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)

We have compared the mechanisms that contribute to endothelium-derived hyperpolarizing factor (EDHF)-type responses induced by ACh and the Ca(2+) ionophore A-23187 in the rabbit iliac artery. Relaxations to both agents were associated with ~1.5-fold elevations in smooth muscle cAMP levels and were attenuated by the adenylyl cyclase inhibitor 2',5'-dideoxyadenosine (DDA) and potentiated by the cAMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Mechanical responses were inhibited by coadministration of the Ca(2+)-activated K(+) channel blockers apamin and charybdotoxin, both in the absence and presence of IBMX, but were unaffected by blockade of ATP-sensitive K(+) channels with the sulphonylurea glibenclamide. Relaxations and elevations in cAMP evoked by ACh were abolished by 18alpha-glycyrrhetinic acid, which disrupts gap junction plaques, whereas the corresponding responses to A-23187 were unaffected by this agent. Consistently, in "sandwich" bioassay experiments, A-23187, but not ACh, elicited extracellular release of a factor that evoked relaxations that were inhibited by DDA and potentiated by IBMX. These findings provide evidence that EDHF-type relaxations of rabbit iliac arteries evoked by ACh and A-23187 depend on cAMP accumulation in smooth muscle, but involve signaling via myoendothelial gap junctions and the extracellular space, respectively.
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PMID:Gap junction-dependent and -independent EDHF-type relaxations may involve smooth muscle cAMP accumulation. 1189 92

The effects of nitric oxide (NO) donors on the L-type Ca(2+) current (I(Ca,L)) and the muscarinic activated K(+) current (I(K,ACh)) were studied in isolated rat cardiac myocytes. The nitrosothiol S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 1 pM-1 microM) strongly potentiated the stimulation of the I(Ca,L) elicited by subthreshold concentrations of isoprenaline (Iso, 0.1-0.5 nM) in ventricular myocytes. The effect of SNAP was mimicked by 2-(N,N-diethylamino)-diazenolate-2-oxide (DEANO, 1 pM-1 nM), a NONOate that spontaneously releases NO in a pH-controlled manner, and was blunted by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (100 microM), a NO trap. 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxaline-1-one (10 microM), a guanylyl cyclase inhibitor, did not alter the effect of SNAP. SNAP (1 pM-1 microM) did not modify the effect of L858051 (0.1-0.3 microM), a forskolin analogue that activates adenylyl cyclase, on I(Ca,L) and did not enhance the basal I(Ca,L) in the presence of rolipram (1 microM), a phosphodiesterase type 4 inhibitor. Superfusion with Rp-CPT-cAMPS (500 microM), or internal dialysis with cAMP-dependent protein kinase (cA-PK) inhibitory peptide (PKI; 20 microM), inhibitors of the cA-PK, blunted the effect of SNAP (1 nM and 1 microM) on the Iso-stimulated (1-100 pM) I(Ca,L). SNAP (1 nM and 1 microM) potentiated the threshold stimulation of I(Ca,L) elicited by internal GTP-gammaS (10 microM), a non-hydrolysable analogue of GTP. SNAP (1 pM-1 microM) and DEANO (1 microM) potentiated the stimulation of I(K,ACh) elicited by low concentrations of ACh (1-2 nM) in rat atrial myocytes. The threshold stimulation of I(K,ACh) elicited by internal 5'-guanylylimidodiphosphate (10 microM) was also potentiated by NO donors. SNAP (1 microM) did not modify I(K,ACh) reconstituted in human embryonic kidney 293 cells, in the absence or in the presence of ACh (1 or 10 nM). Taken together, these data suggest that NO is a cGMP-independent modulator of G-protein-coupled muscarinic and beta-adrenergic receptor actions on cardiac ion channels. Although this action of NO seemed to occur at the level of G proteins, it appeared to require a component distinct from receptors, G proteins or their effectors.
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PMID:NO donors potentiate the beta-adrenergic stimulation of I(Ca,L) and the muscarinic activation of I(K,ACh) in rat cardiac myocytes. 1195 32

