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 potential vasorelaxant, antioxidant and cyclic nucleotide phosphodiesterase (PDE) inhibitory effects of the citrus-fruit flavonoids naringin and (+/-)-naringenin were comparatively studied for the first time in this work. (+/-)-Naringenin (1 microM - 0.3 mM) did not affect the contractile response induced by okadaic acid (OA, 1 microM). However, (+/-)-naringenin relaxed, in a concentration-dependent manner, the contractions elicited by phenylephrine (PHE, 1 microM) or by a high extracellular KCl concentration (60 mM) in intact rat aortic rings. Mechanical removal of endothelium and/or pretreatment of aorta rings with glibenclamide (GB, 10 microM) or tetraethylammonium (TEA, 2 mM) did not significantly modify the vasorelaxant effects of this flavanone. (+/-)-Naringenin (10 microM - 0.1 mM) did not alter the basal uptake of 4) Ca2+ but decreased the influx of 45Ca2+ induced by PHE and KCl in endothelium-containing and endothelium-denuded rat aorta. (+/-)-Naringenin (10 microM - 0.1 mM) was ineffective to scavenge superoxide radicals (O*2-) generated by the hypoxanthine (HX)-xanthine oxidase (XO) system and/or to inhibit XO activity. (+/-)-Naringenin (0.1 mM) significantly increased the production of cGMP and cAMP decreased by PHE (1 microM) and high KCl (60 mM) in cultured rat aortic myocytes. (+/-)-Naringenin preferentially inhibited calmodulin (CaM)-activated PDE1, PDE4 and PDE5 isolated from bovine aorta with IC50 values of about 45 microM, 60 microM and 68 microM, respectively. In contrast, the 7-rhamnoglucoside of (+/-)-naringenin, naringin (1 microM - 0.3 mM), was totally inactive in all experiments. These results indicate that the vasorelaxant effects of (+/-)-naringenin seem to be basically related to the inhibition of PDE1, PDE4 and PDE5 activities.
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PMID:Implication of cyclic nucleotide phosphodiesterase inhibition in the vasorelaxant activity of the citrus-fruits flavonoid (+/-)-naringenin. 1572 16

The effects of inhibitors of different subtypes of potassium (K+) channels were investigated in the mouse forced swimming test (FST). The treatment of animals with tetraethylammonium (TEA, a non-specific inhibitor of potassium channels, 0.25-2.5 ng/site, intracerebroventricular, i.c.v.), glibenclamide (an ATP-sensitive potassium channels (K(ATP) inhibitor, 0.05-5 ng/site, i.c.v.), apamine (a small conductance calcium-activated potassium channels inhibitor (SKCa), 0.1-1 ng/site, i.c.v.), charybdotoxin (a large- (big, BK) and intermediate- (IK) conductance calcium-activated potassium channels inhibitor, 2.5-25 ng/site, i.c.v.) produced an anti-depressant-like effect in the FST. At the highest effective doses, none of the drugs affected the locomotor activity in an open-field. Besides that, the pre-treatment of animals with l-arginine (a nitric oxide (NO) precursor, 750 mg/kg, intraperitoneal, i.p.) or sildenafil (a specific phosphodiesterase type 5 (PDE5) inhibitor, 5 mg/kg, i.p.) prevented the anti-depressant-like effect of all K+ channel inhibitors. The present results demonstrate that the decrease in the immobility time in the FST elicited by the inhibition of several subtypes of K+ channels is also dependent on the inhibition of NO-cGMP synthesis.
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PMID:Effects of potassium channel inhibitors in the forced swimming test: possible involvement of L-arginine-nitric oxide-soluble guanylate cyclase pathway. 1612 18

