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

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of albuterol and terbutaline on the cyclic 3',5'-adenosine monophosphate (cAMP) system was studied in rat uterus, aorta and myocardium and in dog bronchus, and was compared to that of isoproterenol in order to determine whether the tissue specificity observed in their functional effects is reflected in their effect on the cAMP system. Tissue specimens were either homogenized in Tris buffer for enzyme activity measurements or incubated in Krebs-Ringer-bicarbonate medium with the test drugs. Both albuterol and terbutaline produce an increase in cAMP content in the tissues due to a direct effect on adenylate cyclase. This effect can be potentiated by a phosphodiesterase inhibitor and antagonized by a beta adrenergic blocking compound. The cAMP response to each beta adrenergic agonist differs in the tissues examined: in uterus and aorta where the maximal effects are idenitcal, the ED50 values may reflect differences in affinity which may account for the different cAMP response to the compounds at the lower concentrations. In bronchus and myocardium, both the maximum effect and ED50 values of the compounds are different. Albuterol and terbutaline increases cAMP content in bronchus significantly and have only a small effect on cAMP cont in myocardium, whereas isoproterenol increases cAMP level significantly in both tissues. The results indicate that the tissue specificity of albuterol and terbutaline may have its origin at the level of the cAMP system.
...
PMID:Effect of albuterol and terbutaline, synthetic beta adrenergic stimulants, on the cyclic 3',5'-adenosine monophosphate system in smooth muscle. 17 25

Cumulative concentration-effect curves of oxytocin alone and with various antagonists were obtained in vitro on uteri from estrogen-treated rats. Graded concentrations of salbutamol, isoproterenol, papaverine, theophylline, thioglycollate, and MgCl2 produced a decrease in the maximal effect of oxytocin and a shift of the concentration-effect curves to the right. Salbutamol and isoproterenol appeared to act as functional antagonists of oxytocin in which agonist and antagonist each interacted with its own specific receptor to produce a decreased combined effect on a common effector. Antagonism by papaverine or theophylline was increased by prior or simultaneous treatment with salbutamol, isoproterenol, epinephrine, or norepinephrine. The potentiation had a rapid onset, was partially blocked by propranolol, persisted for at least 85 minutes following washout of salbutamol, and was not due to a residual effect of salbutamol. This interaction could result from phosphodiesterase inhibition by papaverine and the accumulation of higher levels of cyclic 3',5'-adenosine monophosphate brought about by adenyl cyclase activation with the sympathomimetic amines.
...
PMID:Antagonism of the uterotonic action of oxytocin in vitro. 111 25

There is now compelling evidence to incriminate bronchial mast cells in the pathogenesis of bronchoconstriction of allergic asthma. Human mast cells isolated from lung tissue or bronchoalveolar lavage release histamine and generate eicosanoids upon IgE-dependent activation. In this paper we present data that raise doubts about the significance of phospholipid methylation in IgE-dependent activation-secretion coupling and provide evidence that drugs such as 3-deazaadenosine inhibit mediator secretion by inhibiting phosphodiesterase, in addition to inhibiting putative methylation pathways. Activation of human mast cells and basophils also stimulates adenylate cyclase to increase levels of cyclic AMP, which, on the basis of pharmacological manipulation with purine nucleosides, we believe is involved in the progression of the secretory response. Human lung cells also generate both cyclo- and lipoxygenase products of arachidonate upon Ca++-dependent stimulation with complex interactions occurring between these pathways in the presence of the leukotriene inhibitor, Piriprost. The role of mast cells in the immediate airway response to inhaled allergens in asthma was demonstrated by showing an interaction between nonspecific bronchial reactivity and mast cell reactivity in predicting the airway response upon antigen inhalation. Further confirmation of this concept was obtained by showing an inverse relationship between the release of histamine and neutrophil chemotactic factor (NCF) into the circulation induced by antigen challenge, and nonspecific airway reactivity. The identification of significant increases in circulating mediators following antigen provocation of patients with seasonal asthma enabled the effects of drugs used in the treatment of asthma to be compared on airway calibre and mast cell mediator release. Sodium cromoglycate partially inhibited the airway and plasma histamine responses with antigen, but totally inhibited the increases in NCF. Salbutamol completely inhibited all responses, while ipratropium bromide, which produced the same bronchoconstriction as achieved with salbutamol, had no effect. The potent H1-antagonist astemizole partially inhibited bronchoconstriction without affecting histamine release. Antigen provocation produced a significant increase in circulating levels of the 13,14-dihydro-15-keto metabolite of PGF2 alpha which could originate from mast cell-derived PGD2. In both retrospective and prospective studies, a close relationship was shown between nonspecific bronchial reactivity and resting airway calibre in asthma.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Relationship between mediator release from human lung mast cells in vitro and in vivo. 240 26

