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Biomedical subjects

A I Ally

Publications and source records attributed to A I Ally.

At least 19 recordsLinked to original sources
PubMed1988

Differentiation and maturation of embryonal carcinoma-derived neurons in cell culture.

We have previously shown that retinoic acid-treated cultures of the P19 line of embryonal carcinoma cells differentiate into neurons, glia, and fibroblast-like cells (Jones-Villeneuve et al., 1982). We report here that the monoclonal antibody HNK-1 reacts with the neurons at a very early stage of their differentiation and is, therefore, an early marker of the neuronal lineage. Cells in differentiated P 19 cultures synthesized acetylcholine but not catecholamines, suggesting that at least some of the neurons are cholinergic. The neurons also carry high-affinity uptake sites for GABA but not for serotonin. In long-term cultures, neuronal processes differentiated into axons and dendrites, which formed synapses. This biological system should prove valuable for examining the development and maturation of cholinergic neurons, since their differentiation occurs in cell culture.

Acetylcholine↗
PubMed1986

Trimethyltin as a selective adrenal chemosympatholytic agent in vivo: effect precedes both clinical and histopathological evidence of toxicity.

Trimethyltin (TMT) is a potent neuronotoxiciant but there is little data regarding its systemic effects. In this study, female BALB/c mice were administered either 0.9% saline or 2.75 mg TMT/kg intraperitoneally (i.p.). The animals were then housed in room air or in glass chambers flushed with either 10%, 40%, or 100% oxygen. Mice were sacrificed at 4, 8, 24, and 48 h after treatment and adrenals analyzed for various neurotransmitters by ion-pairing HPLC with electrochemical detection. In addition, adrenal S-adenosylmethionine (SAM) and blood ketone bodies were determined Sections of adrenals were evaluated by electron microscopy for histopathological changes. In vivo treatment with the toxicant resulted in a significant decrease in adrenal epinephrine and norepinephrine levels as early as 8 h following treatment. This effect preceded the appearance of both clinical signs and histopathological changes in the hippocampus by 12-24 h. With exposure to TMT in room air, mouse adrenal content of epinephrine fell from 1861.3 +/- 97.3 ng/4 mg to 1493.3 +/- 137.0 ng/4 mg while norepinephrine levels fell from 779.6 +/- 32.3 ng/4 mg to 503.4 +/- 44.3 ng/4 after 8 h. Supplementation with 40% oxygen did not attenuate this effect but in the case of mice treated with TMT and housed in 100% oxygen for 48 h, actually exacerbated the adrenal epinephrine depletion. Housing in approximately half normal atmospheric oxygen (10%) neither prevented nor enhanced the effects of TMT. The epinephrine/norepinephrine ratios were: control, 2.44; TMT (room air), 1.56; TMT (10% O2), 1.72; TMT (40% O2), 1.44; TMT (100% O2), 1.07. None of the conditions used in this study caused a decrease in adrenal dopamine, 5-hydroxyindole acetic acid (5-HIAA), 5-hydroxytryptamine (5-HT) or in the level of SAM. TMT treatment significantly increased blood ketone bodies indicating additional metabolic dysfunction. The significance of these findings in relation to TMT neuronotoxicity and fatty liver syndrome are discussed.

3-Hydroxybutyric Acid↗
PubMed1986

Hydralazine inhibits vascular reactivity by a mechanism independent of vascular prostaglandin biosynthesis: role of thromboxane synthetase in blocking hydralazine actions.

To explore the mechanism of action of hydralazine on vascular reactivity of small vessels we have examined its actions in the isolated perfused mesenteric vascular bed. In buffer perfused preparations hydralazine inhibited responses to nondepolarizing stimuli at concentrations comparable to those achieved in vivo. Inhibition of cyclo-oxygenase activity enhanced hydralazine's action as did inhibition of thromboxane synthetase. Hydralazine stimulated mesenteric vascular bed prostaglandin biosynthesis (6-keto PGF1a and PGE2 determined by radio-immunoassay) and stimulated aorta PG12 synthesis (monitored by platelet bioassay). Extracellular calcium opposed hydralazine's action by a mechanism sensitive to cyclo-oxygenase inhibition. Concentrations of hydralazine substantially greater than those effective in the perfused vascular bed were required to demonstrate inhibition of platelet aggregation and ram seminal vesicles cyclooxygenase activity. These data indicate: Hydralazine acts directly on the smooth muscle to attentuate responses to nondepolarizing stimuli. Hydralazine does not inhibit vascular reactivity by a PG12 dependent mechanism although it stimulates prostaglandin biosynthesis. Reduction of vascular bed prostaglandin and thromboxane A2 biosynthesis enhances hydralazine actions. Hydralazine appears to act at a thromboxane A2 sensitive site however it is not a nonselective prostaglandin antagonist. Hydralazine is effective at concentrations which do not inhibit either platelet aggregation or ram seminal vesicle cyclooxygenase. These data suggest that hydralazine is a potent direct acting vasodilator which stimulates prostaglandin biosynthesis and whose potency may in turn be attenuated by the production of proconstrictory prostaglandins.

