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C K Atterwill

Publications and source records attributed to C K Atterwill.

At least 37 records · Page 2Linked to original sources
PubMed1989

Studies on the effects of omeprazole on thyroid function in the rat.

The effects of omeprazole (an H+, K+ -ATPase inhibitor) on thyroid parameters in rats have been examined. SK&F Wistar rats were dosed orally with omeprazole (up to 500 mg kg-1) or vehicle. Treatment for 7 or 14 days resulted in generally decreased plasma T3 concentrations in males (with little change or slight increases in females) and increased serum TSH concentrations (22%-68% increases). No changes were detected in thyroid 125I uptake or organification. Liver 5'-deiodinase activity was decreased in male rats after 7 days treatment. Thyroxine clearance was not altered after a single dose of omeprazole. In-vitro studies showed omeprazole to be only a weak inhibitor of TSH-stimulated 125I organification in cultured porcine thyrocytes. It is concluded that omeprazole has weak effects on the pituitary-thyroid-liver axis, its main action being to inhibit the peripheral deiodination of thyroid hormones.

Animals↗
PubMed1988

Comparison of the toxicity of orally administered L-triiodothyronine (T3) in rat and cynomolgus monkey.

Oral administration of L-triiodothyronine (L-T3) (0.015-1 mg/kg) for 30 days to mature rats or cynomolgus monkeys resulted in both species in a high mortality at 1 mg/kg (after 2 weeks of treatment) and a progressive loss in body weight. Dose-related elevations in plasma marker enzymes occurred, mainly after 1-2 weeks of treatment. The approximate no-effect dose for these changes was around 0.015-0.020 mg/kg for both rat and primate. The large elevations of leucine aminopeptidase (LAP) at 1 mg/kg L-T3 in monkey indicated hepatocellular toxicity although in the rat such large increases in alanine aminotransferase (ALT) and glutamate dehydrogenase (GLDH) were not seen. L-T3 also showed little toxicity to rat hepatocytes in vitro. High concentrations of L-T3 (7 x 10(-9) to 7 x 10(-7) M) had minimal effects on parameters of cell viability such as lactate dehydrogenase (LDH) leakage, chromium-51 release and [3H]leucine incorporation. Urinary enzymes in the rat showed a similar profile to those in plasma. Large rises in alkaline phosphatase (AKP) and N-acetyl glucosaminidase (NAG) at 1 mg/kg indicated possible proximal tubular damage although this was not supported histologically. Clinically, in both species L-T3 appeared more toxic to males than females but this was not supported histologically. The histological lesions observed were different in the 2 species. In the monkeys there was extensive lipid vacuolation of hepatocytes and changes in thyroid and adrenal cortex. In the rat there was fine, non-lipid vacuolation of hepatocytes and thyroid changes. In the rat, 2 previously unreported lesions were also noted. There were multinucleated cells in the renal distal tubular epithelium, and focal fibroplasia of serosal surfaces of abdominal viscera.

Acetylglucosaminidase↗
PubMed1988

Differential effects of D- and L-isomers of triiodothyronine on pituitary TSH secretion and peripheral deiodinase activity in the rat.

The effects of D- and L-T3 were compared in male SK & F Wistar rats to define overall effects on the 'pituitary-thyroid-liver axis' at high doses. After in vivo administration of L-T3 (up to 1 mg/kg orally, or up to 0.1 mg/kg subcutaneously) serum TSH and T4 were decreased in a dose-related manner. Similarly, following in vivo exposure to L-T3, both basal and TRH-stimulated TSH output from isolated superfused pituitary glands was decreased, but only the latter was affected by direct in vitro exposure to L-T3.D-T3 had between 1% and 10% the activity of L-T3 in decreasing these parameters both in vivo and in vitro. In contrast, both enantiomers increased liver and kidney deiodinase activity to approximately the same extent, presumably as a compensatory response to clear hormone from the body. These observations indicate that, following treatment with L- or D-T3 by oral gavage for 14 days, the 'no effect' dose (i.e. the dose which did not significantly decrease serum TSH concentrations as compared with controls) for L-T3 was below 0.01 mg/kg whereas that for D-T3 was 0.1 mg/kg.

Animals↗
PubMed1988

The neurotoxicity of ethylcholine mustard aziridinium (ECMA) in rat brain reaggregate cultures.

The cholinergic neurotoxin ECMA causes a biphasic loss of choline acetyltransferase activity in foetal rat whole brain reaggregate cultures. Initial direct inhibition is followed by longer-term loss of cholinergic neurones. Final muscarinic receptor binding, neurofilament protein and Na+, K+-ATPase concentrations suggest that the lesion is specific for cholinergic neurones at 12.5 microM ECMA, but is more generalised at 50 microM ECMA.