The aim of inotropic therapy is to increase the force of myocardial fibre shortening by improving the availability of calcium to the contractile proteins. Digitalis remains the most widely used drug, but its positive inotropic effects are weak and the therapeutic index is low. Dobutamine is the most useful catecholamine because the most cardioselective and it induces the least increase in myocardial oxygen consumption. There are three groups of new inotropic agents: sympathomimetics: pirbuterol and prenalterol are effective in the short term but tolerance is usually observed within a few weeks. Salbutamol and terbutaline have only been assessed in acute studies, phosphodiesterase inhibitors (MDL 17043, MDL 19025) are powerful inotropic agents in the short and medium term. ARL 115 has mainly been studied by parenteral administration, Amrinone has a largely unknown mode of action, but is a very effective positive inotropic drug; its side-effects limit it as age. However, its derivative, milrinone, seems to be more inotropic and less toxic. The new inotropic drugs currently under assessment are active in the short term but their long-term efficacy and side-effects are still little known. The ideal inotropic agent remains to be discovered.
...
PMID:[Positive inotropic agents. Generalities and classification]. 286 22

Adenosine 3',5'-cyclic monophosphate (cAMP) metabolism was studied in the microcirculation (100- to 150-micrometers arterioles) of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) at different stages of hypertension. Mesenteric arterioles from animals 4, 6, 12, and 18 wk old were incubated in Krebs-Ringer bicarbonate buffer for 30 min at 37 degrees C, pH 7.4, with and without the phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine (MIX). cAMP was assayed by radioimmunoassay. Arteriolar production of cAMP was age related in both WKY and SHR rats although the temporal patterns were different. At 6 wk (developmental stage of hypertension in SHR) cAMP accumulation in the presence or absence of MIX by SHR arterioles was higher than in the WKY before falling to normotensive levels at 12 wk. Salbutamol (a beta 2-agonist) stimulated dose-dependent increases in cAMP in both WKY and SHR at 6 wk. Stimulation of cAMP by salbutamol or by isoproterenol was blocked by propranolol. Neither agonist increased guanosine 3',5'-cyclic monophosphate. These data indicate that differences in cAMP metabolism are evident at the arteriolar level during the developmental stage of SHR hypertension. These differences may contribute to the morphological and physiological changes occurring at this time.
...
PMID:Elevated arteriolar adenosine 3',5'-cyclic monophosphate production by SHR. 618 Jun 47

Isoprenaline (0.01-1 microM) increased the amount of cyclic adenosine 3',5'-monophosphate (cyclic AMP) in rat isolated superior cervical ganglia by up to 10 times after 10 min application. Cyclic AMP levels returned to control values after 20 min washing. Salbutamol, in concentrations (1-100 microM) that depolarized the ganglion and facilitated submaximal transmission, did not significantly raise ganglionic cyclic AMP levels. The action of isoprenaline was antagonized by butoxamine (apparent KI approximately equal to 0.14 microM) and weakly by practolol (apparent KI approximately equal to 9.1 microM). The effect of 0.1 microM isoprenaline was also inhibited 94% by 100 microM of the adenylate cyclase inhibitor, 9-(tetrahydro-2-furyl)adenine (SQ 22,536). Exogenous dibutyryl cyclic AMP did not replicate the effects of isoprenaline on ganglionic d.c. potentials or submaximal transmission. The phosphodiesterase inhibitors theophylline, isobutylmethylxanthine or 4-(3,4-dibutoxybenzyl)-2-imidazolidinone (Ro 20-1724) did not potentiate these electrical responses to isoprenaline. The adenylate cyclase inhibitor, SQ 22,536, did not inhibit the electrical responses to isoprenaline. It is concluded that available evidence does not support the view that the ganglion depolarization or facilitation of submaximal transmission in rat isolated ganglia produced by isoprenaline are likely to be mediated by cyclic AMP.
...
PMID:Cyclic adenosine 3',5'-monophosphate and beta-effects in rat isolated superior cervical ganglia. 631 11

