.1 + or -21.4 pmol/L vs 59.2 + or - 22.0 pmol/L, p = 0.045). There were no associations between peptide concentrations and ICP and BMI, respectively. Plasma proANP and proCNP increased during 3 months follow-up (p=0.01 and p=0.006), n=12. We suggest that decreased plasma proCNP concentration in idiopathic intracranial hypertension may reflect endothelial dysregulation of vascular tone and may be a marker in this disease. Further studies of proCNP and endothelial function are needed to establish such role.

The neuro-cardio-endocrine response to acute subarachnoid haemorrhage.

OBJECTIVE: Whereas cardiac hormones increase after subarachnoid haemorrhage (SAH), and may contribute to sodium wastage and hyponatraemia, there is controversy concerning the relative roles of atrial natriuretic peptide (ANP) vs. brain natriuretic peptide (BNP) and the factors initiating their secretion. Noting previous work linking stress hormone responses with cardiac injury after SAH, we have studied responses in stress hormones, markers of cardiac injury and the temporal changes in ANP and BNP and related them to changes in sodium status post ictus and during recovery from acute SAH. DESIGN, PATIENTS, MEASUREMENTS: Eighteen patients with verified SAH of variable severity were studied in a single unit for a 14-day period post ictus under controlled conditions of sodium and fluid intake. All received a standardized protocol of daily dexamethasone and nimodipine throughout the study. Severity was graded using criteria of Hess and Hunt at admission. Stress hormones (AVP, catecholamines and admission plasma cortisol), markers of cardiac injury (ECG and daily plasma troponin T) and cardiac hormones (ANP and BNP) were measured daily and related to severity, plasma sodium and renin-aldosterone activity. Hormone levels (ANP, BNP and endothelin) in cerebrospinal fluid (CSF) were also measured in nine patients. RESULTS: Intense neurohormonal activation (AVP, cortisol and catecholamines) at admission was associated with increased levels of both plasma ANP and BNP whereas levels in CSF were unaffected. In individual patients plasma levels of ANP and BNP were strongly correlated (P < 0.001). Cardiac events (abnormal ECG and/or elevated troponin) occurred in six of seven patients graded severe but neither stress hormones nor cardiac peptides differed significantly in patients with mild (n = 11) vs. severe (n = 7) SAH. During the course of a progressive fall in plasma sodium concentration (P = 0.001), there was a delayed activation of renin-aldosterone which was inversely correlated with declining levels of plasma ANP/BNP (P < 0.002). CONCLUSIONS: Excessive secretion of both ANP and BNP occurs in all patients after acute subarachnoid haemorrhage and is unrelated to severity, stress hormone activation or markers of cardiac injury. Inhibition of renin-aldosterone by cardiac hormones may impair renal sodium conservation and contribute to developing hyponatraemia. In the absence of evidence for activation of natriuretic peptides within the brain, the prompt and consistent increase in both ANP and BNP strongly supports the view that the heart is the source of increased natriuretic peptide secretion after acute subarachnoid haemorrhage.

Possible regulation of intracranial pressure by human atrial natriuretic peptide in cerebrospinal fluid.

To clarify the function of human atrial natriuretic peptide (hANP) in the cerebrospinal fluid (CSF), we examined hANP levels in the CSF of patients with various neurological diseases. The subjects were 16 controls without neurological disease and 45 patients with neurological disease. The 45 patients with neurological disease were divided into a group of 15 patients with intracranial hypertension (IH) and a group of 30 patients with normal pressure (NP). hANP in both CSF (1-hANP) and serum (s-hANP) was measured by RIA. Patients with IH were followed up. We analyzed correlations between 1-hANP and other parameters of CSF. Increase in concentration of 1-hANP was positively correlated with intracranial pressure (ICP; r = 0.72; p < 0.01), but not with other CSF parameters or with s-hANP. The concentration of 1-hANP appeared to be increased especially over a threshold value of ICP. In a followup study of patients with IH, changes in 1-hANP paralleled changes in ICP in every case (r = 0.79; p < 0.01). Our findings strongly suggest that 1-hANP plays an important role in the regulation of ICP in humans.

