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 dietary flavonol quercetin induces chloride secretion in rat intestine. To clarify the underlying mechanisms, experiments were performed in Ussing chambers with tissue from rat proximal and distal colon. Quercetin induced an increase in short-circuit current (Isc), which was largely independent of submucosal neurons, as it was not affected by the neurotoxin tetrodotoxin. The effect of quercetin was blocked by the calmodulin antagonists trifluoperazine and ophiobolin A and was diminished by a blocker of Ca2+ release from intracellular stores (TMB-8), whereas the muscarinic receptor antagonist atropine was ineffective. The quercetin-induced Isc was abolished in Ca2+-free solution. The flavonol was able to further increase Isc after maximal stimulation of the cAMP pathway by forskolin. The Isc increase by the flavonol was differently affected by two analogous phosphodiesterase inhibitors. Whereas 3-isobutyl-1-methylxanthine (IBMX) antagonized the effect of quercetin, 8-methoxymethyl-IBMX had no effect. Both phosphodiesterase inhibitors similarly influenced the Isc increase induced by forskolin. These results indicate that the chloride secretion induced by quercetin in rat colon depends on Ca2+ and calmodulin. The cAMP pathway and inhibition of phosphodiesterase appear not to be responsible for the secretory activity of the flavonol.
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PMID:The secretory response of the rat colon to the flavonol quercetin is dependent on Ca2+-calmodulin. 1082 11

The effects of a monoclonal antibody (B8E5) directed against the second extracellular loop of the muscarinic M(2) receptor were studied on the L-type Ca(2+) currents (I(Ca,L)) of guinea pig ventricular myocytes using the whole cell patch-clamp technique. Similar to carbachol, B8E5 reduced the isoproterenol (ISO)-stimulated I(Ca,L) but did not significantly affect basal I(Ca,L). Atropine blocked the inhibitory effect of B8E5. The electrophysiological parameters of ISO-stimulated I(Ca,L) were not modified in presence of B8E5. Inhibition of I(Ca,L) by B8E5 was still observed when intracellular cAMP was either enhanced by forskolin or maintained constant by using a hydrolysis-resistant cAMP analog (8-bromoadenosine 3',5'-cyclic monophosphate) or by applying the phosphodiesterase inhibitor IBMX. The effect of B8E5 was mimicked by 8-bromoguanosine 3',5'-cyclic monophosphate, a potent stimulator of cGMP-dependent protein kinase, and prevented by a selective inhibitor of nitric oxide-sensitive guanylyl cyclase [1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one]. These results indicate that the antibody B8E5 inhibits the beta-adrenergic-stimulated I(Ca,L) through activation of the M(2) muscarinic receptor and further suggest that the antibody acts not via the classical pathway of decreasing intracellular cAMP, but rather by increasing cGMP.
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PMID:cGMP-mediated inhibition of cardiac L-type Ca(2+) current by a monoclonal antibody against the M(2) ACh receptor. 1154 62