We report functional neuronal and synaptic transmission properties in Drosophila CNS neurons. Whole cell current- and voltage-clamp recordings were made from dorsally positioned neurons in the larval ventral nerve cord. Comparison of neuronal Green Fluorescent Protein markers and intracellular dye labeling revealed that recorded cells consisted primarily of identified motor neurons. Neurons had resting potentials of -50 to -60 mV and fired repetitive action potentials (APs) in response to depolarizing current injection. Acetylcholine application elicited large excitatory responses and AP bursts that were reversibly blocked by the nicotinic receptor antagonist D-tubocurarine (dtC). GABA and glutamate application elicited similar inhibitory responses that reversed near normal resting potential and were reversibly blocked by the chloride channel blocker picrotoxin. Multiple types of endogenous synaptically driven activity were present in most neurons, including fast spontaneous synaptic events resembling unitary excitatory postsynaptic currents (EPSCs) and sustained excitatory currents and potentials. Sustained forms of endogenous activity ranged in amplitude from smaller subthreshold "intermediate" sustained events to large "rhythmic" events that supported bursts of APs. Electrical stimulation of peripheral nerves or focal stimulation of the neuropil evoked sustained responses and fast EPSCs similar to endogenous events. Endogenous activity and evoked responses required external Ca(2+) and were reversibly blocked by dtC application, indicating that cholinergic synaptic transmission directly underlies observed activity. Synaptic current amplitude and frequency were reduced in shibire conditional dynamin mutants and increased in dunce cAMP phosphodiesterase mutants. These results complement and advance those of recent functional studies in Drosophila embryonic neurons and demonstrate the feasibility of in-depth synaptic transmission and plasticity studies in the Drosophila CNS.
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PMID:Electrophysiological analysis of synaptic transmission in central neurons of Drosophila larvae. 1216 36

In isolated superior mesenteric artery rings from age-matched control rats and streptozotocin (STZ)-induced diabetic rats, we investigated the role of cAMP in endothelium-derived hyperpolarizing factor (EDHF)-type relaxation. The ACh-induced EDHF-type relaxation was significantly weaker in STZ-induced diabetic rats than in control rats, and in both groups of rats it was attenuated by 18alpha-glycyrrhetinic acid (18alpha-GA), an inhibitor of gap junctions, and enhanced by IBMX, a cAMP-phosphodiesterase (PDE) inhibitor. These enhanced EDHF-type responses were very similar in magnitude between diabetic and age-matched control rats. The EDHF-type relaxation was enhanced by cilostamide, a PDE3-selective inhibitor, but not by Ro 20-1724, a PDE4-selective inhibitor. The expression levels of the mRNAs and proteins for two cAMP PDEs (PDE3A, PDE3B) were significantly increased in STZ-induced diabetic rats, but those for PDE4D were not. We conclude that the impairment of EDHF-type relaxations in STZ-induced diabetic rats may be attributed to a reduction in the action of cAMP via increased PDE activity.
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PMID:Alterations in EDHF-type relaxation and phosphodiesterase activity in mesenteric arteries from diabetic rats. 1279 80

The effects of nitric oxide (NO) donors, S-nitroso-N-acetylpenicillamine, S-nitroso-l-glutathione, sodium nitroprusside and sodium nitrite were investigated on the activity of the isolated hearts of Achatina fulica and Helix aspersa. NO donors inhibited heart activity in a concentration-dependent manner. The only exception was sodium nitroprusside, which excited H. aspersa heart. The inhibitory effects of these NO donors were reduced by the NO scavenger, methylene blue, the guanylyl cyclase inhibitor, 1H-(1,2,4) Oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), and potentiated by 8-Br-cGMP and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Acetylcholine also inhibited the heart activity, and this inhibition was reduced by methylene blue and ODQ. Positive NADPH-diaphorase staining was located in the outer pericardial layer of the heart of A. fulica. The present results provide evidence that NO may modulate the activity of gastropod hearts, and this modulation may modify the inhibitory action of acetylcholine on heart activity.
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PMID:Evidence for a possible role for nitric oxide in the modulation of heart activity in Achatina fulica and Helix aspersa. 1505 Sep 21

