Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The content of cyclic nucleotides and the activity of adenylate and guanylate cyclases as well as of cAMP phosphodiesterase in the human hyperplastic adrenals were determined after one- and two-step bilateral adrenalectomy for Itsenko-Cushing's disease. A decrease in cGMP concentration and a corresponding increase in cAMP/cGMP correlation were seen in the 2nd hyperplastic adrenal comparatively to those in the 1st one. An enhanced basal activity of adenylate cyclase and its lowered sensitivity to ACTH were found in the 1st and the 2nd adrenals. These changes correlate with a rise in the blood ACTH concentration in patients after the ablation of one adrenal. It is suggested that the augmented adenylate cyclase activity leads to an increased activation of steroidogenesis enzymes in the rest adrenal, ensuring the elevated rate of corticosteroid secretion. The nature of changes in guanylate cyclase activity is contrary to that of adenylate cyclase; namely, guanylate cyclase basal activity of the 2nd hyperplastic adrenal was shown to be lower than that of the 1st one. The cAMP phosphodiesterase activity in the 1st and the 2nd adrenals remained unchanged.
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PMID:[Adenylate and guanylate cylase system function in human hyperplastic adrenals in Itsenko-Cushing disease]. 614 97

Primary culture of bovine adrenal subcapsular cells was used to investigate direct effects of catecholamines on aldosterone secretion. Cells dispersed with collagenase and DNAse and cultured at high density (1.5-2 million/ml) for 3 days displayed high sensitivity to angiotensin II and ACTH, with an ED50 of 1.4 and 1.5 nM, respectively. Adrenergic agonists elicited a 4- to 6-fold stimulation of aldosterone secretion with potency order (-)isoproterenol greater than (-)epinephrine equals (-)norepinephrine greater than (+)isoproterenol, and corresponding ED50 5, 240, 213, and 3000 nM, respectively. No reproducible inhibition by dopamine of basal or stimulated levels of aldosterone secretion could be detected, but a weak stimulatory effect was sometimes observed at high concentration greater than 10 microM. (-)Isoproterenol stimulation of aldosterone production was potently inhibited by the beta-adrenergic antagonists (-)alprenolol and (+)alprenolol with potencies of 1.8 and 110 nM, respectively. The alpha-adrenergic antagonists prazosin, yohimbine, and phentolamine only weakly inhibited (-)isoproterenol stimulation with potencies of 5, 13, and 140 microM, respectively. The potent beta 2-adrenergic antagonist ICI 118.551 and the weaker beta 1-adrenergic antagonist atenolol were roughly equipotent with potencies of 0.27 and 0.44 microM, respectively. Addition of the phosphodiesterase inhibitor Ro 20-1724 at 10 microM doubled the maximum stimulation effect of (-)isoproterenol without changing the potency of the catecholamine or the basal level of aldosterone secretion, suggesting a potential role of cAMP as a mediator of isoproterenol stimulation. These results indicate the presence of a beta 1-adrenergic receptor stimulating aldosterone secretion in bovine zona glomerulosa cells. The physiological significance of direct beta-adrenergic stimulation of aldosterone production is currently being assessed.
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PMID:Direct beta-adrenergic stimulation of aldosterone secretion in cultured bovine adrenal subcapsular cells. 614 9

