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)

Effects of angiotensin II on corticoid biogenesis and cAMP levels in the zona fasciculata-reticularis (the decapsulated fraction) and the zona glomerulosa (the capsular fraction) from the rat adrenal gland have been studied. Angiotensin II exclusively stimulated steroidogenesis in the zona glomerulosa without stimulation of the cAMP system, suggesting that steroidogenic action of this polypeptide does not involve the adenylate cyclase system. Angiotensin II was also found to stimulate cAMP-phosphodiesterase activity in the zona glomerulosa. An elevation of calcium concentration in the incubation medium has been observed to be effective in stimulating the production of aldosterone and cAMP by the capsular fraction. Angiotensin II caused a significant enhancement of the steroidogenic response of the capsular fraction to increasing calcium concentration regardless of the response of the cAMP system to calcium. This steroidogenic effect of angiotensin II was completely abolished by calcium antagonists added to the incubation medium without any inhibitory effect on the calcium-induced accumulation of tissue cAMP. These results suggest that angiotensin II acts on the adrenal II acts on the adrenal glomerulosa cell to increase intracellular calcium, which in turn directly stimulates steroidogenesis concomitant with the increased activity of phosphodiesterase.
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PMID:Studies on cyclic nucleotides in the adrenal gland. VIII. Effects of angiotensin on adenosine 3',5'-monophosphate and steroidogenesis in the adrenal cortex. 21 76

We have previously shown that recombinant interleukin 1 (IL-1) and recombinant tumour necrosis factor (TNF) synergistically stimulate phospholipase A2 release from mesangial cells. We now report that treatment of mesangial cells with the beta-agonist salbutamol, prostaglandin E2 (PGE2), cholera toxin or forskolin, which all activate adenylate cyclase, increased release of phospholipase A2 activity. Likewise, addition of a membrane-permeant cyclic AMP (cAMP) analogue or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine enhanced release of phospholipase A2 activity from mesangial cells. There was a lag period of about 8 h before a significantly enhanced secretion could be detected. Furthermore, actinomycin D or cycloheximide completely suppressed cAMP-stimulated secretion of phospholipase A2. Angiotensin II, the phorbol ester phorbol 12-myristate 13-acetate, the Ca2+ ionophore A23187 and a membrane-permeant cGMP analogue did not stimulate phospholipase A2 release from the cells. Treatment with indomethacin completely inhibited IL-1 beta- and TNF-stimulated PGE2 synthesis, without having any effect on phospholipase A2 secretion, thus excluding cytokine-induced PGE2 synthesis as the mediator of phospholipase A2 release. Neither IL-1 beta nor TNF induced any increase in intracellular cAMP in mesangial cells. Furthermore, incubation of the cells with 2',5'-dideoxyadenosine, an inhibitor of adenylate cyclase, did not block cytokine-stimulated phospholipase A2 secretion. In addition, IL-1 beta and TNF synergistically interacted with forskolin to stimulate phospholipase A2 release from the cells. The protein kinase inhibitors H-8, staurosporine, K252a and amiloride inhibited IL-1 beta- and TNF-stimulated phospholipase A2 secretion. However, high concentrations that inhibit other protein kinases were needed. These observations suggest that IL-1 beta and TNF cause secretion of phospholipase A2 by a mechanism independent of cAMP. The signalling pathways used by IL-1 beta and TNF may involve a protein kinase that is probably different from protein kinase A or protein kinase C.
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PMID:Cyclic AMP mimics, but does not mediate, interleukin-1- and tumour-necrosis-factor-stimulated phospholipase A2 secretion from rat renal mesangial cells. 184 28

