I. Das

Inositol phospholipid turnover in platelets of schizophrenic patients

Abnormalities in blood cell membrane phospholipid composition and metabolism from schizophrenic patients have been reported by many groups of investigators. Among membrane phospholipids, inositol phospholipids are of special importance as they are involved in transduction system that generates second messengers such as inositol trisphosphate and diacylglycerol. Our studies on platelet inositol phospholipid turnover suggest a significant increase in platelet phosphatidylinositol 4,5-bisphosphate levels, an increased production of inositol trisphosphate in neuroleptic-treated and neuroleptic-free schizophrenic patients platelets and a reduced calcium release by thrombin in neuroleptic-treated schizophrenic patients platelets. The enhanced production of inositol trisphosphate may be due to an increase in its precursor phosphatidylinositol 4,5-bisphosphate with an associated desensitisation of the intracellular inositol trisphosphate receptor by neuroleptics, which may explain the diminished calcium response to thrombin in schizophrenic patients platelets.

Leukotriene B4 generation by polymorphonuclear leukocytes: possible involvement in the pathogenesis of headache.

SYNOPSIS

Hypothalamic and plasma total nitrate/nitrite concentrations in spontaneously hypertensive rats

Stable end‐products of nitric oxide (NO) metabolism, nitrates and nitrites, were measured in hypothalamic extracts and plasma samples of Okamoto spontaneously hypertensive (SH) rats. The mean total nitrate/nitrite concentration was significantly lower in the hypothalami of SH rats compared with the normotensive Wistar Kyoto (WKY) control animals (P < 0.01). In contrast, their plasma concentrations were significantly higher (P < 0.05). These results indicate that the hypertensive state in SH rats is associated with a diminished production of hypothalamic NO, while the raised plasma nitrate/nitrite levels could reflect an increased compensatory endothelial NO synthase activity in these animals compared with the WKY controls.

Hypothalamic Hypertensive Factor: An Inhibitor of Nitric Oxide Synthase Activity

Human and rat plasma and rat hypothalamus contain a cytochemically detectable substance, the concentration of which rises with an increase in salt intake. The plasma concentration of this material is also raised in essential hypertension and in the spontaneously hypertensive rat (SHR), the Milan hypertensive rat, and the reduced renal mass (RRM) hypertensive rat. In the normal rat, the greatest concentration is found in the hypothalamus of the SHR and the RRM hypertensive rat. The physicochemical characteristics of this cytochemically detectable hypothalamic hypertensive factor (HHF), including chromatographic behavior and molecular weight range, suggest that it may share features common to a substituted guanidine that is present in established nitric oxide synthase (NOS) inhibitors. It was therefore decided to determine the effect on NOS activity of the HHF obtained from mature SHR. The ability of HHF to inhibit NOS activity was studied on (1) NOS extracted from bovine aorta, rat brain, and human platelets by measuring the conversion of radiolabeled L-arginine to L-citrulline and (2) rat liver NOS measured indirectly with a cytochemical technique based on the stimulation of soluble guanylate cyclase activity in hepatocytes by NO. HHF showed a biphasic inhibitory action on platelet NOS activity that was greater with HHF obtained from SHR than from Wistar-Kyoto rats. HHF also had a biphasic inhibitory effect on hepatocyte NOS activity that was more potent when obtained from SHR. It is proposed that the increase in HHF, a novel form of NOS inhibitor that is elevated in SHR, may be involved in the rise in arterial pressure.

Abnormal Membrane Composition and Membrane-Dependent Transduction Mechanisms in Cluster Headache

Previous studies have indicated that membrane structure and function may be abnormal in cluster headache. This has been further investigated by analysis of membrane phosphatidylcholine, total phospholipids, and cholesterol in erythrocytes and by assay of receptor-mediated transduction. The stimulation of lymphocyte adenylate cyclase with isoprenaline and prostacyclin was used as the test system. A significant increase in the ratio of membrane phosphatidylcholine to cholesterol without change in cholesterol was found in cluster headache patients as compared with control subjects. This indicated a reduced turnover of phosphatidylcholine, since erythrocyte choline is significantly reduced in this condition. Abnormal membrane function was also indicated from the significant depression of high-affinity prostaglandin receptor stimulation of lymphocyte adenylate cyclase and the similar trend in the β-adrenoceptor response. Since no change in agonist affinity and β-adrenoceptor density occurred, this depression indicates a generalized defect in coupling of receptors to adenylate cyclase. It is hypothesized that the impaired function that would result might contribute to the aetiology of cluster headache.