The ability of hormones to activate responses in a variety of tissues decreases with age. The mechanism(s) responsible for these alterations are unclear. We have confirmed that the ability of a beta-adrenergic receptor agonist to activate lipolysis in isolated rat adipocytes decreases with age. Maximum response to isoproterenol was greater in 2-mo-old rats (600 +/- 30 nmol of glycerol released/10(5) cells per h) than 12-mo-old rats (250 +/- 25 nmol/10(5) cells per h), P less than 0.001. Similarly, ACTH is less effective in activating lipolysis in the adipocytes from the older rats. However, the cAMP analogue 8-(4-chlorophenothio)adenosine 3',5'-monophosphate cyclic activated lipolysis equally in the two groups, suggesting that the deficit in adipocytes from the older rats was proximal to cAMP-dependent protein kinase activation. Both isoproterenol and ACTH were significantly less effective in promoting cAMP accumulation in adipocytes isolated from 12-mo-old rats. There was no difference in phosphodiesterase activity of the adipocytes between the two groups. beta-Adrenergic receptors were measured using the antagonist radioligand [125I]cyanopindolol. The number of beta-adrenergic receptors was actually increased in the adipocytes from 12-mo-old rats (26,000 +/- 2,600 receptors/cell) compared with cells from 2-mo-old rats (7,200 +/- 1,300 receptors/cell). The results suggest that diminished cAMP production is responsible for the diminished lipolytic response in the adipocytes of older rats. The mechanism responsible for this change is uncertain but cannot be explained by a loss in beta-adrenergic receptors.
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PMID:Age-related decrement in hormone-stimulated lipolysis. 615 Jun 43

The present study examined the involvement of prostaglandins (PGs) in the mechanisms of ACTH and beta-endorphin release from rat anterior pituitary quarters incubated in vitro. Various cyclooxygenase inhibitors (indomethacin, diclofenac, flurbiprofen) had no effect on basal release of ACTH-like or beta-endorphin-like immunoreactivity (beta-EI), but enhanced ACTH-immunoreactivity/beta-EI release upon stimulation by arginine-vasopressin (AVP) or synthetic ovine corticotropin-releasing factor [CRF-(1-41)]. The lowest effective concentration of indomethacin was just sufficient to prevent PG synthesis. Indomethacin was similarly active after blockade of the phosphodiesterase by 3-isobutyl-1-methylxanthine. When added to the incubation media in concentrations up to 1 microM, PGE2, D2, F2 alpha, or prostacyclin (PGI2) did not alter basal beta-EI release; however, with stimulation by AVP or CRF-(1-41), PGE2 but not PGD2, F2 alpha, or I2 inhibited beta-EI release by about 60%. The concentrations of PGE2 in the incubation media, as measured by RIA, were somewhat higher than those of any other cyclooxygenase product (PGD2, F2 alpha, 6-keto-PGF1 alpha, thromboxane B2). Upon stimulation by AVP or CRF-(1-41), the concentrations of PGE2 increased, whereas those of PGD2 or F2 alpha remained unchanged. The release of beta-EI stimulated by high potassium concentration was not enhanced by indomethacin, although this release was sensitive to inhibition by PGE2. We conclude that PGE2 is formed locally subsequent to binding of the neurohormones and may act as a negative feedback-modulator of vasopressin's and CRF-(1-41)'s activity in the anterior pituitary gland.
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PMID:Adrenocorticotropin and beta-endorphin release from rat adenohypophysis in vitro: inhibition by prostaglandin E2 formed locally in response to vasopressin and corticotropin-releasing factor. 620 54

Effects of seiwhale somatotropin (STH), its biologically active fragment 77--107, porcine corticotropin (ACTH) and seiwhale prolactin on phosphodiesterase and adenylate cyclase activity of glial cells and synaptosomes isolated from the rat brain cortex were investigated. As compared with control, ACTH increased phosphodiesterase activity of glial cells by 392%, of synaptosomes by 123%, while STH by 49 and 77%, respectively, somatotropin fragment by 455 and 74%, and prolactin by 30 and 37%, respectively. Adenylate cyclase activity was significantly changed only by ACTH and only in synaptosomes (a 50% decrease). STH, its fragment and prolactin virtually failed to alter adenylate cyclase activity. The data obtained indicate that some of pituitary hormones, primarily ACTH and STH, may play the role of neuromodulators in some brain structures by decreasing the cyclic AMP level, by activating phosphodiesterase (STH and ACTH) and inhibiting adenylate cyclase (ACTH in synaptosomes).
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PMID:[Effect of pituitary hormones on phosphodiesterase and adenyl cyclase activity of brain tissue in vitro]. 626 49