C-type natriuretic peptide (CNP) is the major natriuretic peptide in human cerebrospinal fluid.

In order to investigate whether C-type natriuretic peptide (CNP) is present in human cerebrospinal fluid (CSF), we measured CNP-like immunoreactivity (-LI) in human CSF by specific radioimmunoassay (RIA) for CNP. We also measured atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations in human CSF. ANP-LI, BNP-LI, and CNP-LI concentrations of CSF collected from fifteen patients without neurological disorders were 0.20 +/- 0.13, 0.27 +/- 0.10, and 2.13 +/- 0.27 fmol/ml (mean +/- S.D.), respectively. In fifteen patients with neurological disorders, ANP-LI, BNP-LI, and CNP-LI concentrations in CSF were 0.21 +/- 0.18, 0.33 +/- 0.19, and 2.09 +/- 0.82 fmol/ml, respectively. Although ANP-LI and BNP-LI concentrations in plasma were much higher than those in CSF, CNP-LI was undetectable in plasma (less than 0.2 fmol/ml). These results demonstrate that three natriuretic peptides are present in CSF and that CNP is the major natriuretic peptide in human CSF. These results suggest that CNP in CSF is originated from and play important roles in the central nervous system.

[Alteration of atrial natriuretic peptide and cyclic GMP in cerebrospinal fluid in canine kaolin-induced hydrocephalus].

CSF and Plasma concentrations of atrial natriuretic peptide (ANP) and cyclic GMP (cGMP), which is regarded as a second messenger of ANP, were measured intermittently during the progress of canine kaolin-induced hydrocephalus. Data were analyzed being divided into three groups, normal, acute (within 2 weeks after intracisternal injection of kaolin suspension) and chronic (from 3 to 4 weeks after injection of kaolin suspension) stages of hydrocephalus. The presence of ventricular dilatation was evaluated by MRI or postmortal dissection. ANP, cGMP in CSF and CSF pressure significantly increased in the acute stage of hydrocephalus. In the chronic stage, ANP in CSF and CSF pressure had no statistical difference with data of the normal stage. Cyclic GMP in CSF kept significantly high value in the chronic stage of hydrocephalus. CSF concentrations of Na, CSF osmolarity, plasma ANP, plasma cGMP, plasma ADH, serum Na and serum osmolarity did not change significantly in the course of hydrocephalus. There was a significant positive correlation between ANP in CSF and CSF pressure. ANP in CSF did not correlate with degree of ventricular dilatation. Cyclic GMP in CSF did not correlate with ANP in CSF, nor with CSF pressure. These data suggest that concentration of ANP in CSF may alter directly or indirectly depending on CSF pressure in kaolin-induced hydrocephalus. And cGMP in CSF was suggested to depend not on ANP in CSF, but on other unknown factors in kaolin-induced hydrocephalus.

Effect of saline loading on ANP in the cerebrospinal fluid of rats.

In order to investigate the effect of saline loading on the atrial natriuretic peptide (ANP) in the central nervous system (CNS), time course measurements of the ANP content in the cerebrospinal fluid (CSF), blood pressure, water and electrolyte balances were carried out after saline loading in rats. Cisternal saline loading (120 ml/day) was found to induce a significant increase in urinary volume and electrolyte excretion, and to cause an initial rise in mean arterial blood pressure (MAP) in WKY rats. The ANP content in the CSF was significantly increased after saline loading, as compared to that in the control period. The ANP in both the plasma and CSF revealed a significant increase over the control values following chronic saline loading. Based on these results, it is suggested that the ANP in the CSF could exert a regulatory effect on the blood pressure and water balance, either by a direct action on the kidney or indirectly via an action on the CNS.

Intracerebroventricular atrial natriuretic peptide infusion augments the adrenocorticotropin and angiotensin II responses to hemorrhage in sheep.