The present study determined the effects of acetylcholine (ACh) on the L-type Ca(2+) current (I(Ca,L)) stimulated by beta(1)- or beta(2)-adrenergic receptor (AR) agonists in cat atrial myocytes. When isoproterenol (ISO; 0.1 microM) plus the beta(2)-AR antagonist ICI 118,551 (ISO-beta(1)-AR stimulation) or 0.1 microM fenoterol, a beta(2)-AR agonist (FEN-beta(2)-AR stimulation) increased I(Ca,L), ACh (1 microM) inhibited I(Ca,L) by -60 +/- 4 and -63 +/- 6 %, respectively. When ISO plus the beta(1)-AR antagonist atenolol (ISO-beta(2)-AR stimulation) or 1 microM zinterol (ZIN-beta(2)-AR stimulation) increased I(Ca,L), ACh-induced inhibition of I(Ca,L) was significantly smaller, at -21 +/- 3 and -24 +/- 3 %, respectively. L-N(5)-(1-iminoethyl)ornithine (L-NIO, 10 microM), an inhibitor of nitric oxide (NO) synthase, enhanced ACh-induced inhibition of I(Ca,L) when stimulated by ZIN-beta(2)-ARs, but not when stimulated by ISO-beta(1)-ARs or FEN-beta(2)-ARs. Haemoglobin (50 microM), a NO scavenger, also enhanced ACh-induced inhibition when I(Ca,L) was stimulated by ZIN-beta(2)-ARs, but not when stimulated by FEN-beta(2)-ARs. ACh-induced inhibition of I(Ca,L) stimulated by ZIN-beta(2)-ARs was not affected by 10 microM 1H-[1,2,4] oxadiazolo[4,3-a] quinoxaline-1-one (ODQ) a guanylate cyclase inhibitor, but was significantly enhanced by 500 microM reduced glutathione or 100 microM dithiothreitol, agents that act as sinks for S-nitrosylation. ACh-induced inhibition was smaller when I(Ca,L) was stimulated by spermine/NO, a NO donor, than by milrinone, a phosphodiesterase type III inhibitor. ISO (ISO-beta(1)/beta(2)-AR stimulation) increased I(Ca,L) and even though ISO releases NO, ACh prominently inhibited I(Ca,L). This inhibitory effect of ACh was enhanced by L-NIO. Stimulation of ZIN-beta(2)-ARs increased intracellular NO, whereas ISO-beta(1)-ARs or FEN-beta(2)-ARs failed to increase intracellular NO. These results indicate that in atrial myocytes, NO released by selective beta(2)-AR stimulation prevents ACh-induced inhibition of I(Ca,L) stimulated by beta(2)-ARs. NO acts via a cGMP-independent, S-nitrosylation mechanism. Although FEN acts via beta(2)-ARs, it fails to stimulate G(i)-/NO signalling and preferentially stimulates G(s)-/adenylate cyclase signalling, similar to beta(1)-ARs. These findings indicate that NO signalling modulates muscarinic receptor inhibition of atrial function stimulated by beta(2)-ARs.
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PMID:Nitric oxide signalling by selective beta(2)-adrenoceptor stimulation prevents ACh-induced inhibition of beta(2)-stimulated Ca(2+) current in cat atrial myocytes. 1215 73

Current treatments for the overactive detrusor are poorly tolerated and can exert significant adverse effects. Possible targets for the development of new treatments are considered. Potential targets in four locations are examined: detrusor smooth muscle, urothelium, peripheral nerves and the CNS. In the detrusor, the role of various muscarinic receptor subtypes is discussed and beta-adrenoceptor agonists, phosphodiesterase inhibitors and potassium channel openers, all of which inhibit detrusor contractility, are considered for drug development. In the urothelium, a number of substances are released that affect bladder function including ATP, acetylcholine and an inhibitory factor that has yet to be identified. All three systems have the potential to be novel targets for drug development. Other possible therapeutic targets are the mechanisms influencing transmitter release in the bladder, for example, prejunctional 5-hydroxytryptamine (5-HT) 4 receptors. Finally, targets within the CNS and spinal cord are considered, including opioid receptors, 5-HT receptors and alpha-adrenoceptors.
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PMID:Potential therapeutic targets for the treatment of detrusor overactivity. 1510 52

Receptor-mediated changes in cAMP production play an essential role in sympathetic and parasympathetic regulation of the electrical, mechanical, and metabolic activity of cardiac myocytes. However, responses to receptor activation cannot be easily ascribed to a uniform increase or decrease in cAMP activity throughout the entire cell. In this study, we used a computational approach to test the hypothesis that in cardiac ventricular myocytes the effects of beta(1)-adrenergic receptor (beta(1)AR) and M(2) muscarinic receptor (M(2)R) activation involve compartmentation of cAMP. A model consisting of two submembrane (caveolar and extracaveolar) microdomains and one bulk cytosolic domain was created using published information on the location of beta(1)ARs and M(2)Rs, as well as the location of stimulatory (G(s)) and inhibitory (G(i)) G-proteins, adenylyl cyclase isoforms inhibited (AC5/6) and stimulated (AC4/7) by G(i), and multiple phosphodiesterase isoforms (PDE2, PDE3, and PDE4). Results obtained with the model indicate that: 1), bulk basal cAMP can be high ( approximately 1 microM) and only modestly stimulated by beta(1)AR activation ( approximately 2 microM), but caveolar cAMP varies in a range more appropriate for regulation of protein kinase A ( approximately 100 nM to approximately 2 microM); 2), M(2)R activation strongly reduces the beta(1)AR-induced increases in caveolar cAMP, with less effect on bulk cAMP; and 3), during weak beta(1)AR stimulation, M(2)R activation not only reduces caveolar cAMP, but also produces a rebound increase in caveolar cAMP following termination of M(2)R activity. We conclude that compartmentation of cAMP can provide a quantitative explanation for several aspects of cardiac signaling.
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PMID:Compartmentation of cAMP signaling in cardiac myocytes: a computational study. 1729 6