Animals↗
PubMed1987

Studies on the ontogenesis of the different isoenzymes of Na+, K+-ATPase in rat brain in vivo and in vitro in relation to their regulation and cellular localisation.

Na+,K+ ATPase isoenzyme activities (alpha(+)-high ouabain affinity; alpha low ouabain affinity) were investigated in developing rat brain in vivo and in whole rat brain reaggregating cultures in vitro. The perinatal profile of the two isoenzyme forms in vivo revealed that, although alpha activity predominates in immature (P14.5-P16) brain, the activity alpha(+) form increases more increases more rapidly such that it is predominant at birth in both cerebellum and forebrain. No regional variation in the proportional activities of the two isoenzyme forms was seen perinatally to explain the previously reported, differential sensitivity of the cerebellar alpha isoenzyme to neonatally induced hypothyroidism. Whole rat brain reaggregating cultures seeded at P16 show a normal development of Na+,K+ ATPase isoenzyme activity if grown for 14 days in a serum supplemented medium (S+). Cultivation of whole rat brain reaggregates in serum deprived medium (S-) leads to a retarded development of alpha isoenzyme activity possibly due to the absence of T3 from the medium. Hormonally-induced changes in the development of the brain Na+, K+-ATPase isoenzymes are discussed in relation to their possible function and cellular localization.

Animals↗
PubMed1987

The influence of L-triiodothyronine (T3) on the effects of repeated administration of desipramine or electroconvulsive shock on alpha 2- and beta-adrenoceptor function in the brain of the rat: implications for the potentiation of antidepressant therapy by T3.

Repeated, daily administration of either an electroconvulsive shock (ECS; 110 V, 1 sec) or desipramine (DMI; 5 mg/kg X 2) to rats caused a progressive decrease in the function of presynaptic alpha 2-adrenoceptors, assessed by the hypoactivity (sedation) response to clonidine (0.2 mg/kg). This attenuation required approximately 7 days' administration of either treatment for maximum effect. A single injection of triiodothyronine (T3; 100 micrograms/kg) on day 1 of the treatment markedly accelerated the decreased responses to clonidine induced by DMI or electroconvulsive shock, but did not alter the maximum attenuation. By itself T3 did not affect the hypoactivity responses. alpha 2-Adrenoceptors, measured by the binding of [3H]idazoxan in the cortex, which are believed to be predominantly postsynaptic, were decreased by 14 days of DMI or electroconvulsive shock for 10 days, but not 2 days of either treatment. Triiodothyronine did not influence the decreased number of alpha 2-adrenoceptors induced by DMI or electroconvulsive shock but may have delayed the onset produced by DMI. Binding to beta-adrenoceptors in the cortex was measured using [3H]dihydroalprenolol. This was significantly decreased by 14 days administration of DMI, but not significantly by electroconvulsive shock for 10. Down-regulation of beta-adrenoceptors, induced by DMI was rapid, being observed after 1 day of treatment. Injection of T3 did not influence the final decreases produced by DMI or electroconvulsive shocks but moderately delayed their onset. Triiodothyronine alone caused a 25% reduction in cortical beta-adrenoceptors 24 hr after injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

The perchlorate discharge test for examining thyroid function in rats.

A perchlorate discharge test was developed for rats to detect changes in the thyroidal iodide accumulation and organification mechanisms. Rats were pretreated with compounds that alter thyroid function by different mechanisms: SK&F 93479 (an H2-antagonist that enhances pituitary thyroid stimulating hormone drive by increasing thyroid hormone clearance) and propylthiouracil (an inhibitor of iodide organification). Six hours following administration of 125I, either potassium perchlorate (10 mg/kg x 2.5 min) or saline was given i.p. Perchlorate significantly reduced the thyroid: blood 125I ratio in propylthiouracil-treated rats but had no effect in those pretreated with SK&F 93479, indicating an iodide organification block in the former. At the same time thyroidal radioiodide accumulation in SK&F 93479-treated rats (no perchlorate) was enhanced, whereas that in propylthiouracil-treated animals (no perchlorate) was depressed.

Animals↗
PubMed1987

Effects of toxic doses of a novel histamine (H2) antagonist on the rat thyroid gland.

