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)

Cardiac Ca2+ current (ICa) was shown to be regulated by cGMP in a number of different species. Recently, we found that the NO-donor SIN-1 (3-morpholino-sydnonimine) exerts a dual regulation of ICa in frog ventricular myocytes via an accumulation of cGMP. To examine whether NO also regulates Ca2+ channels in human heart, we investigated the effects of SIN-1 on ICa in isolated human atrial myocytes. An extracellular application of SIN-1 produced a profound stimulatory effect on basal ICa at concentrations > 1 pM. Indeed, 10 pM SIN-1 induced a approximately 35% increase in ICa. The stimulatory effect of SIN-1 was maximal at 1 nM (approximately 2-fold increase in ICa) and was comparable with the effect of a saturating concentration (1 microM) of isoprenaline, a beta-adrenergic agonist. Increasing the concentration of SIN-1 to 1-100 microM reduced the stimulatory effect in two thirds of the cells. The stimulatory effect of SIN-1 was not mimicked by SIN-1C, the cleavage product of SIN-1 produced after liberation of NO. This suggests that NO mediates the effects of SIN-1 on ICa. Because, in frog heart, the stimulatory effect of SIN-1 on ICa was found to be due to cGMP-induced inhibition of cGMP-inhibited phosphodiesterase (cGI-PDE), we compared the effects of SIN-1 and milrinone, a cGI-PDE selective inhibitor, on ICa in human. Milrinone (10 microM) induced a strong stimulation of ICa (approximately 150%), demonstrating that cGI-PDE controls the amplitude of basal ICa in this tissue. In the presence of milrinone, SIN-1 (0.1-1 nM) had no stimulatory effect on ICa, suggesting that the effects of SIN-1 and MIL were not additive. We conclude that NO may stimulate ICa in human atrial myocytes via inhibition of the cGI-PDE.
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PMID:Nitric oxide regulates the calcium current in isolated human atrial myocytes. 786 Jul 25

Nonadrenergic, noncholinergic relaxations were elicited by field stimulation (1-16 Hz, 1 msec, 8 V for 15 sec) of guinea pig trachea desensitized with capsaicin (3 microM), pretreated with atropine (1 microM), propranolol (1 microM), indomethacin (3 microM) and treated with alpha-chymotrypsin (2 U/ml) and contracted with 3 microM histamine. The effect of the phosphodiesterase (PDE) isozyme selective inhibitors siguazodan (PDE III-selective), rolipram (PDE IV-selective), denbufylline (PDE IV-selective) and zaprinast (PDE V-selective) was examined on the relaxant responses to field stimulation and on relaxations elicited by the nitric oxide donor 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1). The response to field stimulation in the presence of alpha-chymotrypsin (the putative nitric oxide component), at all the frequencies tested, was potentiated significantly by the PDE IV inhibitors rolipram (1 and 10 microM) and denbufylline (3 and 10 microM) as were responses to SIN-1. The PDE V inhibitor zaprinast (30 microM) potentiated relaxations elicited by field stimulation at 8 and 16 Hz and also potentiated responses to SIN-1. The PDE III inhibitor siguazodan (1 microM), however, was without effect on relaxant responses to field stimulation or to SIN-1. These results suggest that the nitric oxide component of the nonadrenergic, noncholinergic relaxant response is mediated primarily via cyclic AMP whose action is inactivated by a PDE IV isozyme and also by cyclic GMP which is inactivated by a PDE V isozyme.
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PMID:Modulation of relaxant responses evoked by a nitric oxide donor and by nonadrenergic, noncholinergic stimulation by isozyme-selective phosphodiesterase inhibitors in guinea pig trachea. 789 55