The phosphodiesterase (PDE) 5 inhibitor sildenafil has been shown to display psychotropic actions in humans and animals, and has been used for the treatment of antidepressant-associated erectile dysfunction. However, its effects on the neurobiology of depression are unknown. Nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) inhibition is anti-depressant in animals, and increasing cGMP with sildenafil is anxiogenic in rodents. Substantial cholinergic-nitrergic interaction exists in the brain, while sildenafil shows modulatory actions on cholinergic transmission. Depression is also associated with increased cholinergic drive. Here we report that sildenafil increases muscarinic acetylcholine receptor (mAChR) signaling in human neuroblastoma cells. We also show that fluoxetine (20 mg/kg/day x 7 days), as well as a combination of sildenafil (10 mg/kg/day x 7 days) plus the antimuscarinic atropine (1 mg/kg/day x 7 days) demonstrates significant, comparable antidepressant-like effects in the rat forced swim test (FST) and also reduces cortical beta-adrenergic receptor (beta-AR) density, while sildenafil or atropine alone did not. Importantly, sildenafil did not modify fluoxetine's response. Sildenafil thus demonstrates antidepressant-like effects but only after central muscarinic receptor blockade, providing evidence for cholinergic-nitrergic interactions in the neurobiology of depression.
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PMID:Appearance of antidepressant-like effect by sildenafil in rats after central muscarinic receptor blockade: evidence from behavioural and neuro-receptor studies. 1782 68

Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence, usually with frequency and nocturia. OAB symptoms are often associated with detrusor overactivity (DO). Like OAB symptoms, the prevalence of DO increases with age and can have a neurogenic and/or myogenic aetiology. Bladder outlet obstruction can be a contributing factor in DO, possibly through cholinergic denervation of the detrusor and supersensitivity of muscarinic receptors to acetylcholine, although the prevalence of OAB is similar in men and women across age groups. Acetylcholine is the primary contractile neurotransmitter in the human detrusor, and antimuscarinics exert their effects on OAB/DO by inhibiting the binding of acetylcholine at muscarinic receptors M(2) and M(3) on detrusor smooth muscle cells and other structures within the bladder wall. Worldwide, there are six antimuscarinic drugs currently marketed for the treatment of OAB: oxybutynin, tolterodine, propiverine, trospium, darifenacin, and solifenacin. Each has demonstrated efficacy for the treatment of OAB symptoms, but their pharmacokinetic and adverse event profiles differ somewhat due to structural differences (tertiary vs quaternary amines), muscarinic receptor subtype selectivities, and organ selectivities. Antimuscarinics are generally well tolerated, even in special populations (e.g. men with bladder outlet obstruction, elderly patients, children). The most frequently reported adverse events in clinical studies of antimuscarinics are dry mouth, constipation, headache, and blurred vision; few patients withdraw from clinical trials because of adverse events. Development of an antimuscarinic with functional selectivity for the bladder would reduce the occurrence of antimuscarinic adverse events. The therapeutic potential of several other agents, such as alpha(3)-adrenoceptor agonists, purinergic receptor antagonists, phosphodiesterase inhibitors, neurokinin-1 receptor antagonists, opioids, and Rho-kinase inhibitors, is also under investigation for the treatment of OAB.
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PMID:Muscarinic receptor antagonists for overactive bladder. 1792 84

