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 smooth muscle relaxant activity and other pharmacological properties of imidazo[1,2-alpha]pyrazine derivatives were compared with those of theophylline. Imidazo[1,2-alpha]pyrazine derivatives exhibited a potent smooth muscle relaxant activity regardless of the agent which had elicited the contraction and thus showed a broad spectrum of non specific smooth muscle relaxant activity. In the isolated guinea-pig atria, imidazo[1,2-alpha]pyrazine derivatives exhibited potent inotropic and chronotropic activities. As opposed to theophylline, the imidazo[1,2-alpha]pyrazine derivatives tested were unable to antagonize the adenosine-induced inhibition of spontaneous contractile activity of rabbit ileum. Furthermore, as opposed to theophylline, these derivatives did not exhibit a marked diuretic activity. Thus it appears that they do not act as adenosine receptor antagonists. Imidazo[1,2-alpha]pyrazine derivatives inhibited the total cAMP-phosphodiesterase (cAMP-PDE) and the total cGMP-phosphodiesterase (cGMP-PDE) activities of bovine trachea but with relatively low potencies, sharing a discrepancy between their activity on isolated tissues and their ability to inhibit PDE. It is suggested that imidazo[1,2-alpha]pyrazine derivatives may selectively inhibit type III and/or type IV phosphodiesterase isoenzymes involved in the regulation of the mechanical activity of cardiac and smooth muscle tissues.
...
PMID:Pharmacological activities of imidazo[1,2-alpha]pyrazine derivatives. 859 86

Several endogenous factors generated within the vessel wall have been implicated in contributing to the vascular remodeling process associated with hypertension and atherosclerosis. Furthermore, substances generated by smooth muscle cells (SMCs) are known to regulate SMC proliferation in an autocrine fashion. Adenosine is a vasodilator synthesized by SMCs, and exogenous adenosine inhibits SMC proliferation. However, whether adenosine produced endogenously has antimitogenic effects is not known. Hence, we evaluated the effects of SMC-derived adenosine on 2.5% fetal calf serum-induced proliferation of rat aortic SMCs. SMC proliferation was assayed by measurement of DNA synthesis ([3H]thymidine incorporation) and cell counting. To determine the effects of endogenous adenosine on SMC proliferation, we stimulated growth-arrested SMCs with 2.5% fetal calf serum in the presence and absence of modulators of adenosine levels, including (1) erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA; inhibits adenosine deaminase), (2) dipyridamole (blocks adenosine transport and inhibits phosphodiesterase), (3) dipyridamole plus EHNA, and (4) adenosine with or without EHNA. [3H]Thymidine incorporation and cell number were measured after 24 and 96 hours, respectively. EHNA and dipyridamole inhibited both FCS-induced DNA synthesis and cell proliferation in a concentration-dependent manner. Furthermore, extracellular (in medium) adenosine levels were significantly increased when cultured cells were treated with EHNA, and the inhibitory effects of dipyridamole as well as exogenous adenosine were enhanced in the presence of EHNA. Additionally, the inhibitory effects of dipyridamole and EHNA on DNA synthesis were significantly reduced in the presence of KF17837, an A2 adenosine receptor antagonist. These results indicate that SMC-derived adenosine can inhibit SMC proliferation. Hence, it is possible that a defect in localized adenosine synthesis within the vessel wall could contribute to vascular thickening and neointima formation.
...
PMID:Smooth muscle cell-derived adenosine inhibits cell growth. 861 38

Caffeine and related methylxanthines are competitive antagonists at A1- and A2-adenosine receptors, but have other actions at the cellular level that contribute to their effects on behavior. As an approach toward determining the role of adenosine receptors in the behavioural effects of drugs, four squirrel monkeys were trained to discriminate between injections of CGS 15943 (1.0 mg/kg i.m.), a nonxanthine adenosine receptor antagonist that does not inhibit phosphodiesterase, and its vehicle. All monkeys generalized dose-dependently and completely to six of seven methylxanthines: 3-isobutyl-1-methylxanthine (0.1-1.75 mg/kg), theophylline (0.03-3.0 mg/kg), paraxanthine (0.3-30 mg/kg), 8-cyclopentyltheophylline (0.3-30 mg/kg), theobromine (0.3-30 mg/kg) and caffeine (1.0-30 mg/kg). Three of four monkeys did not generalize to 8-p-sulfophenyl-theophylline (1.0-30 mg/kg), which does not cross the blood-brain barrier. When the training dose of CGS 15943 was administered concurrently with adenosine-receptor agonists, its effects were blocked dose-dependently and completely by CGS 21680 (A2 selective), only partially by cyclohexyladenosine (A1 selective), but were not blocked by 5'-N-ethylcarboxamidoadenosine (nonselective). CGS 21680 did not block responding on the CGS 15943-appropriate lever occasioned by 30 mg/kg of caffeine or 3.0 mg/kg of theophylline. These results suggest that stimulus control of behavior by CGS 15943 derives, in part, from blockade of A2-adenosine receptors located in the central nervous system. However, the potency order of methylxanthines as CGS 15943-like discriminative stimuli did not correlate with their relative affinities at either A2- or A1-adenosine receptors or their potencies for other known effects at the cellular level. Therefore, a novel mechanism of action might account for the CGS 15943-like discriminative effects of some or all of these drugs.
...
PMID:Discriminative effects of CGS 15943, a competitive adenosine receptor antagonist, in monkeys: comparison to methylxanthines. 862 53

Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) was shown to reverse the hypoxic pressor response (HPR) in the isolated, blood-perfused rat lung model. EHNA, an adenosine deaminase inhibitor, showed reversal of the HPR in a dose-dependent manner (EC50 = 129 +/- 30 microM). We found that the reversal of HPR by EHNA was not mediated by the adenosine receptors because the EHNA effect was not blocked by the adenosine receptor antagonist, 8-p-sulfophenyl-theophylline (67 microM; n = 6). Pretreatment with a cy-clic-3',5'-adenosine monophosphate (cAMP)-dependent protein kinase inhibitor, Rp-adenosine-3',5'-cyclic monophosphorothioate (0.5 mM; n = 4), blocked EHNA reversal of the HPR. As an alternative mechanism of action, EHNA inhibition of cyclic nucleotide phosphodiesterase(s) isozymes was studied in endothelium intact and denuded pulmonary arteries. Using anion-exchange chromatography the cyclic nucleotide phosphodiesterase (PDE) separated into predominantly PDE families 2 and a mixture of 3 and 4. DEAE fractions showing cAMP hydrolysis activated by 5 microM cyclic-3',5'-guanosine monophosphate (cGMP) had a Km for cAMP of 6.3 microM and an apparent Kact for cGMP of 1.4 microM. EHNA was shown to inhibit PDE2 competitively. In intact vessels, the IC50 for EHNA was 3.3 microM using 0.03 microM [3H]-cAMP substrate assayed in the presence of 2 microM cGMP and in denuded vessels 3.7 microM at 0.03 microM [3H]-cAMP substrate in the presence of 5 microM cGMP. Fractions in which cAMP hydrolysis was inhibited or not affected by 5 microM cGMP (PDE3 and 4, respectively) showed an IC50 of > 200 microM for EHNA. We conclude that reversal of the hypoxic pressor response by EHNA in the isolated, perfused rat lung model occurs with a mechanism involving in part inhibition of smooth muscle PDE2.
...
PMID:Erythro-9-(2-hydroxy-3-nonyl)adenine inhibits cyclic-3',5'-guanosine monophosphate-stimulated phosphodiesterase to reverse hypoxic pulmonary vasoconstriction in the perfused rat lung. 863 46

The present study was carried out to examine whether activation of adenosine receptors by adenosine analogues will affect casein production by mouse mammary epithelial cells. The morphogenesis and functions of epithelial tissue in the mammary gland are influenced by their surrounding adipocytes. Adipocytes are known to release adenosine into the extracellular fluid which can modulate cyclic-AMP levels in surrounding cells through binding to their adenosine receptors. To examine a possible paracrine effect of adenosine, the modulation of casein production in mammary explant culture and mammary epithelial cell (MEC) culture by adenosine receptor agonists has been investigated. We have observed that activation of the A1-adenosine receptor subtype in mammary tissue by an adenosine analogue (-)N6-(R-phenyl-isopropyl)-adenosine (PIA) raised cAMP levels. PIA and another adenosine receptor agonist, isobutylmethylxanthine (IBMX), inhibited casein accumulation both in explants and in MEC cultures in the presence of lactogenic hormones, which suggests that PIA or adenosine can act directly on the epithelial cells. This inhibition does not appear to be caused by elevation of cAMP levels or phosphodiesterase activity. The inhibition of intracellular casein accumulation by PIA and IBMX in explant cultures can be reversed via treatment of pertussis toxin which is known to ADP-ribosylate GTP-binding G alpha i-proteins, indicating that a Gi-protein-dependent pathway may be involved in this inhibition. The results also suggest that local accumulation of adenosine in the extracellular fluids of mammary glands is likely to inhibit the lactogenic response of mammary epithelial cells.
...
PMID:Adenosine-mediated inhibition of casein production by mouse mammary glands in culture. 870 67

