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)

Bovine pulmonary artery endothelial cells in culture were used to assess the influence of cyclic nucleotides, isoproterenol (beta adrenergic agonist), and theophylline (phosphodiesterase inhibitor) on angiotensin-I-converting enzyme (ACE) activity of the cells and culture medium. Dibutyryl cAMP (10(-3) M) but not cAMP or dibutyryl cGMP stimulated angiotensin-I-converting enzyme (ACE) activity of cells in culture approximately 50-100% but had little influence on ACE activity of the medium. Theophylline at 10(-3) M concentration produced a three- to fourfold stimulation of both cellular and medium ACE activity. Isoproterenol by itself had no effect on cellular ACE activity but produced a stimulatory effect at 10(-7)-10(-5) M concentration after pretreatment of cells for 24 hr with 10(-4) M theophylline. The results support the concept that ACE activity of endothelial cells is influenced by the cyclic AMP system. ACE activity in cells and that released into medium may be under different regulatory controls.
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PMID:Stimulation of bovine endothelial cell angiotensin-I-converting enzyme activity by cyclic AMP-related agents. 302 84

Relaxation of vascular smooth muscle following beta-adrenergic stimulation may result from reduction of the cytoplasmic Ca2+ concentration, reduction in the sensitivity of the contractile apparatus to Ca2+, or both. To help resolve these possibilities, we measured the extent of activation of Ca2+ X calmodulin-sensitive phosphodiesterase in intact porcine coronary artery strips as a functional indicator of the cytoplasmic Ca2+ concentration. Both calmodulin-stimulated phosphodiesterase activity and active force increased during K+ stimulation of coronary artery strips. Relaxation of K+-contracted artery strips following stimulus withdrawal was accompanied by rapid inactivation of Ca2+ X calmodulin-sensitive phosphodiesterase. The temporal relationship between isoproterenol-induced relaxation and inactivation of Ca2+ X calmodulin-sensitive phosphodiesterase was studied in both histamine- and K+-contracted tissues. Stimulation of strips with 10 microM histamine or with 44 mM K+ led to comparable increases both in active force and in calmodulin-stimulated phosphodiesterase activity. Thereafter, sustained contraction elicited by histamine was accompanied by a decrease in calmodulin-stimulated phosphodiesterase activity. Isoproterenol rapidly relaxed histamine-contracted strips and accelerated the decrease in phosphodiesterase activity. In contrast, sustained contraction in response to K+ was accompanied by a sustained elevation of calmodulin-stimulated phosphodiesterase activity. Isoproterenol treatment of K+-contracted tissues led to relaxation that was slow and incomplete, and it had very little effect on calmodulin-stimulated phosphodiesterase activity. We conclude that reduction of the cytoplasmic Ca2+ concentration is important for rapid relaxation of the coronary artery following beta-adrenergic stimulation. We cannot disallow the possibility that a decrease in the sensitivity of the contractile apparatus to Ca2+ is involved to some degree.
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PMID:Effects of isoproterenol on active force and Ca2+ X calmodulin-sensitive phosphodiesterase activity in porcine coronary artery. 303 89