In addition to the somatodendritic region, myenteric motoneuron terminals are endowed with nicotinic autoreceptors. We aimed at investigating the effect of nicotinic receptor (nAChR) activation on [3H]-acetylcholine ([3H]-ACh) release from longitudinal muscle-myenteric plexus of the rat ileum and to evaluate whether this could be modulated by adenosine, an endogenous neuromodulator typically operating changes in intracellular cyclic AMP. The nAChR agonist, 1,1-dimethyl-4-phenylpiperazinium (DMPP, 1-30 microM, 3 min) increased [3H]-ACh release in a concentration-dependent manner. DMPP (30 microM)-induced [3H]-ACh outflow was attenuated by hexamethonium (0.1-1 mM), tubocurarine (1-5 microM), or by removing external Ca2+ (plus EGTA, 1 mM). In contrast to veratridine (0.2-10 microM)-induced [3H]-ACh release, the DMPP (30 microM)-induced outflow was resistant to tetrodotoxin (1 microM) and cadmium (0.5 mM). Pretreatment with adenosine deaminase (0.5 U/mL) or with the adenosine A(2A)-receptor antagonist, ZM 241385 (50 nM), enhanced nAChR-induced transmitter release. Activation of A(2A) receptors with CGS 21680C (3 nM) reduced the DMPP-induced release of [3H]-ACh. CGS 21680C (3 nM) inhibition was prevented by MDL 12,330A (10 microM, an adenylate cyclase inhibitor) and by H-89 (10 microM, an inhibitor of protein kinase A), but was potentiated by rolipram (300 microM, a phosphodiesterase inhibitor). DMPP-induced transmitter release was decreased by 8-bromo-cyclic AMP (1 mM, a protein kinase A activator), rolipram (300 microM), and forskolin (3 microM, an activator of adenylate cyclase). Both MDL 12,330A (10 microM) and H-89 (10 microM) facilitated DMPP-induced release of [3H]-ACh. The results indicate that nAChR-induced [3H]-ACh release is triggered by the influx of Ca2+, independent of voltage-sensitive calcium channels, presumably directly through nAChRs located on myenteric axon terminals. It was also shown that endogenous adenosine, activating A(2A) receptors coupled to the adenylate cyclase/cyclic AMP transducing system, is tonically downregulating this nAChR-mediated control of [3H]-ACh release.
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PMID:Adenosine activating A(2A)-receptors coupled to adenylate cyclase/cyclic AMP pathway downregulates nicotinic autoreceptor function at the rat myenteric nerve terminals. 1523 6

The present study addressed whether combined treatment with a phosphodiesterase type 5 inhibitor, sildenafil, and a nitric oxide donor, molsidomine, prevents development of pulmonary hypertension in chronic hypoxic rats. Two weeks of hypoxia increased right ventricular systolic pressure, and right ventricular and lung weight. Treatment with either sildenafil (10 mg/kg/day) or molsidomine (15 mg/kg/day) in drinking water reduced right ventricular systolic pressure and weight, while lung weight was unchanged. Combining sildenafil and molsidomine did not have additional effects compared to molsidomine alone. The number of muscularized pulmonary arteries with diameters below 50 microm was increased in vehicle and sildenafil-treated, but not in molsidomine-treated hypoxic rats. Acetylcholine relaxation was blunted in arteries from vehicle and molsidomine-treated, but not in sildenafil-treated rats. In conclusion, both sildenafil and molsidomine blunts pulmonary hypertension and right ventricular hypertrophy in chronic hypoxic rats, but no synergistic effects were observed.
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PMID:Lack of synergistic effect of molsidomine and sildenafil on development of pulmonary hypertension in chronic hypoxic rats. 1574 Jul 28