The oral administration of high doses of a histamine H2 antagonist SK&F 93479 (up to 1000 mg/kg/day) to male rats for up to 21 days resulted in alterations in thyroid morphology indicative of increased activity of the thyroid gland. Measurement of thyroidal 125I incorporation substantiated these findings. Treatment with SK&F 93479 resulted in a dose-dependent increase in thyroidal iodide incorporation. This was apparent after a single dose of the compound and was reversible after dosing for 7 days. The increased incorporation of 125I into the thyroid gland was apparently dependent on thyroid-stimulating hormone (TSH) since both hypophysectomy and pretreatment with thyroxine (T4) markedly reduced thyroidal 125I uptake. Hypothalamic thyrotropin-releasing hormone (TRH) and pituitary TSH concentrations were not altered by SK&F 93479 treatment, and in TRH challenge experiments circulating TSH concentrations showed no change from control levels. These data suggest that hypothalamic-pituitary sensitivity was unaltered by treatment with SK&F 93479. Pharmacological ablation of thyroidal mast-cell function did not alter the thyroid response to 125I accumulation after SK&F 93479 dosing, indicating that the action of the compound is probably not dependent on changes in thyroid mast-cell histamine. Circulating T4 and TSH levels were altered in SK&F 93479-treated rats. Generally, T4 levels were reduced 6 hr after dosing and TSH levels were elevated 24 hr after dosing. Triiodothyronine (T3) levels were unaffected by SK&F 93479 treatment. The effect of SK&F 93479 treatment on T4 clearance was measured by examining the elimination of radioactivity from the circulation of rats previously injected with 125I-labelled T4. One oral dose of 1000 mg SK&F 93479/kg markedly increased T4 clearance. These results suggest that SK&F 93479 affects thyroid activity indirectly by a primary effect on T4 clearance. Reductions in circulating T4 lead to increased TSH levels and subsequent stimulation of thyroid activity.

Animals↗
PubMed1987

Studies on the effect of chronic L-triiodothyronine (T3) treatment on brain Na+,K+-ATPase activity in the mature rat.

Mature rats were dosed with T3 by different routes and dose-levels at either 0.1 mg/kg for 14 days s.c. (Group A), 1 mg/kg for 3 alternative days i.p. (Group B), 5 mg/kg for 14 days p.o. (Group C), or with propylthiouracil (PTU 50 mg/day for 14 days p.o.-Group D). Measurement of cerebellar and striatal NA+,K+-ATPase activities showed that whereas Groups A, B and D were unaffected when compared with controls, there were 35-70% increases respectively in the activities of both molecular forms of the enzyme, alpha(+), high ouabain affinity, and alpha, low ouabain affinity, in Group C rat brains at the highest dose of T3 tested. Kidney Na+,K+-ATPase activity was also elevated (67% increase) in this group of animals showing significant changes in renal medullary tissue only. Acute elevation of brain dopamine levels by administration of an MAOI plus L-DOPA (50 mg/kg, 60 min) significantly elevated (20% increase) the activities of both molecular forms of Na+,K+-ATPase in corpus striatum. Treatment with L-tryptophan (50 mg/kg, 60 min) failed to produce any changes in the striatal activities. The possible relationship of increases in enzyme activities with T3 and increased brain monoamine function is discussed. Both plasma free T4(FT4) and total T4(TT4) were markedly depressed in all T3-treated rats. Although hypothalamic thyrotropin releasing hormone (TRH) concentrations were unaltered by any of the T3 treatments, pituitary thyroid stimulating hormone (TSH) concentrations were greatly diminished and it is thought that this may reflect a direct effect of T3 on TSH synthesis.

Animals↗
PubMed1985

Serum factors affect Na+ pump activity and DNA synthesis in cultured cerebellar neural cells.

In neurone-enriched cultures derived from early postnatal rat cerebellum and maintained in serum-free medium, addition of serum (10% FCS) evoked a rapid increase in Na+ pump activity (as measured by ouabain-sensitive 86Rb accumulation) by activation of a Na+/H+ exchanger. This effect did not occur with cultured cerebellar astrocytes. In contrast, exposure to serum increased DNA synthesis ([3H]thymidine incorporation) in both cultured cerebellar astrocytes and in the neurone-enriched cultures. However, in the latter cultures this effect was shown by autoradiography to be due to contaminating astrocytes. Thus, in cultured cerebellar neural cells an enhancement of intracellular Na+ accumulation by serum factors may not be linked to initiation of DNA synthesis. Furthermore, raising intracellular Na+ by ouabain exposure actually decreased neural cellular DNA synthesis.

Animals↗
PubMed1985

Effect of thyroid status on the development of the different molecular forms of Na+,K+-ATPase in rat brain.

The effect of thyroid status on the postnatal development of the two molecular forms of Na+,K+-ATPase, distinguished kinetically on the basis of their ouabain sensitivity, was examined in rat brain. Hypothyroidism induced by PTU from day 1 postnatally significantly reduced the Na+,K+-ATPase activity in cerebellum (22-30 days) but not forebrain, whereas hyperthyroidism (T4 treatment from day 1) had no effect. The hypothyroidism-induced reduction in cerebellum was reflected by a 20-45% reduction in the activity of the alpha(+) form of Na+,K+-ATPase (high ouabain affinity) against control brains compared to a 60-70% reduction in the activity of the alpha form (low ouabain affinity). These results show that neonatally induced hypothyroidism leads to a selectively greater impairment of the ontogenesis of the activity of cerebellar alpha form of Na+,K+-ATPase. This may possibly reflect a retarded development of a selective cerebellar cell population containing predominantly the alpha form of the enzyme.