The link between increased usage of beta-adrenoceptor agonists and worsening of asthma symptoms has raised interest in the effects of agents such as salbutamol on airway wall remodelling, and particularly airway smooth muscle proliferation. In the present study we have investigated the role of increases in intracellular cAMP in the inhibitory effect of salbutamol on airway smooth muscle proliferation. The inhibitory effects of a combination of submaximally effective concentrations of salbutamol (10 nM) and the non-selective phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX, 100 microM) on thrombin (0.3 U/mL)-induced mitogenesis in human cultured airway smooth muscle cells was greater than that for either agent alone. In addition, agents known to increase cAMP-dependent protein kinase activity including forskolin (10 microM), 8-bromoadenosine-3',5'-cyclic monophosphate (100 microM), and prostaglandin E2 (1 microM) have an inhibitory effect on thrombin (0.3 U/mL)-induced induced proliferation. Furthermore, the cAMP antagonist, 8-bromoadenosine-3',5'-cyclic monophosphorothioate, Rp-isomer (300 microM) significantly reduced the inhibitory effect of salbutamol (10 nM) on thrombin (0.3 U/mL)-induced DNA synthesis. In IBMX (100 microM)-pretreated cells, salbutamol (100 nM) increased intracellular cAMP levels via stimulation of a beta 2-adrenoceptor. Salbutamol (10 microM), at concentrations supramaximally effective for inhibition of mitogenesis, had no effect on thrombin (0.3 U/mL)-induced increases in intracellular calcium levels. Therefore, our results suggest that the previously reported inhibition of mitogen-induced proliferation in human cultured airway smooth muscle cells by the beta 2-adrenoceptor agonist, salbutamol (100 nM), is at least partly due to elevation of intracellular cAMP, while there is no effect of salbutamol on initial mitogen-induced increases in intracellular calcium.
...
PMID:Salbutamol inhibits the proliferation of human airway smooth muscle cells grown in culture: relationship to elevated cAMP levels. 759 43

Eight agents that increase the intracellular concentration of cyclic AMP were tested for their effect on edema formation. The specificity of the agents for vascular smooth muscle or the endothelium was determined by measuring vasodilation with a laser Doppler flow probe and cAMP production by endothelial cells and vascular smooth muscle cells in culture. The agents were injected intradermally in anesthetized rabbit skin and the local accumulation of 125I-labeled albumin in response to intradermal bradykinin was measured. Iloprost, prostaglandin E1, prostaglandin E2, pituitary adenylate cyclase activating polypeptide (PACAP), and vasoactive intestinal polypeptide (VIP) potentiated bradykinin-induced edema. These same agents also increased blood flow and vascular smooth muscle cAMP concentrations, but did not increase endothelial cell cAMP production. Albuterol suppressed edema formation, did not cause vasodilation, but did increase endothelial cell cAMP concentrations. The phosphodiesterase inhibitor rolipram did not cause vasodilation, but suppressed edema and potentiated the cAMP response to albuterol in cultured endothelial cells. L-Isoproterenol affected both cell types. At a lower concentration L-isoproterenol was a potent stimulus to endothelial cell cAMP production and inhibited edema formation; a higher dose had additional effects on vascular smooth muscle and significantly increased blood flow. These findings support the hypothesis that increasing intracellular cAMP concentrations in vascular smooth muscle promotes edema via increased blood flow. In contrast, increasing cAMP concentrations in endothelium may suppress edema by enhancing the permeability barrier.
...
PMID:Opposing roles of cyclic AMP in the vascular control of edema formation. 769 36