Animals↗
PubMed1979

The nutritional regulation of T lymphocyte function.

Prostaglandin (PG) E1 plays a major role in the regulation of thymus development and T lymphocyte function and the evidence for this is reviewed. The production of PGE1 is dependent on nutritional factors with linoleic acid, gamma-linolenic acid, pyridoxine, zinc and vitamin C playing key roles. Inadequate intake of any one of these will lead to inadequate PGE1 formation and defective T lymphocyte function. Megadoses of any one are likely to be only minimally effective in the absence of adequate intakes of the others. By careful attention to diet it should be possible to activate T lymphocyte function in the large number of diseases including rheumatoid arthritis, various auto-immune diseases, multiple sclerosis, and cancer in which such function is defective. It is possible that T lymphocytes may require both endogenous and exogenous PGE1 in order to function adequately. It is therefore of particular interest that many cancer cells and virally infected cells are unable to make PGE1 because they cannot convert linoleic acid to gamma-linolenic acid. The direct provision of gamma-linolenic or dihomo-gammalinolenic acids in these situations is worthy of full investigation.

Animals↗
PubMed1979

Thymic changes in muscular dystrophy and evidence for an abnormality related to prostaglandin synthesis or action.

In Bar Harbor 129 dystrophic mice, thymic development is abnormal. Before weaning, the thymus is slightly smaller than in phenotypically normal littermates; after weaning, however, the lymphoid elements undergo rapid atrophy. The epithelial elements, in contrast, display hyperlasia. Thymectomy has no influence on the course of the disease, and it is possible that the thymic changes are a reflection of a fundamental metabolic abnormality. Thymic lymphoid tissue development seems to require normal levels of PGE1. Levels that are either too high or too low both result in abnormalities. We have investigated the effects of PGE1 in smooth muscle and have demonstrated that while some PGE1 is required for both calcium release and calcium removal, high levels of PGE1 block both processes. We propose that the muscular dystrophies are related to defects in PG synthesis and action. Myotonic dystrophy may be due to PGE11 excess, whereas Duchenne dystrophy may in part be due to PGE1 deficiency.

Aging↗
PubMed1979

Copper inhibits pressor responses to noradrenaline but not potassium. Interactions with prostaglandins E1, E2, and I2 and penicillamine.

Low concentrations of copper inhibited responses to norepinephrine and angiotensin (IC50 3 X 10(-6) M) but not to potassium in rat mesenteric vascular preparations perfused either with buffer or indomethacin and prostaglandin (PGE2). The dose-response curve was not shifted by indomethacin, imidazole, or PGE2 but was moved to the right by 2.8 X 10(-11) M PGE1 and to the left by 2.8 X 10(-7) M PGE1. These effects of copper are similar to the effects of PGI2 in the preparation. Copper moved the PGI2 dose-response curve against noradrenaline in parallel to the left, suggesting that the two were interacting at some point. Penicillamine, which may stimulate PGE1 synthesis, had PGE1-like interactions with the copper effect, suggesting that its value in Wilson's disease may be partly due to antagonism of the biological action of copper as well as to its copper-chelating properties.

Animals↗
PubMed1978

Low prostaglandin concentrations cause cardiac rhythm disturbances. Effect reversed by low levels of copper or chloroquine.

In perfused male rat hearts concentrations of prostaglandins (PGs) E2 and F2alpha in the range 1 pg/ml to 10 ng/ml (2.8 X 10(-12) to 2.8 X 10(-8)M) consistently caused rhythm irregularities. Higher concentrations had no effect themselves and stabilized rhythm in hearts made unstable by lower concentrations. Copper ions (as the sulphate) at 2 X 10(-6)M stabilized hearts made unstable by PGs and when present prior to the PGs prevented PG induced disturbances. Chloroquine also reversed PG-induced rhythm changes.