1. Divergent evidence suggests that the intracellular signalling pathways for beta-adrenoceptor-mediated vascular relaxation involves either cAMP/protein kinase (PK) A or endothelial nitric oxide (NO) release and subsequent activation of cGMP/PKG. The present study identifies the relative roles of NO and cAMP, as well as dependence on the endothelium for beta-adrenoceptor-mediated relaxation of rat isolated aortas. 2. Cumulative concentration-response curves to isoprenaline (0.01-3 micromol/L) in phenylephrine (0.1 micromol/L)-preconstricted endothelium-intact and -denuded aortas were constructed. Isoprenaline-mediated relaxation was partially reduced by endothelium removal and the presence of the NO synthase inhibitor N(G)-monomethyl-L-arginine (0.1 mmol/L), but not by the cAMP antagonist (Rp)-cyclic adenosine-3',5'-monophosphorothioate (Rp-cAMPS; 0.5 mmol/L). 3. In contrast, in endothelium-denuded aortas, the isoprenaline-mediated relaxation was inhibited by Rp-cAMPS and this inhibition was lost in the presence of the NO donor sodium nitroprusside (1 nmol/L). This effect was not due to phosphodiesterase (PDE) activity because the non-selective PDE inhibitor 3-isobutyl-1-methylxanthine (1 micromol/L) failed to affect the isoprenaline vasorelaxant response. 4. The K(+) channel blocker tetraethylammonium (TEA; 1 mmol/L) attenuated isoprenaline-induced relaxation in endothelium-denuded aorta, but its effect was non-additive with Rp-cAMPS, suggesting that the K(+) channel component may involve cAMP. In endothelium-intact aortas, TEA but not Rp-cAMPS reduced isoprenaline relaxation, suggesting an additional non-cAMP component. 5. These findings suggest that beta-adrenoceptors induce vascular smooth muscle relaxation by acting through the NO-cGMP pathway and, when that is disrupted by endothelium removal or the presence of an NO synthase inhibitor, the cAMP pathway in smooth muscles is used. The lack of cAMP participation in endothelium-intact vessels may be because NO suppresses or overrides the cAMP effect.
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PMID:Endogenous nitric oxide attenuates beta-adrenoceptor-mediated relaxation in rat aorta. 1720 42

Organotypic cerebellar cultures were maintained on multi-electrode dishes (MED) with an 8x8 array of electrodes and examined for physiological activity. The cultures remained viable for up to seven months and exhibited spontaneous discharges most likely originating from Purkinje cells. Spike frequencies varied but were mostly around 10-30 Hz and were often stable over weeks with average drifts of <20% per week. Spontaneous firing was significantly reduced by blockers of sodium channels (riluzole) and several potassium channels (iberiotoxin, TEA, 4-amino-pyridine), but blockers of calcium channels, GIRK channels, and SK-type potassium channels were ineffective. Inhibitors of excitatory and inhibitory synaptic transmission made spike discharges more regular. Particularly robust changes in spike frequency were produced by agents that increase cGMP. Bromo-cGMP, the NO donor SNAP, the guanylate cyclase activator YC-1, and the phosphodiesterase inhibitor zaprinast greatly reduced spike frequency. Activation of the metabotropic receptor mGluR1 and inhibition of I(h) channels caused a majority of cells to switch from tonic firing to a cyclic activity mode in which intense firing alternated with silence. Agonists for cholinergic, serotonergic, histamine, opiate, and CRF receptors had no effect, but those for adrenergic and adenosine A1 receptors reduced firing. Moreover, brief application of bromocriptine caused a delayed decrease in firing that reached a minimum after 24 to 48 h and recovered after 1-2 weeks. Taken together, our results demonstrate that long-term cultures maintained on multi-electrode arrays retain many essential features of cerebellar physiology and that they provide a test system that is well suited for broad screening of pharmacological agents as well as for studying long-term effects of drugs, tissue factors, and pathogens.
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PMID:Spontaneous activity in Purkinje cells: multi-electrode recording from organotypic cerebellar slice cultures. 1853 33

We have investigated effects and mechanisms responsible for the activity of 3, 5, 7, 3', 4'-pentamethoxyflavone (PMF) on isolated human cavernosum. PMF is the major flavone isolated from Kaempferia parviflora claimed to act as an aphrodisiac. PMF caused relaxation of phenylephrine precontracted human cavernosal strips, and this effect was slightly inhibited by N(G)-nitro-l-arginine, a nitric oxide synthase inhibitor, but not by ODQ (soluble guanylate cyclase inhibitor), TEA (tetraethylammonium, blocker of voltage-dependent K(+) channels) or glybenclamide (blocker of ATP-dependent K(+) channels). PMF did not significantly inhibit the relaxant activity of glyceryltrinitrate or acetylcholine on human cavernosal strips precontracted with phenylephrine. In contrast, sildenafil (phosphodiesterase inhibitor) potentiated the relaxant activity of glyceryl trinitrate but not of acetylcholine. In normal Krebs solution with nifedipine (blocker of l-type Ca(2+) channels), or in Ca(2+)-free Krebs solution, PMF caused a further inhibition of human cavernosum contracted with phenylephrine. In human cavernosum treated with thapsigargin (inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase) in Ca(2+)-free medium, PMF suppressed the concentration-response curve of human cavernosum to phenylephrine and a further suppression was found when SKF-96365 (a blocker of store-operated Ca(2+) channels and Y-27632 (inhibitor of Rho-kinase)), but not nifedipine, were added sequentially. Thus, PMF had only a weak effect on the release of nitric oxide, and had no effect as a K(ATP)- or K(Ca) channel opener, a phosphodiesterase inhibitor, a store-operated Ca(2+) channel blocker or a Rho-kinase inhibitor. Therefore, these studies suggest that PMF causes relaxation of human cavernosum through voltage-dependent Ca(2+) channels and other mechanisms associated with calcium mobilization.
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PMID:Relaxant mechanisms of 3, 5, 7, 3', 4'-pentamethoxyflavone on isolated human cavernosum. 2280 Sep 34

