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Biomedical subjects

J Van Sande

Publications and source records attributed to J Van Sande.

At least 109 records · Page 6Linked to original sources
PubMed1982

Inhibition of the cyclic AMP-adenylate cyclase system and of secretion by high concentrations of adenosine in the dog thyroid.

Adenosine inhibits cyclic AMP accumulation in stimulated slices and adenylate cyclase in acellular preparations of dog thyroid. The onset of this inhibition is rapid, requires relatively high adenosine concentrations (greater than or equal to 10 microM) and occurs with all activators tested (TSH, PGE1, forskolin and cholera toxin). The manganous ion, which uncouples receptor and cyclase, enhances the inhibition by adenosine. The effect of 2',5'-dideoxyadenosine, the high concentration of adenosine needed, the Mn2- effect and the lack of reversal by methylxanthines all suggest that this effect bears on the "P"-site, i.e. on the cyclase itself. Adenosine also inhibits thyroid secretion, which shows that its effect bears on the follicular cells. However the fact that cyclic AMP and DB cyclic AMP induced secretion are also reduced by adenosine suggests that adenosine also inhibits cyclic AMP action.

Adenosine↗
PubMed1982

Cooling enhances adenosine 3':5' monophosphate accumulation in thyrotropin stimulated dog thyroid slices.

Dog thyroid slices have been stimulated in vitro by thyrotrophin (TSH) at 37 degrees C and 25 degrees C. Adenosine 3':5'-monophosphate (cyclic AMP) accumulation was enhanced by cooling to 25 degrees C. This observation has been extended to kidney cortex slices stimulated by parathyroid hormone (PTH). However, this phenomenon is not general: it does not apply to thyroid slices stimulated by prostaglandin E1 (PGE1) or adrenal cortex slices stimulated by adrenocorticotrophic hormone (ACTH). Slight cooling provides a useful tool to influence biochemical mechanisms in intact cells and therefore the mechanism of action of cooling on cyclic AMP was investigated in dog thyroid slices stimulated by TSH. Adenylate cyclase and cyclic nucleotide phosphodiesterase activities as measured in acellular preparations decreased in parallel with the temperature. A decrease of the cyclic AMP efflux from the cell at 25 degrees C, although not measurable in this preparation, did not seem to be responsible for the phenomenon. computer simulation of the kinetics of the cyclic AP accumulation curve is compatible with the hypothesis of decrease in the desensitization rate of adenylate cyclase at 25 degrees C. This was demonstrated using an experimental protocol in intact slices and by measurements of adenylate cyclase activities in particulate preparations of slices pretreated or not by the hormone. This decreased adenylate cyclase desensitization can explain the higher cyclic AMP levels in TSH stimulated thyroid slices incubated at 25 degrees C. However, this does not exclude complementary mechanisms.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1980

In vitro effects of arachidonic acid and of inhibitors of its metabolism on the dog thyroid gland.

Incubation of dog thyroid tissue with arachidonic acid (10 to 200 microM) led to the following events: --low conversion to prostaglandins E2 and F2 alpha: 0.07% and 0.02% per hour and 100 mg tissue, respectively --inhibition of the stimulatory effect of low concentrations of TSH on thyroid secretion: the secretory effect of supra-maximal concentrations of TSH and of dB-cAMP was unaffected --inhibition of the cyclic AMP accumulation induced by TSH: this effect was inhibited neither by indomethacin nor by ETYA; cyclic AMP accumulation in response to cholera toxin or PGE1 was unaffected --no effect on cyclic GMP level --stimulation of thyroid proteins iodination. ETYA, but not indomethacin, depressed the iodination of thyroid proteins in resting and stimulated tissue. These data show that arachidonic acid-or a metabolite-can modulate thyroid responsiveness to TSH and suggest that lipoxygenase-products of arachidonic acid metabolism could be involved in thyroid proteins iodination.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1980

The role of calcium and guanosine 3':5'-monophosphate in the action of acetylcholine on thyroid metabolism.