Perinatal adverse events such as limitation of nutrients or oxygen supply are associated with the occurrence of diseases in adulthood, like cardiovascular diseases and diabetes. We investigated the long-term effects of perinatal hypoxia on the lung circulation, with particular attention to the nitric oxide (NO)/cGMP pathway. Mice were placed under hypoxia in utero 5 days before delivery and for 5 days after birth. Pups were then bred in normoxia until adulthood. Adults born in hypoxia displayed an altered regulation of pulmonary vascular tone with higher right ventricular pressure in normoxia and increased sensitivity to acute hypoxia compared with controls. Perinatal hypoxia dramatically decreased endothelium-dependent relaxation induced by ACh in adult pulmonary arteries (PAs) but did not influence NO-mediated endothelium-independent relaxation. The M(3) muscarinic receptor was implicated in the relaxing action of ACh and M(1) muscarinic receptor (M(1)AChR) in its vasoconstrictive effects. Pirenzepine or telenzepine, two preferential inhibitors of M(1)AChR, abolished the adverse effects of perinatal hypoxia on ACh-induced relaxation. M(1)AChR mRNA expression was increased in lungs and PAs of mice born in hypoxia. The phosphodiesterase 1 (PDE1) inhibitor vinpocetine also reversed the decrease in ACh-induced relaxation following perinatal hypoxia, suggesting that M(1)AChR-mediated alteration of ACh-induced relaxation is due to the activation of calcium-dependent PDE1. Therefore, perinatal hypoxia leads to an altered pulmonary circulation in adulthood with vascular dysfunction characterized by impaired endothelium-dependent relaxation and M(1)AChR plays a predominant role. This raises the possibility that muscarinic receptors could be key determinants in pulmonary vascular diseases in relation to "perinatal imprinting."
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PMID:Muscarinic receptor M1 and phosphodiesterase 1 are key determinants in pulmonary vascular dysfunction following perinatal hypoxia in mice. 1846 16

To improve the efficacy of medical treatment of patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH), studies on combination treatment with alpha(1)-blockers and 5alpha-reductase inhibitors, alpha(1)-blockers and muscarinic receptor antagonists, and alpha(1)-blockers and 5-phosphodiesterase inhibitors are increasingly performed. The most substantial data are available on the combination of alpha(1)-blockers and 5alpha-reductase inhibitors. This combination is not suitable for symptom improvement alone but for inhibition of progression. A combination therapy of alpha(1)-blockers and muscarinic receptor antagonists cannot be recommended as routine because of the still limited, although promising, data. Only preliminary data are available for the combination of alpha(1)-blockers and 5-phosphodiesterase inhibitors, which do not show convincing advantages over other combinations.
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PMID:[Medical combination therapy in LUTS suggestive of BPH]. 1921 53

Airway hyperreactivity (AHR), lung inflammation, and atopy are clinical signs of allergic asthma. Gestational exposure to cigarette smoke (CS) markedly increases the risk for childhood allergic asthma. Muscarinic receptors regulate airway smooth muscle tone, and asthmatics exhibit increased AHR to muscarinic agonists. We have previously reported that in a murine model of bronchopulmonary aspergillosis, maternal exposure to mainstream CS increases AHR after acute intratracheal administration of Aspergillus fumigatus extract. However, the mechanism by which gestational CS induces allergic asthma is unclear. We now show for the first time that, compared with controls, mice exposed prenatally to secondhand CS exhibit increased lung inflammation (predominant infiltration by eosinophils and polymorphs), atopy, and airway resistance, and produce proinflammatory cytokines (IL-4, IL-5, IL-6, and IL-13, but not IL-2 or IFN-gamma). These changes, which occur only after an allergen (A. fumigatus extract) treatment, are correlated with marked up-regulated lung expression of M1, M2, and M3 muscarinic receptors and phosphodiesterase (PDE)4D5 isozyme. Interestingly, the PDE4-selective inhibitor rolipram attenuates the increase in AHR, muscarinic receptors, and PDE4D5, but fails to down-regulate lung inflammation, Th2 cytokines, or serum IgE levels. Thus, the fetus is extraordinarily sensitive to CS, inducing allergic asthma after postnatal exposure to allergens. Although the increased AHR might reflect increased PDE4D5 and muscarinic receptor expression, the mechanisms underlying atopy and lung inflammation are unrelated to the PDE4 activity. Thus, PDE4 inhibitors might ease AHR, but are unlikely to attenuate lung inflammation and atopy associated with childhood allergic asthma.
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PMID:Maternal exposure to secondhand cigarette smoke primes the lung for induction of phosphodiesterase-4D5 isozyme and exacerbated Th2 responses: rolipram attenuates the airway hyperreactivity and muscarinic receptor expression but not lung inflammation and atopy. 1959 83


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