The first step in the stimulatory action of most polypeptide hormones, including ACTH, is interaction with a specific target organ plasma membrane receptor. Theophylline, a nonspecific stimulus of several endocrine processes, does so presumably by circumventing the receptor step and directly increasing cAMP by inhibiting phosphodiesterase-mediated hydrolysis. Five patients with adrenal insufficiency, documented by a lack of cortisol secretion in response to exogenous ACTH, underwent a 4-h iv infusion of theophylline. In three of the five individuals, a significant concentration of cortisol was measured in serum for the first time. The patients who responded included one patient with the syndrome of ACTH insensitivity, one with ACTH deficiency, and one with idiopathic primary adrenal failure. Two patients with autoimmune adrenalitis failed to respond to theophylline, although one was tested very early in the course of her disease. We also noted that theophylline stimulated renin secretion and, in one patient with an intact zona glomerulosa, evoked a secondary rise in aldosterone equal to that produced by diuresis and upright posture. These studies suggest that the preservation of cortisol responsiveness to theophylline, after the loss of sensitivity to ACTH, may be relate to either the duration of the adrenal insufficiency or to the etiological mechanism. Patients with autoimmune adrenalitis may undergo more rapid and complete adrenocortical destruction, therapy losing sensitivity to both ACTH and theophylline, whereas patients with insufficient or ineffective ACTH stimulation may have receptor failure before the loss of intracellular function. Thus, responsiveness to iv theophylline may serve not only as a probe of potential adrenocortical reserve, but also as an indicator of pathogenesis.
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PMID:The use of theophylline as an in vivo probe of adrenocortical function. 628 2

Peptide extracts of rat brain powerfully inhibited the cyclic AMP phosphodiesterase activity of rat brain homogenate. Similar extracts of ox brain showed comparable although less potent activity. Preliminary investigation of the physicochemical properties of brain extracts indicated that the rat brain extract contained an active peptide of low molecular weight (about 1400), whereas ox brain contained two such peptides (about 1400 and 900). These studies indicate that endogenous oligopeptides that inhibit cyclic AMP phosphodiesterase are present in brain. Experiments on several pure peptides known to be present in brain. Experiments on several pure peptides known to be present in the CNS showed that the majority were inactive against brain phosphodiesterase, but ACTH(1-24), somatostatin, substance P and Lys8-vasopressin, in descending order of potency, were active. To help distinguish the peptides found in rat and ox brain extracts from known peptides, preliminary analyses of amino acid composition were performed. These suggested that the peptides found in brain extracts were distinct from known peptides having the ability to inhibit cyclic AMP phosphodiesterase.
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PMID:Endogenous peptides that inhibit brain cyclic AMP phosphodiesterase. 628 80

To identify the possible role of calmodulin in ACTH function, we tested the ability of chlorpromazine (CP) and other calmodulin antagonists to inhibit steroidogenesis of isolated adrenocortical cells of the rat. CP reversibly inhibited maximal ACTH-induced corticosterone (B) production. The presence of the drug did not alter the ED50 of ACTH stimulation (3.2 X 10(3) pg/ml), suggesting that it inhibited ACTH-induced steroidogenesis in a noncompetitive manner. The CP concentration required for half-maximal inhibition was 8.2 microM, a value close to the dissociation constant of the CP-calmodulin complex (5.3 microM). Concentrations greater than 40 microM resulted in complete inhibition. Similar concentrations of CP inhibited ACTH-induced cAMP accumulation in a dose-dependent manner, indicating an effect of the drug on early events in ACTH action. In addition, CP also apparently acted at a site distal to the point of cAMP formation, as shown by the finding that it inhibited cAMP-induced B production. CP inhibition of ACTH-induced B production was independent of the Ca2+ concentration, suggesting that the drug did not compete with Ca2+ directly. Concentrations of CP greater than 20 microM inhibited protein synthesis as measured by leucine incorporation into cellular proteins. Thus, although the inhibitory effect of high concentrations of CP on steroidogenesis might be explained by an effect on protein synthesis, the inhibition seen at 10 microM appeared to be independent of protein synthesis. Other antagonists of calmodulin action inhibited maximal ACTH-induced B production with the following relative potencies: trifluoperazine greater than CP greater than haloperidol greater than chlordiazepoxide. This order is similar to that reported for inhibition of calmodulin-activated phosphodiesterase and for binding to calmodulin. These findings suggest that calmodulin may modulate the effect of ACTH on steroidogenesis at multiple sites.
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PMID:Acute inhibition of corticosteroidogenesis by inhibitors of calmodulin action. 629 Jan 82