Sodium fluoride increased the force of contraction in isolated guinea-pig papillary muscles concentration dependently, starting at 3 mmol/1. Sodium fluoride inhibited phosphorylase phosphatase activity in homogenates from guinea pig hearts, starting at 1 mmol/1. The positive inotropic effect of 3 mmol/1 sodium fluoride was not accompanied by an increase in cAMP content in guinea-pig papillary muscles. In papillary muscles, carbachol or (-)-N(6)-phenylisopropyladenosine reduced the positive inotropic effect of isoprenaline (10 nmol/1) or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (60 mu mol/1). These negative inotropic effects of carbachol and (-)-N(6)-phenylisopropyladenosine were attenuated by additional sodium fluoride (3 mmol/l). It is concluded that sodium fluoride can impair the signal transduction of muscarinic M2 (carbachol) and adenosine receptor (-)-N(6)-phenylisopropyladenosine) agonists. This effect of sodium fluoride could support the hypothesis that the cardiac effects of muscarinic M2 and adenosine receptor agonists involve, at least in part, the activation of phosphatases.
...
PMID:Sodium fluoride attenuates the negative inotropic effects of muscarinic M2 and adenosine receptor agonists. 875 Jul 5

It has been previously demonstrated that activation of A1 adenosine receptors in frog melanotrophs causes inhibition of spontaneous action potential discharges and alpha-melanocyte-stimulating hormone secretion. In the present study, we have investigated the effect of adenosine on high-voltage-activated (HVA) calcium currents in cultured melanotrophs, using the whole-cell variant of the patch-clamp technique with barium as a charge carrier. Adenosine and the specific A1 adenosine receptor agonist R-PIA (50 microM each) produced a decrease of the amplitude of the barium current, while the selective A2 adenosine receptor agonist CGS 21680 did not affect the current. The inhibitory effect of R-PIA was observed throughout the activation range of the current, with stronger responses at more positive potentials. R-PIA inhibited both the L- and N-type components of the current, the effect on the N-component being two-fold higher than on the L-component. The inhibitory effect of R-PIA was rendered irreversible by addition of GTP gamma S (100 microM) to the intracellular solution. Pre-treatment of the cells with pertussis toxin (1 microgram/ml; 12 h) totally abolished the effect of R-PIA on the HVA calcium channels. Conversely, addition of a high concentration of cAMP (100 microM) together with the phosphodiesterase inhibitor IBMX (100 microM) to the intracellular solution did not modify the effect of R-PIA on the current. It is concluded that, in frog melanotrophs, adenosine induces inhibition of L- and N-calcium currents and that this effect is mediated by a pertussis toxin-sensitive G protein. Our data also indicate that the inhibitory effect of adenosine on the calcium currents is not mediated by inhibition of adenylyl cyclase.
...
PMID:Adenosine inhibits L- and N-type calcium channels in pituitary melanotrophs. Evidence for the involvement of a G protein in calcium channel gating. 886 54

In this study we determined whether cAMP is metabolized to adenosine in vascular smooth muscle cells and whether cAMP-derived adenosine modulates vascular smooth muscle cell growth. Confluent smooth muscle cells were exposed to cAMP (0.01 to 30 mumol/L) in the presence and absence of 3-isobutyl-1-methylxanthine (IBMX, 1 mmol/L; an inhibitor of both extracellular and intracellular phosphodiesterase), alpha, beta-methyleneadenosine 5'-diphosphate (AMP-CP, 100 mumol/L; an ecto-5'-nucleotidase inhibitor), and 1,3-dipropyl-8-p-sulfophenyl-xanthine (DPSPX, 100 mumol/L; a xanthine that can inhibit extracellular phosphodiesterase) for 0 to 60 minutes. Medium was then sampled and assayed for AMP, adenosine, and inosine. cAMP increased the amount of AMP, adenosine, and inosine in the medium in a time- and concentration-dependent manner. The conversion of cAMP to adenosine and inosine was inhibited by blockade of phosphodiesterase with IBMX, of ecto-phosphodiesterase with DPSPX, and of ecto-5'-nucleotidase with AMP-CP. To evaluate the physiological relevance of cAMP-derived adenosine in vascular smooth muscle cell proliferation, we studied the inhibitory effects of cAMP (10(-4) mol/L) and 8-bromo-cAMP (10(-4) mol/L) on fetal calf serum-induced DNA synthesis ([3H]thymidine incorporation) in the presence and absence of erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, an inhibitor of adenosine deaminase), dipyridamole (a blocker of adenosine transport), KF17837 (a selective A2 adenosine receptor antagonist), and DPSPX (a nonselective adenosine receptor antagonist). cAMP inhibited DNA synthesis, and both EHNA and dipyridamole enhanced this effect. Both KF17837 and DPSPX significantly reduced the inhibitory effects of cAMP on DNA synthesis; however, they did not reduce the inhibitory effects of 8-bromo-cAMP on DNA synthesis. These results indicate that vascular smooth muscle cells metabolize cAMP to adenosine via the sequential action of ecto-phosphodiesterase and ecto-5'-nucleotidase and provide the first evidence that cAMP-derived adenosine can inhibit vascular smooth muscle cell growth. Hence, this cAMP-adenosine pathway may importantly contribute to the regulation of vascular biology.
...
PMID:Cyclic AMP-adenosine pathway inhibits vascular smooth muscle cell growth. 890 21