Atrial natriuretic factor administered in the large dose did not change glomerular filtration rate, but it was diuretic in low-sodium rats. In response to ANF, excretion of c-GMP was decreased in low-sodium rats in comparison with normal-sodium stimulated c-GMP accumulation in isolated glomeruli was more diminished in low- than normal sodium rats. These results indicate that attenuated glomerular responses to ANF in low-sodium rats might be due to increase of plasma Angiotensin II (Ang II) level, which increases intracellular Ca++ concentration. Theophylline can potentiate the renal response to ANF. We suggest that Ca(++)-activated c-GMP phosphodiesterase plays a major role in the regulation of intracellular accumulation of c-GMP in glomeruli exposed to ANF.
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PMID:Attenuated glomerular responses to atrial natriuretic factor in low-sodium rats is prevented by theophylline. 216 1

The rat adipocyte contains two separate mechanisms for prostaglandin (PG) production. Norepinephrine stimulates prostacyclin (PGI2) and PGE2 production and triglyceride lipolysis in isolated rat adipocytes. In contrast, the vasoactive peptides angiotensin II, vasopressin, and bradykinin stimulate PGI2 production, but not PGE2 production or triglyceride lipolysis, in these cells. In this study, we characterized the two separate mechanisms of PG production with respect to the time course, the role of cAMP, the identity of the adrenergic receptor, and the effects of insulin and glucocorticoids. Angiotensin II stimulated PGI2 production rapidly (at 5 min) and independently of cAMP. beta-Adrenergic stimulation with isoproterenol produced a rapid 11-fold increase in the cAMP concentration and stimulated PGI2 production more slowly (at 120 min). The phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine (0.2 and 0.5 mM) and the adenylate cyclase activator forskolin (10 microM) also stimulated cAMP production rapidly and PGI2 production more slowly. 1-Methyl-3-isobutylxanthine (5.0 mM) further stimulated cAMP levels, but prevented the increase in PGI2 production and blunted the increase in glycerol release seen at lower concentrations. beta-Adrenergic blockade with propranolol or timolol completely inhibited the norepinephrine- or isoproterenol-stimulated production of PGI2 and triglyceride lipolysis, respectively. Insulin selectively inhibited isoproterenol-stimulated PGI2 production and triglyceride lipolysis at physiological concentrations, but had no effect on angiotensin II-stimulated PGI2 production. In contrast, dexamethasone inhibited PGI2 production induced by both isoproterenol and angiotensin II. We conclude that: angiotensin II stimulates PGI2 production rapidly and independently of cAMP, but isoproterenol stimulates PGI2 production more slowly, an effect that is cAMP dependent; insulin inhibits the cAMP-dependent beta-adrenergic stimulation of PGI2 production (and triglyceride lipolysis), but not the cAMP-independent angiotensin II-induced stimulation of PGI2 production (this suggests that the former effect is mediated by a decrease in cAMP levels in the adipocyte); and dexamethasone inhibits both mechanisms of PGI2 production. Both mechanisms of PGI2 production by rat adipocytes are exquisitely sensitive to hormonal regulation.
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PMID:Prostacyclin production by isolated rat adipocytes: evidence for cyclic adenosine 3',5'-monophosphate-dependent and independent mechanisms and for a selective effect of insulin. 242 31

Pretreatment with pertussis toxin inhibits angiotensin II-induced activation of polyphosphoinositide phosphodiesterase in rat renal mesangial cells [Pfeilschifter & Bauer (1986) Biochem. J. 236, 289-294]. Furthermore, activation of protein kinase C by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) and by 1-oleoyl-2-acetylglycerol (OAG) abolishes angiotensin II-induced formation of inositol trisphosphate (IP3) in mesangial cells [Pfeilschifter (1986) FEBS Lett. 203, 262-266]. Using membrane preparations of [3H]inositol-labelled mesangial cells we tried to obtain further insight as to the step at which protein kinase C might interfere with the signal transduction mechanism in mesangial cells. Angiotensin II (100 nM) stimulates IP3 formation from membrane preparations of [3H]inositol-labelled mesangial cells with a half-maximal potency of 1.1 nM. The angiotensin II-induced formation of IP3 is enhanced by GTP. This effect of angiotensin II is completely blocked by the competitive antagonist [Sar1,Ala8]angiotensin II. Guanosine 5'-[gamma-thio]triphosphate (GTP gamma S) and guanosine 5'-[beta gamma-imido]triphosphate (Gpp[NH]p), non-hydrolysable analogues of GTP, stimulate IP3 production in the absence of angiotensin II with Kd values of 0.19 microM and 2.4 microM, respectively. Angiotensin II augments the increase in IP3 formation induced by GTP gamma S. However, when mesangial cells were pretreated with TPA there was a dose-dependent inhibition of the synergistic action of angiotensin II on GTP gamma S-induced IP3 production. Comparable results are obtained with OAG, while the non-tumour-promoting phorbol ester 4 alpha-phorbol 12,13-didecanoate is without effect. These results suggest that activation of protein kinase C in mesangial cells does not impair phosphoinositide hydrolysis by stable GTP analogues but somehow seems to interfere with the stimulatory interaction of the occupied angiotensin II receptor with the transducing G-protein.
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PMID:Different effects of phorbol ester on angiotensin II- and stable GTP analogue-induced activation of polyphosphoinositide phosphodiesterase in membranes isolated from rat renal mesangial cells. 282 20

