Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipolysis and intracellular levels of cyclic AMP of adipose tissue from man and rat in both hypothyroid and euthyroid states were studied in response to stimulation by catecholamines in vitro. Hypothyroid patients were studied before and after treatment, and were also compared with euthyroid obese controls. The experimental group of rats was rendered hypothyroid by the addition of 2.9 mM-propylthiouracil to their drinking water, and their status confirmed by plasma thyroid function tests. Evidence for alpha-adrenergic receptor activity was found in rat adipose tissue, but was less marked than the pronounced alpha-adrenergic activity in human adipose tissue. Glycerol release from adipose tissue in response to noradrenaline stimulation was less marked in hypothyroidism in both species, and was related to an increased alpha-adrenergic activity. No evidence was found for increased alpha-adrenergic effects on cyclic AMP level in hypothyroid subjects, and little evidence was found in adipose tissue from hypothyroid rats. This discrepancy may be due to the presence of the phosphodiesterase inhibitor, theophylline, in the incubation system. The possible modulatory role of thyroid hormones on receptor and phosphodiesterase activity, and on lipolysis, is discussed.
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PMID:Alpha-adrenergic receptor activity, cyclic AMP and lipolysis in adipose tissue of hypothyroid man and rat. 17 7

The in vitro effects of insulin on different phosphodiesterase activities present in rat epididymal fat cells from normal and hypothyroid rats have been studied. Evidence is presented that insulin increases the maximum velocity of a particulate, low Km, cyclic adenosine-3', 5'-monophosphate (cyclic AMP) phosphodiesterase in both types of cells, this effect being more clearly evident with the fat cells from hypothyroid animals; combination of insulin and thyroidectomy resulted in a 400% stimulation with 10-10 - 10-9 M insulin. A clear and significant effect was apparent at 10-11 M insulin. However, the dose-response curve was biphasic, since stimulation by insulin was suppressed for doses of hormone higher 10-8 - 10-7 M. Moreover, insulin effects were very fast, since clear stimulation was observed after only 2 min of incubation; the maximal increase was obtained after 10 min. Insulin did not significantly affect the soluble cyclic AMP phosphodiesterase activity in normal cells, thus confirming results obtained by others. However, the soluble cyclic AMP phosphodiesterase activity was clearly stimulated by insulin when the fat cells were prepared from hypothyroid rats. Maximal stimulation was obtained with 10-9 M insulin; the response was again very fast. Soluble cyclic GMP phosphodiesterase activity was also increased additively by hypothyroidism and insulin, maximal stimulation being obtained with 10-9 M insulin. With this dose of insulin the additive effects of thyroidectomy and insulin produced a 5-fold stimulation. The effect of insulin on the soluble cyclic GMP phosphodiesterase was very fast (2-5 min). With both soluble cyclic nucleotide phosphodiesterase activities, insulin increased the maximal velocity but not apparent Km of the enzyme. Thus, hypothyroidism and insulin produced additive effects suggesting a different mechanism of action of these two hormonal situations on the degradation of the intracellular pools of cyclic AMP and cyclic GMP.
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PMID:Cyclic nucleotide phosphodiesterases, insulin and thyroid hormones. 18 75

Previous observations that cyclic 3',5'-nucleotide phosphodiesterase activity exists in mammalian sera including human serum prompted us to investigate the phosphodiesterase levels in sera of patients with various thyroid disorders. Both serum cyclic AMP phosphodiesterase (cAMP-PDE) and cyclic GMP phosphodiesterase (cGMP-PDE) activities measured in a low substrate concentration were elevated 3-fold in subacute thyroiditis and slightly in hyperthyroidism, compared to the normal. Slight decreases of these enzyme activities were observed in primary hypothyroidism. PDE activities were positively correlated with the value of T3-RSU and serum thyroid hormone levels in hyper- and hypothyroidism. Altered enzyme activities returned to normal during the course of recovery. Identical results were obtained when plasma was tested. These results suggest that serum PDE activities may be partly related to the thyroid function.
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PMID:Serum cyclic 3',5'-nucleotide phosphodiesterase in patients with various thyroid disorders. 298 79

The effects of thyroid status on the activity of hepatic cAMP phosphodiesterase (PDE) were studied in the rat. Male rats were rendered hyperthyroid by treatment with T3 or hypothyroid by treatment with propylthiouracil. The hepatic particulate low Km PDE was solubilized, and its activity was measured at concentrations of 0.12-1.3 microM cAMP. The Km decreased in hypothyroidism and tended to increase in hyperthyroidism with respect to individual controls. The maximal velocity (Vmax) was unaffected by changes in thyroid status. The increases in Km correlated with increasing plasma T3, whereas the Vmax did not. Concentrations of cAMP increased in the livers from hyperthyroid rats and decreased in those from hypothyroid, in comparison with euthyroid rat livers. The effects of thyroid status on various aspects of hepatic lipid metabolism reported from this laboratory may, in part, have resulted from alterations in hepatic cAMP concentrations. These alterations, may have resulted secondarily from changes in the activity of hepatic PDE by changes in the Km for cAMP with little change in the Vmax.
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PMID:Modulation by thyroid status of hepatic low Km phosphodiesterase. 627 22