Effects of the new selectively beta 1-adrenergic cardiotonic drug denopamine (TA-064), (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol, on the adenylate cyclase-adenosine-3',5'-monophosphate (c-AMP) system of various tissues and cells in rats and guinea pigs were investigated in comparison with those of isoproterenol. Denopamine at concentrations above 10(-6) M stimulated lipolysis in vitro, and, above 10(-5) M, elevated the c-AMP level in isolated rat fat cells. The c-AMP level of guinea-pig heart ventricular muscle was also elevated when the heart was perfused with 3 X 10(-6) M denopamine or when slices of ventricular muscle were incubated with 10(-6) M denopamine. These changes were abolished in the presence of beta-adrenergic antagonists. Incubation with denopamine did not cause substantial elevation of c-AMP levels in rat reticulocytes and diaphragm. Denopamine activated adenylate cyclase of the rat cell membranes in a concentration-dependent manner. Although dose dependence was less apparent, denopamine also activated adenylate cyclase of the membrane fraction from guinea pig cardiac muscle, but it hardly activated the same enzyme from rat reticulocytes. Isoproterenol, on the other hand, showed marked concentration-dependent activation of adenylate cyclase in all these preparations. Denopamine did not inhibit c-AMP phosphodiesterase of both particulate and supernatant fractions of guinea-pig cardiac muscle. The stimulation of lipolysis by denopamine was observed even when elevation of the c-AMP level was not detected, while the stimulation of lipolysis by isoproterenol was always accompanied with an elevation of c-AMP. When guinea-pig hearts were perfused with 3 X 10(-6) M denopamine or 10(-7) M isoproterenol, their cardiotonic effects were of the same magnitude whereas the degree of c-AMP elevation in the ventricular tissue by denopamine was significantly less than that by isoproterenol. It was concluded that stimulation of the adenylate cyclase-c-AMP system by denopamine was restricted to the tissues whose receptors were predominantly of the beta 1-type, and that the elevation of c-AMP levels in these tissues by denopamine was less marked than by isoproterenol, suggesting that the stimulation of lipolysis and heart by denopamine may be mediated by a special pool of c-AMP or some other unknown factor(s).
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PMID:Beta 1-adrenergic selectivity of the new cardiotonic agent denopamine in its stimulating effects on adenylate cyclase. 303 56

Several hormones, including catecholamines, histamine, and prostaglandin E1, regulate the function of human mononuclear leukocytes (MNL) by stimulating the accumulation of cAMP. Isoproterenol-stimulated cAMP accumulation in MNL isolated and washed at 4 degrees is five times greater than in cells prepared at ambient temperature. The current study was aimed at understanding this difference. cAMP accumulation in MNL prepared at ambient temperature could not be increased by chilling the cells for 4 hours. Warming MNL prepared at 4 degrees for 30 min, however, reduced later isoproterenol-, histamine-, and PGE1-stimulated cAMP accumulation by 65-85% without altering forskolin-stimulated cAMP accumulation and without altering cellular viability or ATP content. In broken cell preparations, there was no difference in either adenylate cyclase or phosphodiesterase activities, and no difference in the binding of isoproterenol to the beta-adrenergic receptors. The reduction in isoproterenol-stimulated cAMP accumulation in warmed intact cells was reversed when the MNL were incubated with autologous leukocyte-depleted blood or with plasma. These data suggest the presence of one or more factors in plasma that enhances hormone-stimulated adenylate cyclase activity in intact MNL.
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PMID:Regulation of hormone-stimulated cyclic AMP accumulation in intact human mononuclear leukocytes by blood plasma. 304 Aug 17

1 In mouse isolated atria previously incubated with [3H]-noradrenaline, 8-bromo-cyclic AMP (3-270 microM) produced a concentration-dependent increase in the fractional stimulation-induced outflow of radioactivity. 8-Bromo-cyclic GMP induced a lesser increase in the stimulation-induced outflow. 2 The phosphodiesterase inhibitors: M&B 22948 (90 microM); ICI 63197 (30 and 90 microM) and 3-isobutyl-1-methylxanthine (90 microM) increased the fractional stimulation-induced outflow. Together these results indicate that cyclic AMP may have a modulatory effect on noradrenaline release. 3 The inhibition of the stimulation-induced outflow produced by clonidine (0.03 microM) and its facilitation produced by phentolamine (1 microM) were unaltered in the presence of 8-bromo-cyclic AMP (90 microM). However, in the presence of 8-bromo-cyclic AMP (270 microM), the facilitatory effect of phentolamine was enhanced, but the inhibitory effect of clonidine (0.03 microM) was unaltered. In the presence of ICI 63197 (30 microM) the inhibitory effect of clonidine (0.03 microM) was unaltered, but the facilitatory effect of phentolamine (1 microM) was slightly enhanced. 4 Isoprenaline (0.003-0.1 microM) enhanced the fractional stimulation-induced outflow, an effect blocked by propranolol (0.1 microM). In the presence of 8-bromo-cyclic AMP (90 microM), the facilitatory effect of isoprenaline (0.01 microM) was blocked. In the presence of ICI 63197 (30 microM) the facilitatory effect of isoprenaline (0.003 microM) was potentiated. 5 These results suggest that whereas beta-adrenoceptor-mediated enhancement of noradrenaline release is linked to the stimulation of adenylate cyclase and enhanced formation of cyclic AMP, alpha-adrenoceptor-mediated inhibition of noradrenaline release is not linked to inhibition of adenylate cyclase activity.
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PMID:Involvement of cyclic nucleotides in prejunctional modulation of noradrenaline release in mouse atria. 366 78