Animals↗
PubMed1978

A defect in thromboxane A2 synthesis may be a factor predisposing to cancer.

A failure of thromboxane (TX) A2 synthesis may be a factor in cancer. Such a loss could explain the susceptibility to mutation, the excess prostaglandin production, the glycolytic mode of metabolism and the deranged calcium pumping characteristic of cancers. Ionising radiation and phorbols both have actions similar to inhibitors of TXA2 synthesis whereas colchicine and oxygen have actions consistent with stimulation of TXA2 synthesis. The concept accounts logically for hitherto unexplained features of cancer and suggests new strategies for the prevention and treatment of cancer.

Animals↗
PubMed1978

Ultra-violet radiation and 8-methoxypsoralen have actions similar to those of known inhibitors of thromboxane A2 synthesis in rat mesenteric blood vessels.

In the rat mesenteric vascular bed three structurally different agents (imidazole, benzydamine and N-0164) which have been reported to be inhibitors of thromboxane (TX) A2 synthesis at certain concentrations, all have a characteristic spectrum of action. They inhibit pressor responses to noradrenaline and angiotensin with equal potency and the inhibition can be reversed by exogenous PGE2: they do not inhibit responses to potassium. Ultra-violet (UV) radiation has a similar spectrum of action. The main difference between the action of imidazole and that of UV radiation is that the former is rapidly reversible while the latter is not. However, irradiation administered to preparations inhibited by imidazole has no irreversible effect provided that the radiation is switched off before the imidazole is removed. The imidazole protects against radiation damage suggesting that the drug may stabilize the site affected by UV light. 8-methoxypsoralen, a light sensitizing agent used in treatment of psoriasis also inhibited noradrenaline and angiotensin but not potassium responses and seemed to make the preparation more sensitive to radiation damage. It is possible that UV radiation and 8-methoxypsoralen may inhibit TXA2 synthesis but this requires confirmation by direct methods.

Angiotensin II↗
PubMed1978

Influence of agents which modulate thromboxane A2 synthesis or action on R3230AC mammary carcinoma.

The effects of agents which modulate thromboxane A2 synthesis or action, were tested in the R3230AC transplanted mammary tumour. Three different inhibitors of thromboxane A2 synthesis or action (copper, dipyridamole and diazepam) all caused an increase in tumour growth. Colchicine and melatonin, both stimulators of thromboxane A2 synthesis, inhibited the growth of the tumour significantly.

Animals↗
PubMed1978

Prostaglandins and schizophrenia: further discussion of the evidence.

It has been proposed that schizophrenia is a prostaglandin-deficiency disease and also that it is a disease of prostaglandin excess. New evidence is reviewed which suggests that 'classic' schizophrenia is due to a specific deficiency of prostaglandin E1 while certain toxic and vitamin-deficiency psychoses may be due to a broader spectrum of prostaglandin deficiency. There is also good evidence that a particular schizophrenic subgroup, which includes catatonic schizophrenia but may not be confirmed to it, is associated with an excess of prostaglandins. Part of the explanation may be that prostaglandin E1 has a 'bell-shaped' dose-response curve with high concentrations having effects similar to those of prostaglandin deficiency.

Animals↗
PubMed1978

Dantrolene blocks intracellular calcium release in smooth muscle: competitive antagonism of thromboxane A2.

Dantrolene sodium has been shown to block the release of intracellular calcium in skeletal muscle. It has been proposed that dantrolene blocks the movement and (or) action of a natural calcium ionophore. In a rat vascular preparation dantrolene was found to inhibit pressor responses to noradrenaline and angiotensin but not those to potassium with an IC50 concentration within the therapeutic levels in man. Imidazole, an inhibitor of thromboxane A2 (TXA2) synthesis, had similar actions to dantrolene. Interactions between imidazole and dantrolene suggested that dantrolene may be a competitive antagonist of TXA2 in muscle. We report the first demonstration of an effect of dantrolene sodium on smooth muscle contractility and suggest that TXA2 is an essential modulator of vascular reactivity. A similar role has been shown for TXA2 in platelets.

Angiotensin II↗