The level of cyclic AMP in primary cultures of bovine adrenal medulla cells is elevated by prostaglandin E1. Angiotensin II is commonly reported to act on receptors linked to phosphoinositide metabolism or to inhibition of adenylate cyclase. We have investigated the effect of angiotensin II on prostaglandin E1-stimulated cyclic AMP levels in these primary cultures. Rather than reducing cyclic AMP levels, we have found that angiotensin II powerfully potentiates prostaglandin E1-stimulated cyclic AMP accumulation in intact cells, both in the presence and absence of phosphodiesterase inhibitors. The 50% maximal response was similar to that for stimulation of phosphoinositide breakdown by angiotensin II in these cultures. The potentiation of stimulated cyclic AMP levels was seen, although to a smaller maximum, with the protein kinase C (Ca2+/phospholipid-dependent enzyme) activating phorbol ester tetradecanoyl phorbolacetate and with the synthetic diacylglycerol 1-oleoyl-2-acetylglycerol; pretreatment (24 h) with active phorbol ester, which would be expected to diminish protein kinase C levels, attenuated the angiotensin II potentiation of cyclic AMP. Using digitonin-permeabilized cells we showed that adenylate cyclase activity was stimulated by prostaglandin E1 with the same dose-response relationship as was cyclic AMP accumulation in intact cells, but the permeabilized cells showed no response to angiotensin II. The results are discussed with respect to the hypothesis that the angiotensin II influence on cyclic AMP levels is mediated, in part, by diacylglycerol stimulation of protein kinase C.
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PMID:Angiotensin II potentiates prostaglandin stimulation of cyclic AMP levels in intact bovine adrenal medulla cells but not adenylate cyclase in permeabilized cells. 284 8

The comparative effects of angiotensin II and adrenocorticotropic hormone (ACTH) on cyclic AMP and steroidogenesis were investigated employing isolated bovine adrenal cells from the zona fasciculata. Like ACTH, angiotensin produced a prompt increase in cyclic AMP which preceded the increase in corticosteroid production. Although this increase in cyclic AMP was small when compared to that induced by ACTH, it correlated with the amount of steroidogenesis. This observation is consistent with the view that cyclic AMP is the intracellular mediator of the steroidogenic action of angiotensin. Angiotensin acted synergistically with ACTH on cyclic AMP levels. This synergism was not explained by inhibition of phosphodiesterase activity. Unlike ACTH, angiotensin failed to stimulate adenylate cyclase in broken cell preparations. The observations suggest that more than one mechanism may be involved in effects of ACTH and angiotensin on cyclic AMP levels.
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PMID:Comparative effects of angiotensin and ACTH on cyclic AMP and steroidogenesis in isolated bovine adrenal cells. 434 44