Adenosine Triphosphatases↗
PubMed1985

Effect of thyroid hormone and serum on the development of Na+, K+-adenosine triphosphatase and associated ion fluxes in cultures from rat brain.

The effect of culture conditions, serum supplementation or chemically defined medium and the influence of thyroid hormone were studied on the development of the Na+, K+-adenosine triphosphatase (Na+,K+-ATPase) and on the intracellular content of K+ and Na+ ions in cultures which either were greatly enriched in a neuronal cell type, the cerebellar granule cells, or contained a mixed population of cells (brain reaggregates). Foetal rat brain reaggregates displayed lower Na+,K+-ATPase activity when cultured in chemically defined medium than in the presence of serum. Supplementation of the serum-free medium with thyroid hormone resulted in a rise in the Na+,K+-ATPase activity and [3H]ouabain binding to levels similar to those found in the cultures grown in the serum-containing medium. Thyroid hormone had no significant effect on the Mg2+-ATPase activity and on the intracellular content of Na+ and K+ ions. In the granule cell-enriched cerebellar surface cultures the Na+,K+-ATPase activity was lower when the cells were grown in chemically defined medium compared with the serum-containing medium, and the intracellular Na+ to K+ ratio was higher. Thyroid hormone had no effect on the Na+,K+-ATPase activity, [3H]ouabain binding or Mg2+-ATPase activity. The hormone also failed to influence ATPase activities in cerebellar astrocytes maintained in chemically defined medium. Although thyroid hormone had no effect on the Na+,K+-ATPase activity of cultured cerebellar granule cells, treatment with the hormone resulted in a decrease in the ratio of intracellular Na+ to K+ ion content. The effect of the hormone on the Na+,K+-pump activity in live cells was therefore tested by estimating ouabain-sensitive 86Rb uptake. This was regulated as in other cell types, by the rate of Na+ entry: the Na+-ionophore monensin trebled the rate of 86Rb uptake, which was also increased (+30-100%) by 10% foetal calf serum, the maximal response being obtained by about 20 min exposure to serum. The effect was completely blocked by the Na+/H+ exchange inhibitor amiloride. The factor(s) in the serum responsible for the regulation of the Na+,K+-pump were, however, not the thyroid hormones, which failed to affect 86Rb uptake. On the basis of comparing thyroid hormone effects on the different cultures studied it was concluded that not every type of neural cell is target of the hormone action during development.

Animals↗
PubMed1985

Does thyroid hormone influence the maturation of cerebellar granule neurones?

The following hypotheses were tested: is the degeneration of differentiating granule cells in the internal granular layer of the thyroid deficient cerebellum due to a direct requirement of these cells for thyroid hormone, or is it mediated through the failure of some of these cells to make synaptic contact with the hypoplastic Purkinje cells? The effect of thyroid hormone (T3) was studied in rat cerebellar cultures which contain predominantly granule cells. The cultures were grown in a chemically defined medium (S-) in the presence or absence of T3, and were also compared with serum (and thus thyroid hormone) containing cultures (S+). It would appear that T3 is not essential for the relatively long-term survival of the granule cells. Furthermore, cell growth in terms of protein accretion, and the morphological appearance of the cultures were also similar in S- in the presence and absence of T3. Maturation of granule cells was followed by estimating indices, which in the cerebellum in vivo are influenced by the hormone. However, developmental changes affecting the D2 protein, which is implicated in adhesion among nerve cells, and muscarinic receptor binding were not influenced by T3 in vitro. The voltage (veratridine)-sensitive uptake of 22Na was also unaffected, although T3 increased the rate of the relatively small veratridine insensitive component of the 22Na-influx. However, in comparison with cells grown in S+, the rate of both the veratridine sensitive and insensitive component of 22Na-influx was similar under serum-free conditions, whereas the maturation of the D2 protein and muscarinic receptor binding was retarded. The failure of thyroid hormone to influence the differentiation of granule cells, is not due to the in vitro conditions, since T3 is known to have a marked effect on the maturation of certain other classes of neural cells in culture. The results are consistent with the view that the effect of thyroid hormone on neural maturation is cell-type specific, and that granule cells are not targets of thyroid hormone action. They support our second hypothesis, that is, that the degeneration of granule cells in thyroid deficiency is a consequence of the reduction in available postsynaptic sites for the granule cell axons due to the retarded differentiation of Purkinje cells.

Animals↗