1. We have investigated the bronchodilator potential of type V phosphodiesterase (PDE V) inhibitors in anaesthetized ventilated guinea-pigs using the potent and selective PDE V inhibitor, SK&F 96231. We have compared its activity to that of salbutamol, the PDE III inhibitors, siguazodan and SK&F 95654 and to the PDE IV inhibitor rolipram. 2. Administered as an i.v. infusion SK&F 96231 (0.6 and 1 mg kg-1 min-1, i.v.) caused a slowly developing inhibition of histamine (100 nmol kg-1, i.v.)-induced bronchoconstriction and elevated tracheal cyclic GMP levels in the anaesthetized guinea-pig. SK&F 96231 (0.1 and 0.3 mg kg-1 min-1, i.v.) was without effect on histamine-induced bronchoconstriction. In the presence of a sub-threshold infusion of SNP (0.1 mumol kg-1 min-1, i.v.) there was a marked enhancement of SK&F 96231-induced inhibition of histamine responses such that at infusion rates that were ineffective alone, SK&F 96231 caused a > 50% inhibition of histamine responses. The stimulation of tracheal cyclic GMP accumulation by SK&F 96231 was also potentiated. 3. Administered directly into the airway, SK&F 96231 (300 micrograms in 5 mg lactose carrier) was largely without effect on histamine-induced bronchoconstriction (4.9 +/- 1.9% inhibition). In the presence of SNP (0.1 mumol kg-1 min-1, i.v.) or isosorbide dinitrate (200 micrograms administered by insufflation into the trachea) there was a marked potentiation of the inhibitory activity of SK&F 96231 (40 +/- 4% and 62 +/- 1.8% respectively). 4. Salbutamol and rolipram (3-300 microg by insufflation) caused a dose-related inhibition of histamine responses with a maximum of 91 +/- 2% and 59 +/- 10% respectively. The PDE III inhibitor, siguazodan,was without effect on histamine responses but they were reduced (27.7 +/- 4.8% at 300 microg) by SK&F95654. There was a marked enhancement of the inhibitory activity of rolipram in the presence of SK&F 95654.5. We conclude that SK&F 96231 has weak anti-spasmogenic activity in the guinea-pig in vivo, we suggest that this is primarily a consequence of a low endogenous guanylate cyclase activity in the airway. The potentiation of the anti-spasmogenic activity of SK&F 96231 by SNP suggests that a combination of PDE V inhibitor and guanylate cyclase agonist might provide significant bronchodilator activity.6. We have established that PDE IV inhibitors are bronchodilators when administered directly into the airway of anaesthetized guinea-pigs but that PDE III inhibitors are only weakly active. The marked enhancement of the inhibitory activity of rolipram by the PDE III inhibitor, SK&F 95654, indicates that inhibitors of both PDE III and PDE IV might offer greater potential as bronchodilators than inhibitors of either isoenzyme alone.
...
PMID:Pulmonary effects of type V cyclic GMP specific phosphodiesterase inhibition in the anaesthetized guinea-pig. 803 6

The ability of low concentrations of salbutamol to potentiate the relaxant effects of the phosphodiesterase (PDE) inhibitors, rolipram, Ro 20-1724 (PDE type IV inhibitor), siguazodan and milrinone (PDE type III inhibitor) was studied on guinea pig isolated trachea. These PDE inhibitors were strong relaxants of guinea pig trachealis under basal tone, but had only a weak activity on tissues precontracted with histamine (10(-5) M). In both cases, PDE type IV inhibitors showed a relaxant effect composed of two phases. The first phase represented 20 and 40% and the second, 90 and 140%, respectively, of relaxation of basal tone and histamine-induced tone. A second characteristic of PDE type IV inhibitors was the very fast and partially reversible relaxation observed at concentrations greater than 3 x 10(-8) M (for histamine-induced tone) at the first addition of inhibitor, followed by a residual relaxant activity. The latter relaxant effect was stable at concentrations of 3 x 10(-8)-10(-5) M and was equivalent to a 20% relaxation (for histamine-induced tone). In the presence of low concentrations (10(-9) and 10(-8) M) of salbutamol, there was a significant concentration-dependent potentiation of the effects of PDE inhibitors on trachea precontracted with histamine. Salbutamol, at a concentration of 10(-9) M, potentiated the effects of PDE inhibitors between 1.4- and 3.6-fold. In the presence of salbutamol 10(-8) M, the potentiation was more marked for siguazodan (37.9-fold), milrinone (11.0-fold) and Ro 20-1724 (14.5-fold) than for rolipram (4.3-fold). These results suggest that low concentrations of salbutamol can potentiate the relaxant effects of both PDE type III and PDE type IV inhibitors. Thus, PDE type IV inhibitors, which have antiinflammatory properties, could also provide adequate bronchodilation when used in combination with lower than usual doses of beta 2-agonists.
...
PMID:Salbutamol potentiates the relaxant effects of selective phosphodiesterase inhibitors on guinea pig isolated trachea. 887 Nov 35


1 2 3 Next >>

---