Calcium mobilization in platelets from schizophrenic and healthy subjects. Regulation by lithium and neuroleptics.

Intracellular free calcium concentrations ([Ca2+]1) were measured in platelets from healthy volunteers before and after adding thrombin, chlorpromazine, haloperidol and/or lithium, and in platelets from DSM-III-R diagnosed schizophrenic patients receiving neuroleptic medication. Thrombin increased [Ca2+] 1 in a dose- dependent fashion. Chlorpromazine and haloperidol also mobilized Ca2+ in a dose-dependent fashion, and augmented the response to low doses of thrombin without changing the maximal response to thrombin. The effects of all three drugs were not additive, suggesting that they affected the same intraplatelet calcium pool; most likely the dense tubular system. Lithium also increased [Ca2+ ] but without affecting the response to thrombin, chlorpromazine or haloperidol. The effects of the latter three drugs were additive to that of lithium, suggesting that lithium was acting on a different calcium pool. The response to thrombin was significantly lower in platelets from schizophrenic patients than in platelets from healthy volunteers. Further studies are required to explore potential causes for this observation. Such causes include schizophrenia per se and chronic neuroleptic treatment.

Ion-exchange chromatography of biologically important phosphate esters and other compounds

Abstract Borate complexed sugars, sugar phosphates, and nucleotides present in tissue extracts were separated and quantitated in 4 hr. An anion-exchange resin column and a programmed borate/acetate buffer gradient were used. Sugar residues were determined by a very sensitive orcinol/H2SO4 reaction. Samples required little preparation, and recovery of standard compounds added to tissue extracts was quantitative.

An assessment of the effect of hormone and neurotransmitters on adenine and gluanine derivatives simultaneously in rat brain cortical slices

A 2-dimensional thin-layer method has been developed for the separation on cellulose of adenine and guanine derivatives. Using incubated rat cerebral cortex slices it was shown that noradrenaline and acetylcholine stirnulated cAMP and cGMP production respectively but glutamate and γ-aminobutyric acid stimulated production of both cyclic nucleotides.

Headache Erythrocyte choline concentrations and cluster headache: Brit, med. J., 288 (1984) 268–270

Clinical diagnosis and computer analysis of headache symptonis. P.D. Drummond and J.W. Lance, J. Neurol. Neurosurg. Psychiat., 47 (1984) 128-133. Six hundred case histories from patients with a clinical diagnosis of classic migraine, common migraine, tension-vascular headache, tension headache and cluster headache were subjected to computer analysis. In 537 patients the computer arrived at the same category as the clinical diagnosis. Major discrepancies were between common migraine, tension-vascular headache and tension headache. Cluster headache and classic migraine emerged as clearly definable syndromes. It is suggested that the difference between common migraine, tension-vascular headache and tension headache is more quantitative than qualitative and that in fact they may be part of a continuum. This problem can only be solved by further pathophysiological studies.

Erythrocyte Choline Levels in Cluster Headache

Lithium is known to be beneficial in the treatment of cluster headache (CH) [4, 9, 11,13]. Patients with both episodic and chronic forms of CH show a high degree of improvement with it, although the mode of action of lithium in this condition is unknown. Lithium treatment has, however, been shown to markedly elevate erythrocyte choline levels in manic-depressive patients where it is also used in treatment [6, 7]. In addition, choline levels prior to treatment differ significantly between controls and manic-depressive patients, as well as between controls and two other conditions which have been investigated, Gilles de la Tourette syndrome and dementia [1, 3, 5,6,8]. In view of these observations, we have measured choline levels in erythrocytes and plasma of CH patients in comparison with age-matched controls to establish whether abnormal choline levels also occur in this condition.