Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isoliquiritigenin, glabridin, licoarylcoumarin and licoricidin were identified as strong inhibitors of adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase in waste materials which were obtained during the industrial extraction of glycyrrhizin from licorice roots. The structure-activity relationships of 12 flavonoids from licorice roots and 34 4-arylcoumarins were studied. In 4-arylcoumarins, 5,7-dihydroxy derivatives were generally highly inhibitory towards cAMP phosphodiesterase.
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PMID:Inhibition of adenosine 3',5'-cyclic monophosphate phosphodiesterase by flavonoids from licorice roots and 4-arylcoumarins. 165 20

1. The vasorelaxant activity of isoliquiritigenin, isolated from Dalbergia odorifera T, was investigated in the phenylephrine-precontracted rat aorta by measuring tension, guanylate and adenylate cyclase activities, guanosine 3':5'-cyclic monophosphate (cyclic GMP) and adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. 2. Isoliquiritigenin concentration-dependently relaxed rat aorta contracted with phenylephrine, KCl, U-46619, endothelin and 5-hydroxytryptamine, with EC50s of 7.4 +/- 1.6, 10.5 +/- 2.3, 14.3 +/- 3.3, 11.8 +/- 2.0 and 13.6 +/- 3.7 microM, respectively. 3. Isoliquiritigenin caused endothelium-independent relaxation of phenylephrine-precontracted rat aortic rings. Neither NG-monomethyl-L-arginine (L-NMMA) (an inhibitor of the L-arginine-NO pathway) nor oxyhaemoglobin (which binds NO) modified the relaxant effect of isoliquiritigenin. The relaxant action of isoliquiritigenin also persisted in intact aorta in the presence of indomethacin or glibenclamide. However, methylene blue, an inhibitor of soluble guanylate cyclase, abolished relaxation induced by isoliquiritigenin. 4. Incubation of rat aorta with isoliquiritigenin not only increased aortic cyclic GMP content but also caused small increases in aortic cyclic AMP content, and greatly potentiated the increases in cyclic AMP observed in the presence of forskolin. The maximum increase in cyclic GMP by isoliquiritigenin was reached earlier than the increase in cyclic AMP. This result suggests that the increases in cyclic GMP caused by isoliquiritigenin might stimulate the accumulation of cyclic AMP. 5. Concentration-dependent increases in soluble guanylate cyclase activity were observed in isoliquiritigenin (1-100 microM)- or sodium nitroprusside (SNP)-treated rat aortic smooth muscle cells, while adenylate cyclase activity was unchanged in isoliquiritigenin (100 microM)-treated cells. 6. Relaxation and cyclic AMP formation of rat aorta caused by isoliquiritigenin was potentiated in the presence of forskolin (10 nM), which had little effect when given alone. 2',5'-Dideoxyadenosine (DDA,200 microM), an adenylate cyclase inhibitor, diminished the relaxation and cyclic AMP formation of rat aorta by isoliquiritigenin only in the presence of forskolin. DDA did not affect the increases in cyclic GMP formation induced by isoliquiritigenin. These results suggest that elevated levels of cyclic GMP may mediate the majority of the relaxation of the phenylephrine-precontracted aorta induced byisoliquiritigenin, while the synergistic interaction with a low concentration of forskolin depends on an enhanced accumulation of cyclic AMP.7. Relaxation of phenylephrine-precontracted rat aorta and carbachol-precontracted guinea-pig trachea by rolipram (phosphodiesterase, PDE IV inhibitor) was markedly enhanced by isoliquiritigenin, while response to cilostamide (PDE III inhibitor) was not significantly changed by isoliquiritigenin.8. It is concluded that isoliquiritigenin exerts a vasorelaxant effect by activating soluble guanylatecyclase and increasing cyclic GMP. Synergistic effects of isoliquiritigenin and forskolin on muscle relaxation and cyclic AMP accumulation indicate that inhibition of cyclic AMP breakdown by cyclic GMP via the inhibition of PDE III (cyclic GMP-inhibited PDE) is the dominant mechanism.
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PMID:Vasorelaxant effect of isoliquiritigenin, a novel soluble guanylate cyclase activator, in rat aorta. 759 26