The role of cyclic AMP in the stimulation of corticotropin (ACTH) release by corticotropin-releasing factor (CRF), angiotensin II (AII), vasopressin (VP), and norepinephrine (NE) was examined in cultured rat anterior pituitary cells. Synthetic CRF rapidly stimulated cyclic AMP production, from 4- to 6-fold in 3 min to a maximum of 10- to 15-fold at 30 min. Stimulation of ACTH release by increasing concentrations of CRF was accompanied by a parallel increase in cyclic AMP formation, with ED50 values of 0.5 and 1.3 nM CRF for ACTH and cyclic AMP, respectively. A good correlation between cyclic AMP formation and ACTH release was also found when pituitary cells were incubated with the synthetic CRF(15-41) fragment, which displayed full agonist activity on both cyclic AMP and ACTH release with about 0.1% of the potency of the intact peptide. In contrast, the CRF(21-41) and CRF(36-41) fragments were completely inactive. The other regulators were less effective stimuli of ACTH release and caused either no change in cyclic AMP (AII and VP) or a 50% decrease in cyclic AMP (NE). Addition of the phosphodiesterase inhibitor, methylisobutylxanthine, increased the sensitivity of the ACTH response to CRF but did not change the responses to AII, VP, and NE. In pituitary membranes, adenylate cyclase activity was stimulated by CRF in a dose-dependent manner with ED50 of 0.28 nM, indicating that the CRF-induced elevation of cyclic AMP production in intact pituitary cells is due to increased cyclic AMP biosynthesis. The intermediate role of cyclic AMP in the stimulation of ACTH release by CRF was further indicated by the dose-related increase in cyclic AMP-dependent protein kinase activity in pituitary cells stimulated by CRF with ED50 of 1.1 nM. These data demonstrate that the action of CRF on ACTH release is mediated by the adenylate cyclase-protein kinase pathway and that the sequence requirement for bioactivity includes the COOH-terminal 27 amino acid residues of the molecule. The other recognized regulators of ACTH release are less effective stimuli than CRF and do not exert their actions on the corticotroph through cyclic AMP-dependent mechanisms.
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PMID:Mechanisms of action of corticotropin-releasing factor and other regulators of corticotropin release in rat pituitary cells. 630 67

Presynaptic release-modulating receptors on sympathetic nerve fibres have been found not only in a great number of animal tissues but also in various human blood vessels. Although basically the same types of receptors are present in animals and man (e.g., inhibitory muscarinic receptors and alpha 2-adrenoceptors; facilitatory beta-adrenoceptors), there may be considerable species differences if a certain blood vessel or the effect of a certain agonist or antagonist is considered. Hormones may also influence noradrenergic transmission by acting presynaptically. Thus, ACTH increases the impulse-evoked noradrenaline (NA) release in the rabbit pulmonary artery by activating presynaptic ACTH receptors, and an adenylate cyclase may be involved in this effect. Results obtained with new pharmacological tools (forskolin and selective inhibitors of cAMP phosphodiesterase) support the suggestion that the sympathetic nerves of the rabbit pulmonary arteries are endowed with an adenylate cyclase activation of which increases evoked NA release.
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PMID:Adrenergic transmitter release. 632


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