Between the 4th and 10th days of postnatal life in the rat, serum corticosterone levels were low and basal, while the rate of [3H]thymidine incorporation into lung DNA was maximal. From day 13, serum corticosterone levels began to rise significantly, and the lung [3H]thymidine incorporation rate began to fall dramatically; however, these events were obtunded by propylthiouracil-induced hypothyroidism. When 6- to 8-day-old euthyroid pups were given a single sc injection of 10 micrograms dexamethasone, the rate of DNA synthesis in the lung fell by 96.7% of the initial rate at 24 h. This steroidal effect was blunted in hypothyroid pups and restored by exogenous thyroid hormone. The thyroid status of the pup did not modify the response patterns of lung phosphodiesterase and cytosolic glucocorticoid receptor levels to dexamethasone treatment, although both parameters were influenced by thyroid hormone availability. Radiocholine incorporation into lung phospholipids, which was altered in hypothyroidism, was unaffected by dexamethasone treatment. An in vivo assessment of radiothymidine incorporation into DNA of various tissues in 5-day-old euthyroid pups given 10 micrograms dexamethasone 24 h earlier revealed that of the several tissues in which inhibition of DNA synthesis was demonstrable, the developing lung was the most sensitive to the anti-mitogenic steroidal effect. When considered in the light of existing evidence, these observations suggest that glucocorticoids play an important role in triggering lung cytodifferentiation during the third postnatal week in the rat, and that preconditioning of the lung by thyroid hormone optimizes this developmental effect of glucocorticoids.
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PMID:Influence of glucocorticoids on postnatal lung development in the rat: possible modulation by thyroid hormone. 712 28

The two isomers of the positive inotropic compound EMD 53998, (+)EMD 57033 and (-)EMD 57439, possess selective calcium sensitizing and phosphodiesterase (PDE) inhibitory properties, respectively. We measured the pharmacological responses to both enantiomers in isolated rat cardiac and vascular tissues and in muscles from severely failing human hearts. We also measured positive inotropic and chronotropic responses to EMD 57033 in cardiac tissues from rats with thyroid dysfunction, diabetes, or hypertension. Both compounds increased force of contraction in isolated rat cardiac tissues, although the ventricular response to EMD 57439 was only approximately 10% that of calcium chloride. Forskolin pretreatment potentiated responses to both compounds in atria but only to EMD 57439 in ventricles. Hyperthyroidism increased ventricular responses to EMD 57033 relative to calcium chloride; hypothyroidism and diabetes decreased these responses. Ventricular responses were unchanged in hypertensive rats. Both enantiomers produced positive inotropy in human isolated right atrial trabeculae, although the maximal increases were only 14% (EMD 57033) and 26% (EMD 57439) that of calcium chloride. In rat thoracic aortic rings, both enantiomers produced relaxation; the responses due to EMD 57033 were endothelium dependent. Thus, calcium sensitization produces positive inotropy and vascular relaxation in rats. Positive chronotropic responses to EMD 57033 are most likely due to PDE inhibition. The limited inotropic response in severely failing human myocardium, together with possible vasorelaxation, may provide cardiac support in heart failure without an excessive increase in cardiac O2 demand.
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PMID:Calcium sensitization as a positive inotropic mechanism in diseased rat and human heart. 752 44

The aim of this study was to determine (i) whether phosphodiesterase inhibitors influenced ATPase activity of maximally calcium activated cardiac myofibrils and (ii) whether this effect varied in relation to isomyosin composition. Myofibrils were prepared from ventricular myocardium of 2- to 3-month-old rats. ATPase activity was determined at low ionic strength at high (> 7.5) and low (4.4) pCa. Five compounds (amrinone, milrinone, enoximone, piroximone, and rolipram) were examined at concentrations between 10 microM and 1 mM. The results obtained showed that only milrinone and amrinone inhibited ATPase activity; inhibition was dose dependent, and milrinone was more potent than amrinone. To assess whether isomyosin composition might influence the responsiveness of myofibrils to phosphodiesterase inhibitors, the effect of 1 mM milrinone was also determined in myofibrils from hypothyroid rats. According to previous observations hypothyroidism caused an isomyosin shift from V1 to V3 in rat ventricular myocardium. The inhibitory effect of milrinone was lower in myofibrils prepared from hypothyroid rats than in myofibrils from euthyroid rats.
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PMID:Direct depressant effect of phosphodiesterase inhibitors on ATPase activity of rat cardiac myofibrils. 758 34