The effects of isoliquiritigenin on force of contraction (Fc), L-type Ca2+ current (I(Ca)) and intracellular Ca2+ concentration ([Ca2+]i) were investigated in rat ventricular heart muscle. Isoliquiritigenin increased Fc and I(Ca) and, after longer exposure times, resting tension and [Ca2+]i. The effect of isoliquiritigenin (100 microM) on I(Ca) was diminished by Rp-cAMPS (30 microM). 1H-[1,2,4]oxa- diazolo[4,3-a]quinoxalin-1-one (50 microM) did not influence the effects of isoliquiritigenin on Fc and I(Ca). The positive inotropic effects of isoprenaline and forskolin, but not of 3-isobutyl-1-methylxanthine, were potentiated by isoliquiritigenin (100 microM). In the presence of milrinone (10 microM), no further effects of isoliquiritigenin (100 microM) on Fc and I(Ca) were observed. It is suggested that the increase in Fc and I(Ca) by isoliquiritigenin is due to an accumulation of cyclic AMP. These effects are probably unrelated to an effect of the drug on soluble guanylyl cyclase, as reported for smooth muscle, but rather due to a direct inhibition of phosphodiesterase III activity.
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PMID:Cardiac effects of isoliquiritigenin. 917 53

Glycyrrhizae radix is used to treat abdominal pain as a component of shakuyakukanzoto (shaoyao-gancao-tang), a traditional Chinese medicine formulation. Previously, we have reported the isolation of glycycoumarin as a potent antispasmodic with an IC50 value of 2.93+/-0.94 microM for carbamylcholine (CCh)-induced contraction of mouse jejunum from an aqueous extract of Glycyrrhizae radix (licorice), and clarified that its mechanism of action involves inhibition of phosphodiesterase 3. The purpose of the present study was to examine an antispasmodic principle of licorice other than glycycoumarin. Isoliquiritigenin was isolated from an aqueous extract of licorice as a potent relaxant, which inhibited the contraction induced by various types of stimulants, such as CCh, KCl, and BaCl2 with IC50 values of 4.96+/-1.97 microM, 4.03+/-1.34 microM and 3.70+/-0.58 microM, respectively, which are close to those of papaverine. However, the amount of isoliquiritigenin in the aqueous extract of licorice was very small. When the aqueous licorice extract was treated with naringinase, the amounts of glycosides such as isoliquiritin, which were abundant but had much less potent relaxant activity, were decreased while isoliquiritigenin was increased. At the time, the relaxant activity of the treated sample was increased significantly, shifting the IC50 from 358+/-104 to 150+/-38 microg/ml for CCh-induced contraction. Isoliquiritigenin also showed the most potent inhibition of mouse rectal contraction induced by CCh with an IC50 value of 1.70+/-0.07 microM. These results suggest that isoliquiritigenin acts as a potent relaxant in the lower part of the intestine by transformation from its glycosides.
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PMID:Isoliquiritigenin, one of the antispasmodic principles of Glycyrrhiza ularensis roots, acts in the lower part of intestine. 1720 75

Licorice root is used to treat asthma as a component of Shaoyao-Gancao-tang, a traditional Chinese medicine formula. In this study, we investigated the tracheal relaxation effects of isoliquiritigenin, a flavonoid isolated from the roots of Glycyrrhiza glabra (a kind of Licorice), on guinea-pig tracheal smooth muscle in vitro and in vivo. The tension changes of isolated tracheal rings were isometrically recorded on a polygraph. The large-conductance Ca2+-activated K+ channels (BKCa) were measured by inside-out patch-clamp techniques and intracellular Ca2+concentrations ([Ca2+]i) were tested by microfluorometric method in guinea-pig tracheal smooth muscle cells (TSMCs). Isoliquiritigenin produced concentration-dependent relaxation in isolated guinea-pig tracheal rings precontracted with acetylcholine, KCl, and histamine. Pretreatments with charybdotoxin, ODQ and KT5823 attenuated the relaxation induced by isoliquiritigenin. Isoliquiritigenin significantly increased intracellular cGMP level in cultured TSMCs and inhibited the activity of phosphodiesterase (PDE) 5 in human platelets. Moreover, isoliquiritigenin increased by 9-fold the probability of BKCa channel openings of TSMCs in inside-out patches and markedly reduced [Ca2+]i rise induced by acetylcholine inTSMCs, pretreatment with KT5823 attenuated above two responses to isoliquiritigenin. In vivo experiment isoliquiritigenin significantly prolonged the latency time of histamine-acetylcholine aerosol-induced collapse and inhibited the increase of lung overflow induced by intravenously administered histamine dose-dependently. These data indicate that isoliquiritigenin relaxes guinea-pig trachea through a multiple of intracellular actions, including sGC activation, inhibition of PDEs, and associated activation of the cGMP/PKG signaling cascade, leading to the opening of BKCa channels and [Ca2+]i decrease through PKG-dependent mechanism and thus to tracheal relaxation.
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PMID:Isoliquiritigenin, a flavonoid from licorice, relaxes guinea-pig tracheal smooth muscle in vitro and in vivo: role of cGMP/PKG pathway. 1846 16