The central actions of atrial natriuretic peptide (ANP) in rats include inhibition of arginine vasopressin (AVP) release, and less consistently, ACTH suppression and hypotension. To explore any such inhibitory actions on basal and stimulated levels of AVP and ACTH, we have studied the effect of intracerebroventricular (ICV) infusion of ANP on the hemodynamic and hormonal response to acute hemorrhage in conscious sheep. Two groups of 5 sheep received rat ANP(101-126) by ICV infusion (0.5 microgram bolus followed by 0.5 microgram/h for 3 h, or 5 micrograms bolus followed by 5 micrograms/h for 3 h) as well as artificial cerebrospinal fluid control infusions in random order. One hour after the start of the ICV infusion, acute hemorrhage (15 ml/kg BW within 10 min) was performed. Basal levels before hemorrhage of mean arterial pressure (MAP), heart rate and plasma hormones were unaltered by either dose of ICV ANP. After hemorrhage, the fall in MAP and rise in heart rate were similar in each group. However, compared to control infusions the response to hemorrhage of ACTH (433 +/- 147 to 2,175 +/- 588 vs. control 541 +/- 103 to 893 +/- 244 ng/l; p less than 0.016) and angiotensin II (AII) (18 +/- 3 to 94 +/- 23 vs. control 18 +/- 4 to 58 +/- 8 pmol/l; p less than 0.001) were significantly greater during high-dose ANP infusion. Although peak AVP levels more than doubled those observed on the control day, the increase did not reach statistical significance (p less than 0.1053). Plasma concentration of cortisol, aldosterone, epinephrine and norepinephrine were not significantly different in control and ANP-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid atrial natriuretic factor in intracranial disease.

We tested the hypothesis that the concentration of atrial natriuretic factor in the cerebrospinal fluid is an indicator of brain injury in patients with intracranial disease. Atrial natriuretic factor concentration was measured in 72 samples of cerebrospinal fluid from 28 patients with intraventricular drains and in nine samples from outpatient controls undergoing diagnostic lumbar puncture. Levels were correlated with diagnosis; systemic fluid administration; concentration of atrial natriuretic factor in the plasma; intracranial pressure; sodium, glucose, and protein concentrations, osmolality, and cell count in the cerebrospinal fluid; sodium concentration in the serum; and hemodynamics. Atrial natriuretic factor concentration was highest in cerebrospinal fluid from patients with intracerebral hematoma, followed by those with obstructive hydrocephalus and subarachnoid hemorrhage (19 +/- 2, 13 +/- 3, and 8 +/- 2 pg/ml, respectively); atrial natriuretic factor concentration was less than 4 pg/ml in the controls. Patients treated with fluid restriction had significantly higher atrial natriuretic factor levels than those receiving maintenance or high-volume fluids (16 +/- 3, 8 +/- 2, 10 +/- 1 pg/ml, respectively). The concentration of atrial natriuretic factor in the plasma was significantly elevated in patients with intracerebral hematoma and subarachnoid hemorrhage (155 +/- 38 and 92 +/- 20 pg/ml, respectively) and did not correlate with fluid administration or the concentration of atrial natriuretic factor in the cerebrospinal fluid. Neither cerebrospinal fluid nor plasma concentrations of atrial natriuretic factor correlated with intracranial pressure; cerebrospinal fluid sodium, glucose, or protein concentrations, osmolality, or cell count; serum sodium concentration; or hemodynamics. We conclude that the concentration of atrial natriuretic factor in the cerebrospinal fluid is a nonspecific indicator of brain injury.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Cerebrospinal fluid concentrations of atrial natriuretic peptide in children.

Concentrations of atrial natriuretic peptide (ANP) in plasma and in cerebrospinal fluid (CSF) were measured in preterm neonates, in infants and in children with hydrocephalus. Plasma ANP in preterm neonates were elevated compared to infants and children with hydrocephalus. CSF-ANP in all groups were lower than plasma levels. ANP concentrations in the liquor exhibited higher values in children with hydrocephalus. No correlation was found between plasma and CSF-ANP levels while CSF-pressure and ANP concentration in the liquor correlated positively. Our data provide evidence for the existence of a cerebral ANP system in humans. The CSF-ANP system seems to be independent from the systemic, atrial ANP. CSF-ANP may be of great importance in the regulation of water and ion content of central nervous system and probably liquor formation.