Brown adipose tissue (BAT) thermogenesis is activated by the sympathetic nervous system. BAT responses to norepinephrine are blunted in hypothyroidism and are rapidly restored by thyroid hormone. We examined in rats the effects of thyroid hormone on BAT beta 1- and beta 2-adrenergic receptors (AR) expression and capacity to generate cAMP in response to adrenergic stimulation. Both are reduced in hypothyroidism. The reduction in cAMP generation is equal to or greater than that in beta 1,2-AR; it is the same whether cAMP production is stimulated with norepinephrine, selective beta 3-AR agonists, or forskolin; and it is not affected by the inhibition of phosphodiesterase. Both beta 1,2-AR and the capacity to generate cAMP were slowly corrected by thyroid hormone. T3 normalized beta 1,2-AR between 1 and 2 days, whereas the improvement in cAMP generation lagged 1 or 2 days behind. Within 2 days of acclimation of athyreotic rats at 30 C, the number of beta 1,2-AR reached the euthyroid level, whereas exposure to 4 C decreased these receptors. We reached the following conclusions: 1) BAT beta 1,2-AR and capacity to generate cAMP are reduced in hypothyroidism; 2) the latter, however, is not explained by the reduction in beta 1,2-AR, but, rather, reflects a fault at the postreceptor level; 3) the reduction in beta 1.2-AR number is largely caused by the cold stress derived from the low metabolic rate of the hypothyroid state; and 4) the slow restoration of both receptor number and capacity to generate cAMP after T3 are not consistent with these defects being a significant factor in the previously reported blunted uncoupling protein responses to adrenergic stimulation in hypothyroidism.
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PMID:Effects of thyroid hormone on norepinephrine signaling in brown adipose tissue. I. Beta 1- and beta 2-adrenergic receptors and cyclic adenosine 3',5'-monophosphate generation. 762 60

Rats were made hypothyroid by adding propylthiouracil (PTU) to their drinking water. Some of the PTU-treated rats were given thyroid hormone injections for 5 days. Both soluble and particulate cAMP-phosphodiesterase activities of adipose and ventricular tissues were increased by 25-60% in hypothyroidism. In left atria, soluble cAMP-phosphodiesterase activity was not significantly altered in hypothyroidism, while total particulate cAMP-phosphodiesterase activity was lowered by 30%. This lowering was due to diminished isoenzyme IV activity, as studied with the isoenzyme-specific inhibitors rolipram and SK&F 94836. In conclusion, the present results show decreased particulate type IV cAMP-phosphodiesterase activity in hypothyroid rat atria. This may explain the increased responsiveness to isoproterenol in hypothyroid atria.
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PMID:Low particulate type IV phosphodiesterase activity in hypothyroid rat atria. 773 Oct 53

The influence of thyroid hormones on the adrenergic regulation of lipolysis was studied in isolated adipocytes removed from the gluteal region of hyper- and hypothyroid women and compared in adipocytes from euthyroid normal women. Noradrenaline significantly enhanced lipolysis in hyperthyroid patients, whereas noradrenaline inhibited lipolysis in hypothyroid patients compared to that in controls. Moreover, beta-adrenergic sensitivity and responsiveness were 10- and 2-fold increased, respectively, in hyperthyroid patients. In hypothyroid patients, beta-adrenoceptor responsiveness was reduced by 50%, whereas beta-adrenergic sensitivity remained unchanged compared with that in controls. Furthermore, the alpha 2-adrenergic and adenosine-induced antilipolytic effects were similar in all thyroid states. The lowered beta-adrenergic responsiveness seen in hypothyroidism could be mimicked by agents acting at the levels of phosphodiesterase (enprofylline), adenylate cyclase (forskolin) and protein kinase (dibutyryl cAMP). In hyperthyroidism, the increased beta-adrenergic sensitivity and responsiveness were not seen when lipolysis was stimulated at the adenylate cyclase, phosphodiesterase, or protein kinase levels. There was no change in the numbers of adipocyte beta- and alpha 2-adrenoceptors in hypothyroidism. However, the number of beta-adrenergic binding sites was doubled, whereas the fraction and affinities of isoprenaline high affinity sites remained unchanged in hyperthyroidism. Thus, the influence of thyroid hormone on catecholamine-stimulated lipolysis in man acts through different mechanisms when adipocytes are exposed to high or low levels of thyroid hormones. In hyperthyroidism, lipolysis adapts to increasing energy demands through an increase in the beta-adrenoceptor number and, thus, a more effective coupling of the adenylate-cyclase complex. In hypothyroidism, the low lipolytic effect of catecholamines seems to be mainly due to an impairment at the protein kinase level or to the hormone-sensitive lipase itself.
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PMID:Adrenergic regulation of lipolysis in fat cells from hyperthyroid and hypothyroid patients. 815 18


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