We previously reported that in mesenteric arteries from streptozotocin (STZ)-induced diabetic rats that 1) endothelium-derived hyperpolarizing factor (EDHF)-type relaxation is impaired, possibly due to a reduced action of cAMP via increased phosphodiesterase 3 (PDE3) activity (Matsumoto T, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 285: H283-H291, 2003) and that 2) PKA activity is decreased (Matsumoto T, Wakabayashi K, Kobayashi T, and Kamata K. Am J Physiol Heart Circ Physiol 287: H1064-H1071, 2004). Here we investigated whether chronic treatment with cilostazol, a PDE3 inhibitor, improves EDHF-type relaxation in mesenteric arteries isolated from STZ rats. We found that in such arteries 1) cilostazol treatment (2 wk) improved ACh-, A-23187-, and cyclopiazonic acid-induced EDHF-type relaxations; 2) the ACh-induced cAMP accumulation was transient and sustained in arteries from cilostazol-treated STZ rats; 3) the EDHF-type relaxation was significantly decreased by a PKA inhibitor in the cilostazol-treated group, but not in the cilostazol-untreated group; 4) cilostazol treatment improved both the relaxations induced by cAMP analogs and the PKA activity level; and 5) PKA catalytic subunit (Cat-alpha) protein was significantly decreased, but the regulatory subunit RII-beta was increased (and the latter effect was significantly decreased by cilostazol treatment). These results strongly suggest that cilostazol improves EDHF-type relaxations in STZ rats via an increase in cAMP and PKA signaling.
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PMID:Cilostazol improves endothelium-derived hyperpolarizing factor-type relaxation in mesenteric arteries from diabetic rats. 1590 66

It is known that cAMP and cGMP are important for vasorelaxation, and cyclic nucleotide phosphodiesterases (PDEs) regulate their levels. Balloon angioplasty (BAL) is associated with reduced cAMP and cGMP levels, and inhibition of PDE-3 reduces restenosis. In this study, we found that BAL increased PDE-3 activity, which affected vasoreactivity of rat aortic rings 24-h post-BAL; these were compared with intact (INT) and ex vivo endothelium-denuded rings (RUB) from sham rats. In BAL and RUB rings, vasorelaxant responses to ACh were abolished. The EC(50) for phenylephrine (PE) was 1.8-fold less in RUB than in INT or BAL, whereas the maximal contractile effect of PE was greater in BAL than in INT or RUB. PDE-3 inhibitors reduced the maximal response to PE by >65% in BAL compared with 10-30% in INT and RUB; the reduction of the maximal response to U-46619 was 37% in BAL compared with 8% in INT with no reduction in RUB. PDE-4 inhibitors reduced PE-induced tone by <30% in an endothelium-dependent manner. Vasorelaxant responses to agonists that utilize cAMP were greatly impaired in BAL and RUB rings, and inhibition of PDE-3 enhanced the vasorelaxant responses in BAL or RUB. Inhibition of PDE-4 increased vasorelaxant responses to isoproterenol (ISO) to a much lesser degree. Thus PDE-3 and PDE-4 inhibitors exhibited differential effects on PE-induced tone and vasorelaxant responses to ISO. Inhibition of PDE-3 also produced a greater increase in cAMP in BAL than INT or RUB rings. These results suggest that increased PDE-3 activity after BAL may promote a vasospastic state and that the reduction in cAMP may, possibly, influence vessel remodeling.
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PMID:Differential effects of phosphodiesterase PDE-3/PDE-4-specific inhibitors on vasoconstriction and cAMP-dependent vasorelaxation following balloon angioplasty. 1729 98

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


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