The role of the phosphodiesterase type IV isozyme (PDE IV) in the regulation of cerebrovascular tone was investigated in the canine basilar artery in vitro and in vivo. The PDE isozymes extracted from the canine basilar artery were isolated by diethylaminoethanol (DEAE)-Sepharose affinity chromatography and identified based on sensitivity to isozyme-selective PDE inhibitors. [3H]cAMP hydrolysis was observed in one major and one minor peak of activity. The predominant peak was inhibited by the addition of cGMP (25%), siguazodan (26%), rolipram (39%), and the combination of siguazodan and rolipram (95%). Selective PDE IV inhibitors BRL 61063, rolipram, and denbufylline were equieffective inhibitors of [3H]-ccAMP hydrolysis mediated by PDE IV isolated from the canine basilar artery [concentrations producing 50% inhibition (IC50S) = 0.21 +/- 0.05 microM, 0.67 +/- 0.23 microM, and 0.73 +/- 0.16 microM, respectively]. In precontracted isolated ring segments of the canine basilar artery, selective PDE IV inhibitors produced potent and complete relaxation (IC50S < 150 nM). In contrast, zaprinast (a selective PDE V inhibitor) and siguazodan (a selective PDE III inhibitor) produced only weak relaxation of the basilar artery (IC50S = 4.5 microM and > 10 microM, respectively). Vasorelaxation produced by PDE IV inhibitors was not altered by removing the endothelium, 1-NAME, or adenosine receptor antagonism. In a canine model of acute cerebral vasospasm, all three selective PDE IV inhibitors reversed basilar artery spasm produced by autologous blood without altering mean arterial blood pressure. In contrast, prolonged treatment with BRL 61063 failed to alter the development of basilar spasm in the two hemorrhage canine models of chronic cerebral vasospasm. Denbufylline-induced relaxation in vitro was also significantly impaired in basilar arteries obtained from the model of chronic vasospasm. In conclusion, PDE IV appears to be the predominant isozyme regulating vascular tone mediated by cAMP hydrolysis in cerebral vessels. In addition, vasorelaxation modulated by PDE IV is compromised in chronic cerebral vasospasm associated with subarachnoid hemorrhage.
...
PMID:Identification, characterization, and functional role of phosphodiesterase type IV in cerebral vessels: effects of selective phosphodiesterase inhibitors. 904 May 1

Prolonged activation of an A2A adenosine receptor significantly inhibits the cellular response to subsequent stimulation (A2A desensitization). We have reported previously that activation of phosphodiesterase (PDE) contributes to A2A desensitization in PC12 cells. In the present study, we show that a type IV PDE (PDE4)-selective inhibitor (Ro 20-1724) effectively blocks the increase in PDE activity in desensitized cells. Thus, PDE4 appears to be the PDE specifically activated during A2A desensitization in PC12 cells. Prolonged treatment of PC12 cells with an A2A-selective agonist (CGS21680) leads to increased PDE4 activity in a dose-dependent manner, which can be blocked by an A2A-selective antagonist [8-(3-chlorostyryl)caffeine]. Using two PDE4 antibodies, we were able to demonstrate that the levels of two PDE4-immunoreactive bands (72 and 79 kDa) were increased significantly during A2A desensitization. Prolonged treatment with forskolin to elevate intracellular cyclic AMP contents also resulted in increased PDE4 activity. In addition, activation of PDE4 activity during A2A desensitization could be blocked by a protein kinase A (PKA)-selective inhibitor (H89) and was not observed in a PKA-deficient PC12 cell line (A123). Taken together, activation of PDE4 via a cyclic AMP/PKA-dependent pathway plays a critical role in dampening the signal of the A2A receptor.
...
PMID:Activation of phosphodiesterase IV during desensitization of the A2A adenosine receptor-mediated cyclic AMP response in rat pheochromocytoma (PC12) cells. 928 56


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---