The role of calcium and guanosine 3':5'-monophosphate (cyclic GMP) in the regulation of thyroid metabolism has been investigated in dog thyroid slices. Carbamoylcholine enhanced glucose carbon-1 oxidation, protein iodination, cyclic GMP accumulation and decreased thyrotropin-induced adenosine 3':5'-monophosphate (cyclic AMP) accumulation and iodine secretion; it did not affect protein synthesis. The effects of carbamoylcholine were reproduced under various experimental conditions by supplementary calcium in the medium, ouabain, and in media in which Na+ had been replaced by choline chloride. They were inhibited by lanthanum. These results further support the hypothesis that free intracellular Ca2+ is the intracellular signal for carbamoylcholine effects and suggest that a Na+ -gradient-driven Ca2+ extrusion mechanism operates in the thyroid cell. Mn2+ reproduced the effect of Ca2+ on glucose oxidation, protein iodination and cyclic GMP accumulation in Ca2+ -depleted slices and medium, and thus mimicked some intracellular effects of Ca2+. On the other hand Mn2+ inhibited the carbamoylcholine effect on thyrotropin-induced thyroid secretion and cyclic AMP accumulation, and Ca2+ inhibited the Mn2+-induced cyclic GMP accumulation. This suggests that the two ions compete for the same channel. Similarly Mn2+ inhibited calcium effects in the presence of ionophore A23187. Procaine inhibited protein iodination under all conditions suggesting a primary effect; it also inhibited all carbamoylcholine and ouabain actions. However the drug did not inhibit the effects of choline chloride and its action was reversed by raising carbamoylcholine but not Ca2+ concentration; it is therefore doubtful that procaine acts by blocking Ca2+ channels. In media without added Ca2+, Mn2+ increased cyclic GMP accumulation but did not decrease thyrotropin-induced cyclic AMP accumulation or iodine secretion, which suggests that cyclic GMP cannot be the sole mediator of the latter two effects of carbamoylcholine.

Acetylcholine↗
PubMed1980

Regulation of cyclic nucleotide and prostaglandin formation in normal human thyroid tissue and in autonomous nodules.

We have investigated the regulation of the human throid gland based on controls discovered in the dog thyroid gland. TSH and thyroid-stimulating immunoglobulin enhanced cAMP accumulation, which supports the validity of the Sutherland model for the action of TSH on the human thyroid. Iodide inhibited TSH- and thyroid-stimulating immunoglobulin-activated cAMP accumulation and this effect was reduced by methimazole, showing that, in this tissue, iodide, through an oxidized derivative, depresses the TSH-cAMP system. Contrary to the hypothesis of a short feedback loop of thyroid hormone, no thyroid effect of T3 or T4 was found. Adrenergic agents (norepinephrine and isoproterenol) enhanced cAMP accumulation; this effect was inhibited by dl-propranolol but not by d-propranolol or phentolamine. This suggests a positive control of the thyroid cAMP system by beta-adrenergic receptors. Histamine also increased cAMP accumulation. However, the role of these controls is unknown. Acetylcholine, by a muscarinic type effect, enhanced cGMP accumulation and prostaglandin E2 and prostaglandin F2 alpha release. These effects were mimicked by ionophore A23187 and abolished in a calcium-deprived medium, which suggests that they are secondary to a raised Ca++ influx. The results are summarized in a general working model of human thyroid regulation. These biochemical controls have been compared in normal tissue and autonomous nodules. No evidence of increased sensitivity to TSH of the nodular tissue was found. On the other hand, this tissue was less sensitive to acetylcholine (cGMP accumulation) and more sensitive to norepinephrine (cAMP accumulation).

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1980

Presence and influence of cholinergic nerves in the human thyroid.

There is evidence that the sympathetic nervous system exerts a control on human thyroid function via an adrenergic innervation of follicle cells. The present study demonstrates that cholinergic nerve fibers also reach follicle cells in the normal human thyroid. In addition, cholinergic agents were found to enhance cGMP accumulation in human thyroid tissue. This effect was blocked by atropine, a muscarinic receptor antagonist, but not by d-tubocurarine, a nicotinic receptor antagonist. These results provide morphological and biochemical arguments supporting a role of the parasympathetic nervous system in the regulation of thyroid function in man.