The effects of the nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1) on the L-type Ca2+ current (ICa) were examined in frog ventricular myocytes under basal and phosphorylated conditions. SIN-1 was found to exert insignificant effects on basal ICa but to induce a biphasic action on stimulated ICa. Indeed, in the nanomolar range of concentrations (0.1-10 nM), SIN-1 induced a pronounced (approximately 40%) stimulation of ICa elevated by a non-maximal concentration of forskolin (0.3 microM). However, the stimulatory effects of SIN-1 on ICa were not additive with those of maximal concentrations (10 microM) of forskolin or intracellular cAMP. In contrast, at higher concentrations (100 nM to 1 mM), SIN-1 strongly reduced ICa (by up to 85%) which had been previously stimulated by cAMP, forskolin, or isoprenaline. All the effects of SIN-1 appeared to be mediated by the liberation of NO since they were suppressed by methylene blue and LY83583 and were not mimicked by SIN-1C, a metabolite of SIN-1. The stimulatory or inhibitory effects of SIN-1 were absent, respectively, in the presence of milrinone (10 microM) or when the hydrolysis-resistant cAMP analog 8-bromo-cAMP was used instead of cAMP to stimulate ICa. In addition to its effects on ICa, SIN-1 induced a dose-dependent stimulation of guanylyl cyclase activity in the cytosolic and membrane fractions of frog ventricle. The membrane form of guanylyl cyclase displayed a higher sensitivity to SIN-1 than the cytosolic form, which correlated with SIN-1 sensitivity of ICa. Our data suggest that the activatory and inhibitory effects of NO donors on ICa result from an inhibition of the cGMP-inhibited cAMP-phosphodiesterase and an activation of the cGMP-stimulated cAMP-phosphodiesterase, respectively, both linked to the activation of guanylyl cyclase, possibly a membrane form of the enzyme.
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PMID:Nitric oxide regulates cardiac Ca2+ current. Involvement of cGMP-inhibited and cGMP-stimulated phosphodiesterases through guanylyl cyclase activation. 790 37

Human bronchial rings were contracted with histamine (3 microM), and inhibitory responses were obtained with electrical field stimulation (EFS) in the presence of propranolol (1 microM), atropine (1 microM), and indomethacin (3 microM). These nonadrenergic noncholinergic (NANC) relaxations were frequency-dependent (1 to 32 Hz) and inhibited by either tetrodotoxin or Nw-nitro-L-arginine (L-NNA, 100 microM). The selective cAMP-specific phosphodiesterase (PDE) type IV inhibitors rolipram (3 microM) and Ro 20-1724 (3 microM) significantly potentiated NANC relaxations at each frequency of stimulation. The selective cGMP-specific PDE type V inhibitor zaprinast (3 microM) failed to significantly alter the maximal NANC response, but it caused a slight potentiation of the response at lower frequencies. The adenylyl cyclase stimulant forskolin, the nitric oxide donor compound 3-morpholinosydnonimine (SIN-1), and the guanylyl cyclase stimulant sodium nitroprusside caused concentration-dependent relaxation of histamine-contracted airway smooth muscle. Rolipram significantly potentiated the relaxation elicited by forskolin. Rolipram also potentiated responses to SIN-1 and sodium nitroprusside. Considered together these data support the hypothesis that cAMP plays a facilitory role in NANC relaxation of the human bronchi.
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PMID:Potentiation of nonadrenergic noncholinergic relaxation of human isolated bronchus by selective inhibitors of phosphodiesterase isozymes. 773 37

The effects of the NO-donor 3-morpholinosydnonimin (SIN-1) on isometric tension, cyclic guanosine 3',5'-monophosphate (cyclic GMP) accumulation and neuronal release of 3H-noradrenaline were investigated in rabbit isolated corpus cavernosum (CC), and compared to the actions of sodium nitroprusside (SNP) and the cyclic GMP-specific phosphodiesterase inhibitor zaprinast. SIN-1, zaprinast and SNP concentration dependently relaxed rabbit CC preparations contracted by 1 microM. phenylephrine. All the drugs were highly effective, and the order of potency was SNP > zaprinast > SIN-1. SIN-1 had a biphasic effect on contractions evoked by electrical field stimulation of nerves: at low concentrations (1 and 10 microM.), SIN-1 inhibited the contractions, while at concentrations > or = 100 microM., the contractions were again increased. There were no changes in baseline tension. Electrically evoked contractions were inhibited by zaprinast in a concentration-dependent manner. Compared with controls, 1 mM. SIN-1 caused a significant (p < 0.05) increase in both the basal efflux and in the electrically induced release of 3H from CC preparations incubated with 3H-noradrenaline. SIN-1, zaprinast and SNP increased tissue levels of cyclic GMP. There was no positive correlation between cyclic GMP accumulation and the relaxant effects of the drugs. The effects of SIN-1 and SNP on the tissue content of cyclic GMP were not significantly affected by methylene blue, an inhibitor of soluble guanylate cyclase. It may be concluded that SIN-1, zaprinast and SNP are effective in relaxing isolated penile erectile tissue, and this effect is associated with an increase in the tissue content of cyclic GMP via pathways not sensitive to methylene blue. However, additional mechanisms beside stimulation of adrenergic neurotransmission and activation of guanylate cyclase in the smooth muscle cell seem to participate in the action of SIN-1 on rabbit penile erectile tissue.
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PMID:Actions of 3-morpholinosydnonimin (SIN-1) on rabbit isolated penile erectile tissue. 839 90