Increased neuropeptide Y concentrations in cerebrospinal fluid from patients with aneurysmal subarachnoid hemorrhage.

We investigated the possible relation between neuropeptides and cerebral vasoconstriction in samples of ventricular or cisternal cerebrospinal fluid from 14 patients with subarachnoid hemorrhage. Neuropeptide Y, calcitonin gene-related peptide, atrial natriuretic peptide, and pituitary polypeptide 7B2 were present in the cerebrospinal fluid of these patients. Concentrations of calcitonin gene-related peptide and 7B2 were not significantly different from those in control subjects, but that of atrial natriuretic peptide was significantly lower. Although the mean concentration of neuropeptide Y was not significantly higher than control, consecutive determinations showed an increase 6-11 days after the onset of subarachnoid hemorrhage. An initially high 7B2 concentration decreased gradually, although half the patients showed a second increase greater than 10 days after the onset. Considering the well-recognized vasoconstrictive effect of neuropeptide Y, it is possible that this increase in its concentration in the cerebrospinal fluid plays a role in the pathogenesis of the cerebral vasospasm that is often seen after subarachnoid hemorrhage.

Atrial natriuretic peptide in human cerebrospinal fluid.

We measured immunoreactive atrial natriuretic peptide (ANP) levels in cerebrospinal fluid (CSF) collected from patients with various neurologic disorders requiring diagnostic lumbar puncture. ANP was present in all of the CSF samples from 45 patients (1.7 +/- 0.6 pmol/L, mean +/- SD). CSF ANP levels were not related to the underlying central nervous diseases of the patients, to the presence or the absence of consciousness disturbance, or to CSF osmolalities in individual patients. In 35 patients, the mean ANP concentration in CSF corresponded to 27% of that in plasma, and there was no significant correlation between ANP concentrations in each paired sample. When ANP in pooled CSF was extracted by anti-ANP-agarose and analyzed by reverse-phase high performance liquid chromatography (HPLC), multiple peaks of ANP were found. One of the major ANP peaks was identified as ANP-(103-126) on the basis of its retention time on HPLC and the specificity of the antiserum used in the radioimmunoassay; however, none of other peaks coeluted with ANP-(99-126), ANP-(101-126), ANP-(102-126), ANP-(103-125), or ANP-(105-126). We conclude from these results that ANP is present in human CSF that is differently processed from ANP in the cardiac atrium.

[Presence of atrial natriuretic peptide in canine cerebrospinal fluid and its origin].

The purposes of the present study are to demonstrate the presence of atrial natriuretic peptide (ANP) in canine cerebrospinal fluid (CSF) and to determine its origin as either the brain or atrium. Fifty-seven mongrel canines weighing from 7.5 to 23.0kg (male: 28, female: 29) were anesthetized with sodium pentobarbital (30mg/mg, iv) and were ventilated with a Harvard respirator. 16 canines (11.5 to 16.0kg) were used to examine the effect of endogenously increased plasma ANP level on the ANP concentration of the CSF in acute heart failure induced by experimental aortic regurgitation. Subsequently to examine the effect of exogenously increased plasma ANP level on the ANP concentration of the CSF, physiological and pharmacological doses of synthetic human alpha-ANP were continuously infused into the right ventricle (25ng/kg/min. and 250ng/kg/min., respectively) for 32 min. in 15 canines (8.0 to 23.0kg), only physiological dose (25ng/kg/min.) was infused for 180 min. in 8 canines (12.5 to 23.0kg). The concentrations of ANP in canine CSF and plasma were measured by our highly sensitive and specific radioimmunoassay (RIA). The molecular forms in the plasma, CSF and the atrium and hypothalamus tissues were determined by gel permeation chromatography (GPC). The ANP concentration in CSF was 2.8 +/- 1.2pg/ml (mean +/- SD), lower than that in the plasma which was 51.5 +/- 19.9pg/ml, and no correlation was found between them (r = 0.16, p = ns). Plasma ANP concentrations increased from 46.5 +/- 13.0pg/ml to 94.6 +/- 27.7pg/ml according to a rise of the left atrial pressure by experimental aortic regurgitation. However, no significant change was noted from 3.7 +/- 0.7pg/ml to 3.8 +/- 1.0pg/ml in CSF ANP concentrations during the aortic regurgitation. The ANP concentration in the CSF did not change significantly while the plasma ANP concentration greatly increased following each intravenous infusion of the synthetic alpha-ANP. Only a single peak corresponding to a low molecular weight form of ANP in the position of authentic alpha-ANP in the canine CSF was observed by GPC, while there were peaks for both low and high molecular forms of ANP in the canine plasma. Furthermore, both low and high molecular weight peaks were observed for the right atrium and hypothalamus tissue extracts by GPC, and those tissues of the right atrium and hypothalamus contained ANP concentrations of 1.97ng/mg wet tissue and 2.6pg/ml wet tissue, respectively. These results indicate the presence of ANP in canine CSF and that it does not come from blood that has seeped across the blood-CSF barriers but may originate in the brain.