Calcium-tolerant myocytes were isolated from rat hearts. Isoproterenol produced a dose-dependent increase in glycerol output (lipolysis) that could be blocked by propranolol. The presence of glucose in the incubation medium enhanced the release of glycerol from myocytes but had no effect on the decline in triacylglycerol content. No incorporation of radioactivity from [U-14C]glucose into glycerol could be detected. In incubations with isoproterenol, there was a stoichiometric relationship between the glycerol output and the decrease in triacylglycerol levels. The addition of the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine resulted in an increase in the basal glycerol output and an enhancement of the isoproterenol-stimulated lipolytic rate. Forskolin and 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate also produced a concentration-dependent stimulation of lipolysis in myocytes. Therefore, lipolysis in isolated myocytes must be regulated by adenosine 3',5'-cyclic monophosphate-dependent mechanisms. These results demonstrate that lipolysis can be observed in myocardial cells and that the lipolytic response to isoproterenol cannot be secondary to a physiological (inotropic) response since these myocyte preparations are quiescent.
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PMID:Stimulation of lipolysis in rat heart myocytes by isoproterenol. 403 87

Treatment of ROS 17/2.8 osteosarcoma-derived cells with dexamethasone potentiates the PTH stimulation of adenylate cyclase in these cells, yielding a detectable response to as little as 10 pM PTH. Isoproterenol stimulation was also enhanced. The dexamethasone effect is first apparent at 12 h and increases with time of treatment. The apparent EC50 for dexamethasone is 3 nM. Hydrocortisone and corticosterone act similarly to dexamethasone, but require 30-fold higher concentrations. Dexamethasone treatment produces no change in high affinity phosphodiesterase activity. Glucocorticoid-potentiating effects are much more pronounced in whole cells than in broken cells and do not influence forskolin stimulation. Particulate fractions of dexamethasone-treated cells have higher adenylate cyclase specific activity, but are stimulated by guanyl-5'-yl imidodiphosphate to the same extent as control cells. These findings suggest that the glucocorticoids potentiate hormone responsiveness through promotion of hormone receptor-adenylate cyclase coupling by a mechanism dependent on cellular integrity.
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PMID:The effect of dexamethasone on parathyroid hormone stimulation of adenylate cyclase in ROS 17/2.8 cells. 608 91

The effects of papaverine and isoprenaline on smooth muscle cells of the dog basilar artery were investigated using radioimmunoassay, electrophysiological and isometric tension recording methods. For comparative purposes, the actions of these drugs on the guinea-pig basilar artery were also examined. Papaverine and isoprenaline (1 microM and 10 microM) increased the amount of cyclic AMP in both dog and guinea-pig basilar arteries. Papaverine (up to 100 microM) and isoprenaline (up to 1 microM) had no effect on the membrane potential and membrane resistance measured by recording the amplitudes of the electrotonic potentials in smooth muscle cells of the dog and guinea-pig basilar arteries. The action potential evoked by outward current pulses after pretreatment with tetraethylammonium chloride (5-10 mM) was inhibited by papaverine (greater than 1 microM) but not by isoprenaline (up to 10 microM) in smooth muscle cells of the dog and guinea-pig basilar arteries. In the dog basilar artery, papaverine (greater than 1 microM) consistently inhibited the contractions evoked by excess concentrations of [K]o (greater than 20.2 mM) or 5-hydroxytryptamine (10 nM-10 microM), dose-dependently. Isoprenaline (1 microM) had only slight effects on the contraction evoked by low concentrations of 5-hydroxytryptamine (10 nM). In the Ca2+-free solution containing EGTA (2 mM), the contraction evoked by 5-hydroxytryptamine (10 microM) or caffeine (10 mM) was dose-dependently inhibited by papaverine (greater than 1 microM). However, isoprenaline (1 microM) had no effect on these contractions. These results indicate that the vasodilator actions of papaverine on the dog basilar artery are mainly due to inhibition of the voltage-dependent influx of Ca2+ and also to inhibition of the receptor-activated release of Ca2+ stored in the cell. Since isoprenaline increased the cyclic AMP to the same extent as papaverine but had no effect on the electrical and mechanical responses, the inhibitory actions of papaverine on this tissue may not be causally related to the increased levels of cyclic AMP induced by inhibition of phosphodiesterase.
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PMID:Lack of a causal relationship between the vasodilator effect of papaverine and cyclic AMP production in the dog basilar artery. 609 22