Acetylcholine↗
PubMed1978

Uncoupling by cooling of secretion and adenosine 3',5'-monophosphate accumulation in stimulated dog thyroid slices.

Thyroid metabolism undergoes general activation in the presence of TSH. Secretion, [1-14C]-glucose oxidation, protein iodination, and cyclic AMP (cAMP) accumulation are stimulated. In intact tissue, it is difficult to dissociate effects of cAMP itself and effects secondary to cAMP-induced secretion. We report herein that cooling to 20 C dissociates the action of TSH on secretion from all its other effects. At this temperature, TSH stimulation of secretion was completely inhibited whereas cAMP accumulation was enhanced. The TSH effect on [1-14C]glucose oxidation was maintained and its action on protein iodination was diminished but not abolished. The ATP content was not decreased. The mechanism of action of cooling was investigated. No pseudopod formation of intracellular colloid droplets were observed by scanning electron microscopy and transmission electron microscopy, thus indicating that the inhibition affects the first step of secretion, i.e., colloid phagocytosis. Microtubules were not seen at 2 C but were normally present at 20 C. The data are compatible with the hypothesis that inhibition of phagocytosis at 20 C could be a consequence of a lipid phase transition in the membrane.

Animals↗
PubMed1978

[Calcium, cGMP and cAMP roles in thyroid regulation (author's transl)].

Cholinergic agents induce an accumulation of cGMP in thyroid tissue and inhibit cAMP accumulation and thyroid hormone secretion resulting from TSH action. The aim of the present work was to determine the respective roles of Ca++ and/or cGMP in these actions. The results show that two complementary mechanisms may be demonstrated: 1) cGMP activates phosphodiesterase activity and cAMP hydrolysis. 2) Independently of cyclic nucleotide concentrations, increased intracytoplasmic Ca++ directly inhibits TSH induced stimulated hormone secretion.

Animals↗
PubMed1977

Cyclic nucleotide hydrolysis in the thyroid gland. General properties and key role in the interrelations between concentrations of adenosine 3':5'-monophosphate and guanosine 3':5'-monophosphate.

Phosphodiesterase activities of horse (and dog) thyroid soluble fraction were compared with either cyclic AMP (adenosine 3':3'-monophosphate) or cyclic GMP (guanosine 3':5'-monophosphate) as substrate. Optimal activity for cyclic AMP hydrolysis was observed at pH 8, and at pH 7.6 for cyclic GMP. Increasing concentrations of ethyleneglycol bis(2-aminoethyl)-N,N'-tetraacetic acid inhibited both phosphodiesterase activities; in the presence of exogenous Ca2+, this effect was shifted to higher concentrations of the chelator. In a dialysed supernatant preparation, Ca2+ had no significant stimulatory effect, but both Mg2+ and Mn2+ increased cyclic nucleotides breakdown. Mn2+ promoted the hydrolysis of cyclic AMP more effectively than that of cyclic GMP. For both substrates, substrate velocity curves exhibited a two-slope pattern in a Hofstee plot. Cyclic GMP stimulated cyclic AMP hydrolysis, both nucleotides being at micromolar concentrations. Conversely, at no concentration had cyclic AMP any stimulatory effect on cyclic GMP hydrolysis. 1-Methyl-3-isobutylxanthine and theophylline blocked the activation by cyclic GMP of cyclic GMP of cyclic AMP hydrolysis, whereas Ro 20-1724 (4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone), a non-methylxanthine inhibitor of phosphodiesterases, did not alter this effect. In dog thyroid slices, carbamoylcholine, which promotes an accumulation of cyclic GMP, inhibits the thyrotropin-induced increase in cyclic AMP. This inhibitory effect of carbamoylcholine was blocked by theophylline and 1-methyl-3-isobutylxanthine, but not by Ro 20-1724. It is suggested that the cholinergic inhibitory effect on cyclic AMP accumulation is mediated by cyclic GMP, through a direct activation of phosphodiesterase activity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1977

Adenosine 3':5'-monophosphate metabolism and turnover in dog thyroid slices.