Choline esters fail to depress developed tension or the maximum upstroke velocity (Vmax) of slow action potentials in embryonic chick ventricles, but they inhibit the stimulatory effect of the phosphodiesterase inhibitor methylisobutylxanthine (MIX). The mechanism by which the choline ester methacholine (MCh) counteracts the effects of MIX was examined in ventricular myocardium obtained from 7-day-old embryonic chicks. Four possible hypotheses were 1) that the physiological response to MCh is mediated by cyclic GMP, the production of which is potentiated by MIX; 2) that MCh acts by a mechanism independent of cyclic nucleotides; 3) that the binding of MIX to adenosine receptors induces sensitivity to MCh; or 4) that MCh acts by depressing basal cyclic AMP levels. Interactions between MCh, Angiotensin II and a nonmethylxanthine phosphodiesterase inhibitor (Ro 7-2956) were assessed by measuring tissue levels of cyclic nucleotides and the Vmax of slow action potentials. MCh significantly reduced the basal cyclic AMP level of embryonic chick ventricles, despite having no physiological effect. The results favor the final hypothesis and imply that MCh effects are mediated by inhibition of adenylate cyclase activity. The physiological response of the myocardium to a reduction in basal adenylate cyclase activity appears to be dependent on the initial tissue level of cyclic AMP.
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PMID:Sensitivity of Ca-dependent slow action potentials to methacholine is induced by phosphodiesterase inhibitors in embryonic chick ventricles. 617 16

New agents for treating chronic heart failure include angiotensin converting enzyme (ACE) inhibitors, betablockers and phosphodiesterase inhibitors. The ACE inhibitors represent the major therapeutic advance of the 1980-1990 decade. This is the most effective class of drugs on survival, whatever the stage of heart failure and it shows the evolution towards symptoms in asymptomatic patients. Studies currently under way are evaluating the dose-effect relationship of ACE inhibitors. Betablockers improve the quality of life and physical performance but a benefit on mortality has not been shown in two recent trials. Phosphodiesterase inhibitors improve quality of life and physical performance at the price of an increase in mortality. Therefore, they are not indicated in the treatment of heart failure. However, new molecules such as vesnarininone or pimobendan are under trial. Finally, in the next few years, the introduction of antagonists to Angiotensin II receptors is eagerly awaited.
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PMID:[Treatment of chronic heart failure: current views]. 748 9

The present experiments were devoted to analyzing the hypothesis that somatostatin (SS) could modulate glomerular filtration rate by interacting with mesangial cells. Studies were performed in cultured human mesangial cells, passages 3-5. Radioligand experiments demonstrated the presence in the cells of two kinds of receptors, with high (dissociation constant 14 pM. Number of sites: 426 fmol/mg) and low (dissociation constant 56 pM. Number of sites: 20, 111 fmol/mg) affinity. SS prevented in a dose-dependent manner the reduction in planar cell surface area induced by 100 nM Angiotensin II (AII). This effect was not inhibited by the blockade of the vasorelaxing prostaglandins (indomethacin, 10 microM), nitric oxide (L-N-methyl-arginine, 0.2 mM), adenylate cyclase (2,5'-dideoxyadenosine, 0.1 mM), or guanylate cyclase (Methylene blue, 30 microM; LY-83583, 10 microM), but it was potentiated by zaprinast, an inhibitor of the cyclic GMP (cGMP)-specific phosphodiesterase. SS also blocked the increase in myosin light chain phosphorylation induced by AII. SS increased cGMP synthesis by cultured human mesangial cells, an effect that seemed to be dependent on the stimulation of a particulate guanylate cyclase. Preincubation of the cells with pertussis toxin (0.5 microgram/ml) inhibited the effect of SS on the AII-dependent changes in planar cell surface area, as well as the SS-dependent cGMP stimulation. In summary, these results demonstrate the ability of SS to relax cultured human mesangial cells, thus supporting a role for this peptide in the regulation of the glomerular filtration rate. The SS-dependent mesangial cell relaxation may be due to changes in the intracellular concentrations of cGMP, as a consequence of the activation of a particulate guanylate cyclase.
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PMID:Effects of somatostatin on cultured human mesangial cells. 762 80


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