Slow afterhyperpolarizations (sAHPs) play an important role in establishing the firing pattern of neurons that in turn influence network activity. sAHPs are mediated by calcium-activated potassium channels. However, the molecular identity of these channels and the mechanism linking calcium entry to their activation are still unknown. Here we present several lines of evidence suggesting that the sAHPs in developing starburst amacrine cells (SACs) are mediated by two-pore potassium channels. First, we use whole cell and perforated patch voltage clamp recordings to characterize the sAHP conductance under different pharmacological conditions. We find that this conductance was calcium dependent, reversed at EK, blocked by barium, insensitive to apamin and TEA, and activated by arachidonic acid. In addition, pharmacological inhibition of calcium-activated phosphodiesterase reduced the sAHP. Second, we performed gene profiling on isolated SACs and found that they showed strong preferential expression of the two-pore channel gene kcnk2 that encodes TREK1. Third, we demonstrated that TREK1 knockout animals exhibited an altered frequency of retinal waves, a frequency that is set by the sAHPs in SACs. With these results, we propose a model in which depolarization-induced decreases in cAMP lead to disinhibition of the two-pore potassium channels and in which the kinetics of this biochemical pathway dictate the slow activation and deactivation of the sAHP conductance. Our model offers a novel pathway for the activation of a conductance that is physiologically important.
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PMID:A role for TREK1 in generating the slow afterhyperpolarization in developing starburst amacrine cells. 2339 Mar 12

The aim of this study was to evaluate the relaxant effect of resveratrol (RVT), one of the most commonly employed dietary polyphenols, in rat corpus cavernosum, and to further investigate the contribution of possible underlying mechanisms. Strips of corpus cavernosum were used in organ baths for isometric tension studies. RVT (10(-6)-10(-4) M) produced concentration-dependent relaxation responses in rat corpus cavernosum precontracted by phenylephrine. The relaxant responses to RVT partially, but significantly inhibited by removal of endothelium. Nitric oxide (NO) synthase (NOS) blocker N-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10(-5) M) caused a significant inhibition on relaxation response to RVT, whereas cyclooxygenase inhibitor indomethacin (10(-5) M) did not significantly alter relaxant responses of corpus cavernosum strips to RVT. Corpus cavernosum contractions induced by stepwise addition to Ca2+ to high KCl solution with no Ca2+ were significantly inhibited by RVT incubation. The treatment of corpus cavernosum tissues with non-specific potassium channel inhibitor tetraethylammonium (TEA, 10(-2) M) did also significantly affect the relaxant activity of RVT. Otherwise, the relaxation response of corpus cavernosum induced by the phosphodiesterase-5 inhibitor sildenafil increased significantly in the group pretreated with 10(-5) M RVT. These results demonstrated that RVT has a potent relaxant effect on rat corpus cavernosum via endothelium-dependent and -independent mechanisms. Endothelium-dependent relaxation of corpus cavernosum to RVT is thought to be mediated primarily through NO/cGMP signaling pathway, and possibly an additional mechanism, endothelium-dependent hyperpolarization factor (EDHF). The residual endothelium-independent corpus cavernosum relaxation induced by RVT is uncertain but seems to depend on the interactions of RVT with Ca2+ entry mechanism from the extracellular space and also other undefined direct effects in this tissue.
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PMID:The potent relaxant effect of resveratrol in rat corpus cavernosum and its underlying mechanisms. 2346 62


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