The effect of subarachnoid hemorrhage on blood and CSF atrial natriuretic factor.

Atrial natriuretic factor (ANF) is a diuretic natriuretic peptide hormone produced by both the heart and brain which has been postulated to play a role in the hemodynamic and sodium instability that frequently follows subarachnoid hemorrhage (SAH). Levels of ANF were measured in 12 patients with nontraumatic SAH and nine control patients with unruptured cerebral aneurysms. At surgery, the mean plasma ANF level (+/- standard deviation) of the SAH group was significantly higher than that of the control group (158.1 +/- 83.8 vs. 57.8 +/- 45.3 pg/ml, respectively; p = 0.01). There was no significant difference in serum sodium concentration, blood pressure, or central venous pressure between these groups. Nine patients with SAH due to aneurysm rupture had plasma ANF levels similar to those in three patients with SAH due to other causes. Four patients with moderate to severe SAH had significantly higher mean cerebrospinal fluid (CSF) ANF values (17.7 +/- 12.8 pg/ml) than five patients with minimal SAH (0.6 +/- 0.9 pg/ml) or the control group of nine patients (3.7 +/- 1.3 pg/ml) (p less than 0.05). Five patients with moderate to severe SAH had significantly higher plasma ANF values (202.6 +/- 72.2 pg/ml) than five with minimal SAH (86.8 +/- 29.2 pg/ml) or the control group (57.8 +/- 45.3 pg/ml) (p less than 0.05). Plasma ANF values were substantially higher than CSF ANF content in the SAH group (p less than 0.01) and in the control group (p = 0.05). From these data it is concluded that: 1) plasma ANF is elevated significantly after SAH; 2) this rise appears unrelated to the cause of hemorrhage, serum sodium concentration, blood pressure, or central venous pressure, but is related to the extent of the hemorrhage; 3) ANF concentrations in the CSF are significantly lower than in plasma, and are elevated after moderate to severe SAH; and 4) the source of CSF ANF is probably the plasma, and the source of plasma ANF is likely the heart.

Pituitary protein 7B2-like immunoreactivity in cerebrospinal fluid: comparison with other neuropeptides.

A pituitary protein, designated 7B2, was demonstrated to be present in the cerebrospinal fluid (CSF) obtained from control subjects and patients with various cerebrovascular accidents (CVAs). Although there was not any significant difference in mean immunoreactive 7B2 concentrations among various CVA groups, the CSF immunoreactive 7B2 levels in control subjects were 10 to 100 times higher than those in control plasma samples. Immunoreactive calcitonin gene-related peptide (CGRP) and immunoreactive atrial natriuretic peptide (ANP) levels in the CSF were comparable to those in corresponding normal plasma samples. The CSF ANP concentrations in patients with cerebral bleeding and subarachnoid hemorrhage were significantly lower than those in control subjects. Gel chromatography or high-performance liquid chromatography indicated that the main immunoreactivities of 7B2, CGRP, and ANP coeluted with corresponding standard material. The high CSF concentrations of immunoreactive 7B2 observed might indicate a functional role of 7B2 in the central nervous system.