The metabolism and turnover of adenosine 3':5'-monophosphate (cyclic AMP) have been studied in intact thyroid cells incubated in vitro. Thyroid slices have been stimulated by 1 mU thyrotropin/ml, then washed with buffer, or with buffer containing thyrotropin antibody, or trypsin so as to cut off the stimulation. The decline of cyclic AMP levels has been followed and the time required to decrease this level to half of the initial value estimated. Computer simulation taking into account the penetration of trypsin in the slices, the kinetics of thyrotropin inactivation and the relation between thyrotropin concentration and cyclic AMP concentration at the steady state has made it possible to estimate the true cellular half-life of cyclic AMP in the stimulated cell to 1 min 50 s. The method provides an experimental approach to the demonstration in intact cells of effective on cyclic AMP disappearance. The methodology of the calculation of half-life and turnover from such data is discussed.

Animals↗
PubMed1977

Negative control of TSH action by iodide and acetylcholine: mechanism of action in intact thyroid cells.

Iodide, a substrate of thyroid metabolism, and acetylcholine depress cyclic AMP intracellular content and secretion in dog thyroid slices under TSH stimulation. A direct or indirect pseudocompetitive effect at the level of TSH receptor interaction has been rejected. Iodide and carbachol, both inhibited cyclic AMP accumulation in TSH stimulated dog thyroid slices but only the effect of carbachol was suppressed in the presence of isobutylmethylanthine. Ro 20-1724 did not relieve either inhibitory effect. Carbachol greatly enhanced cyclic AMP disposal in TSH prestimulated slices after the cut off of hormone action by a trypsin treatment. This effect was also suppressed by isobutylmethylxanthine but not by Ro 20-1724. No action of iodide could be evidenced on cyclic AMP disposal in similar slices, although a clear effect after the same time of iodide action was observed on cyclic AMP accumulation. Neither carbachol, nor iodide depresses ATP levels in these slices. The data suggest that carbachol exerts its action through an activation of cyclic AMP disappearance probably by an activation of cyclic AMP phosphodiesterase and that iodide, through an oxidized intermediate, experts its inhibitory effect at the level of cyclic AMP synthesis.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1976

Kinetics of adenosine 3':5'-monophosphate accumulation in dog thyroid slices.

Dog thyroid slices have been stimulated in vitro by thyrotropin. The kinetics of adenosine 3':5'-monophosphate (cyclic AMP) accumulation due to the activation of adenylate cyclase were measured. Experimental results have been interpreted by means of a numerical simulation based on a theoretical description of the overall process which consists of three steps: (a) the penetration of thyrotropin in the slices, (b) the binding of the hormone to the specific receptor and the consequent activation of adenylate cyclase, (c) the kinetics of cyclic AMP accumulation in each cell due to the interplay between synthesis and degradation. The numerical values of the parameters needed for the simulation were deduced from separate experiments. Diffusion of thyrotropin in the slices has been calculated from the kinetics of efflux of [3H]sucrose, and with or without albumin. Adenylate cyclase activity and activation by thyrotropin in homogenates and purified membranes were measured. Binding experiments of cyclic AMP on crude extract of dog thyroid lead to the conclusion that the maximal capacity of the specific binding site is close to the cyclic AMP content in resting thyroid cells. The purpose of this paper is to verify the validity of the current concepts about the mechanisms taking place in this process by comparing experimental results and theoretical simulation. It results from the study that for this system the time between the activation of adenylate cyclase and half maximal cyclic AMPaccumulation is equal to 3 min 45 s and the pool of cyclic AMP is renewed three times per minute. It has been also stressed that the thickness of the slices as well as inhibitors of phosphodiesterases change the apparent kinetics of cyclic AMP accumulation.

Adenylyl Cyclases↗