1. The cyclic AMP levels in the sublingual glands of the mouse has been determined in relation to mucin secretion under the influence of several agonists in vivo and in vitro. 2. Isoprenaline increased the cyclic AMP level in these glands only in the presence of a phosphodiesterase inhibitor, indicating the presence of an active cyclic AMP phosphodiesterase. 3. Inhibition of phosphodiesterase results in an increase of the cyclic AMP levels. EGTA prolonged the effect of the PDE-inhibitors, indicating that Ca2+-ions may be involved in the maintenance of the cyclic AMP concentration in the sublingual glands. 4. NaF is able to induce both a slight increase of the cyclic AMP level and a significant mucin secretion by the sublingual glands. However, other secretagogues do not significantly influence the cyclic AMP concentration in these glands, and compounds which do not elevate its level, do not significantly stimulate sublingual mucin secretion. 5. These data suggest that there is no direct relationship between cyclic AMP and sublingual mucin secretion.
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PMID:Cyclic AMP in the sublingual glands of the mouse. 610 81

In primary cultures of rat hepatocytes, addition of dexamethasone (10 microM) plus glucagon (0.5 microM) caused several-fold increases in the activities of serine dehydratase (EC 4.2.1.13), tryptophan oxygenase (EC 1.13.11.11), and tyrosine aminotransferase (EC 2.6.1.5) in 24 h. These inductions were inhibited by insulin. Addition of epinephrine or phenylephrine at 10 microM blocked these inductions. This suppressive effect of adrenergic compounds was completely abolished by the alpha-adrenergic antagonist phenoxybenzamine at 10 microM. Immunochemical analysis with antiserum to serine dehydratase showed that the changes in enzyme activity were due to changes in the amount of enzyme. Epinephrine was effective even when glucagon was replaced by dibutyryl cAMP (50 microM), indicating that alpha-adrenergic suppression of enzyme inductions was mediated by a cAMP-independent mechanism. Furthermore, the findings that prazosin antagonized this epinephrine effect, but yohimbine did not, indicate that the alpha 1- but not the alpha 2-receptor is involved in this inhibition. However, the alpha-adrenergic effect was different from that of insulin in that, unlike the latter, the inductions of tryptophan oxygenase and tyrosine amino-transferase by dexamethasone alone were not inhibited. The alpha-adrenergic action apparently counteracts the action of glucagon and cAMP. For determination of the beta-adrenergic effect of catecholamines on the inductions of enzymes, beta-adrenergic compounds were tested without glucagon. Isoproterenol or epinephrine plus phenoxybenzamine induced tryptophan oxygenase and tyrosine aminotransferase. Induction of serine dehydratase was shown by isoproterenol only in the presence of 1-methyl-3-isobutylxanthine, an inhibitor of phosphodiesterase. These results indicate that catecholamines play dual roles in regulation of the amount of enzyme through their alpha 1- and beta-adrenergic actions.
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PMID:alpha-Adrenergic regulation of enzymes of amino acid metabolism in primary cultures of adult rat hepatocytes. 613 92


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