The presence of atrial natriuretic peptide in canine cerebrospinal fluid and its possible origin in the brain.

The presence of atrial natriuretic peptide (ANP) in canine cerebrospinal fluid (CSF) was clearly demonstrated and an attempt was made to determine its origin as either the brain or the atrium. The concentration of ANP in canine CSF was 0.78 +/- 0.37 pmol/l (n = 31) and showed no evident correlation with that in plasma (r = 0.12). Physiological doses of human alpha-ANP (alpha-hANP) were continuously infused intravenously into nine dogs, and ANP concentrations in CSF and plasma were examined six to eight times within a 120-min period following this. The ANP level in CSF was not influenced by the systemic administration of alpha-hANP up to 180 min. Only one low molecular weight peak corresponding to alpha-hANP could be obtained from the CSF samples, while both low and high molecular weight peaks were observed for plasma ANP by gel permeation chromatography. In the atrial and hypothalamic tissue extracts the same kinds of peaks were also evident. These results prove the presence of ANP in canine CSF and that it does not come from blood that has seeped across the blood-CSF barriers, but suggest that it may originate from the brain.

Increased concentration of atrial natriuretic factor in the cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage and raised intracranial pressure.

Plasma and cerebrospinal fluid (CSF) atrial natriuretic factors/peptides (ANFs/ANPs) were measured in 26 patients with normal or raised intracranial pressure (ICP) by means of an instant radioreceptor assay. All 26 patients were suffering from aneurysmal subarachnoid hemorrhage (SAH), and 11 had also developed raised ICP (ICP greater than 20 mm Hg). In SAH patients with normal ICP, the plasma levels of ANF were 20 to 200 pg/ml (mean +/- SE, 89 +/- 68 pg/ml); in the 11 SAH patients with raised ICP, however, ANF levels were 14 to 262 pg/ml (mean 114 +/- 79 pg/ml). The difference was not statistically significant. The ANF/ANP plasma levels in 6 healthy volunteers were 15 to 167 pg/ml (mean 77 +/- 32 pg/ml). Although the ANF/ANP concentration in the CSF of patients with normal ICP did not reach the lower limit of detectability (i.e., 4 pg/ml) in any case, in those with elevated ICP it was 14 to 120 pg/ml (mean 49 +/- 37 pg/ml). This difference was statistically highly significant. The results of this preliminary study suggest that the ANF/ANP concentration in human CSF is 1 to 2 orders lower than that in the plasma and that there is no significant correlation between ANF/ANP levels in the CSF and the plasma. After SAH in patients with raised ICP, there was an accompanying increase in the ANF/ANP concentration in the CSF, but the ANF/ANP concentration in the plasma was not changed significantly. Accordingly, a central ANF/ANP release might be hypothesized to play a causative or adaptive role in the neuroendocrine regulation of ICP dynamics, although this may simply be an epiphenomenon.

The existence of low concentrations of atrial natriuretic peptide (ANP) in canine cerebrospinal fluid which does not correlate with plasma ANP levels.

Atrial natriuretic peptide (ANP) concentrations in the cerebrospinal fluid (CSF) and plasma of canine were 2.1 +/- 1.1 pg/ml (mean +/- S.D.) and 53.1 +/- 21.1 (n = 20), respectively. The regression coefficient between these concentrations was -0.0045 (P = n.s.). The ANP concentration in the CSF did not change even after the plasma ANP concentration was altered following the change of left atrial pressure, as in 4 cases of an experimental aortic regurgitation. Thus, ANP concentration in the CSF is not influenced by ANP concentrations in the plasma at least under our condition. Gel permeation chromatography revealed a single form of ANP in the position of authentic alpha-ANP in canine CSF, while a high molecular weight ANP peak was observed as well as alpha-ANP in the plasma.