In the presence of 3-isobutyl-methylxanthine (IBMX), induction of cyclic 3',5'-guanosine monophosphate (GMP) production in human washed platelets (HWP) by nitric oxide donors (NOD) is followed by its accumulation in the surrounding medium in a time- and concentration-dependent manner. Thirty minutes incubation of HWP with 3-morpholino-sydonimine (SIN-1, 10 microM) at 37 degrees C resulted in a 4.6-fold increase of cyclic GMP in platelets, whereas in the extracellular medium the increase was 17.6-fold. Similar results were obtained when other NOD such as S-nitroso-N-acetylpenicyllamine (SNAP) and 3-(2-methoxy-5-chlorophenyl)oxatriazol-5-imine (GEA 3184) and the selective phosphodiesterase inhibitor, zaprinast (M&B 22948, 10 microM), were used. Probenecid (1-300 microM), an inhibitor of organic anion transport, or ouabain (1-300 microM), an inhibitor of Na+/K+ adenine triphosphate (ATP)-ase had no effect on cyclic GMP production or extrusion after stimulation with SIN-1. Significantly prostaglandin A1 (PGA1) and prostaglandin D2 (PGD2) inhibited the efflux of cyclic GMP from platelets induced by SNAP (10 microM) in a concentration-dependent fashion, with an IC50 of 63 +/- 16 and 143 +/- 17 microM, respectively. These studies suggest that the extrusion of cyclic GMP from human platelets after activation of soluble guanylate cyclase by NOD may contribute to the control of cyclic GMP levels in platelets with potential physiological and therapeutic consequences.
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PMID:Nitric oxide donors induce extrusion of cyclic GMP from isolated human blood platelets by a mechanism which may be modulated by prostaglandins. 858 70

We examined the role of endogenous NO in the autonomic regulation of atrioventricular (AV) nodal function by studying spontaneous action potentials (SAPs) and L-type Ca2+ current (ICa-L) in isolated single AV nodal cells from adult rabbit hearts. Both the perforated and the membrane-ruptured patch-clamp techniques in the whole-cell configuration were used under conditions known to alter NO production. Three NO donors, 3-morpholinosydnonimine (SIN-1, 0.1 mmol/L), S-nitroso-acetylcysteine (0.1 mmol/L), and sodium nitroprusside (0.1 mmol/L), suppressed the beta-adrenergic agonist isoproterenol (ISO, 1 mumol/L)-stimulated increase in ICa-L. SIN-1 also decreased the frequency and amplitude of SAPs. In cells in which ICa-L had been previously attenuated by the muscarinic agonist carbamylcholine (CCh, 1 mumol/L), SIN-1 had no additive effect. CCh activated an acetylcholine-sensitive outward K+ current (IK(ACh)) in AV nodal cells, in addition to the ICa-L inhibition. Intracellular dialysis with the NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA, 0.5 mmol/L) blocked CCh-induced, but not SIN-1-induced, ICa.L attenuation. However, intracellular dialysis with methylene blue (20 mumol/L), which inhibits NO-mediated activation of guanylyl cyclase and cGMP production, blocked the effects of both CCh and SIN-1 on ICa-L. In these cells, neither L-NMMA nor methylene blue affected the CCh-activated IK(ACh). Direct application of cGMP (10 mumol/L) via internal dialysis significantly inhibited ISO-stimulated ICa-L. In AV nodal cells internally perfused with either a nonhydrolyzable cAMP analogue, 8-Br-cAMP (0.5 mmol/L), or a high concentration of cAMP (0.5 mmol/L), CCh did not inhibit, ICa-L but still activated IK(ACh). CCh-induced ICa-L attenuation could be abolished or quickly reversed by the nonselective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (20 mumol/L). However, CCh still significantly suppressed ISO-stimulated ICa-L after the cGMP-inhibited PDE isozyme (PDE3) had been selectively inhibited by milrinone (5 mumol/L). Immunohistochemical staining identified the presence of the endothelial constitutive NO synthase (ecNOS or NOS3) in both single AV nodal cells in vitro and in cryostat sections of AV nodal tissue in situ. These results demonstrate that endogenous NO is involved in the muscarinic cholinergic attenuation of ICa-L in AV nodal cell; the mechanism likely involves the cGMP-stimulated PDE.
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PMID:Nitric oxide synthase (NOS3)-mediated cholinergic modulation of Ca2+ current in adult rabbit atrioventricular nodal cells. 863 50

Left ventricular hypertrophy (LVH) produced by aortic valve plication leads to increased myocardial cyclic GMP. We tested whether this was a result of increased soluble guanylate cyclase activity or nitric oxide (NO) synthase and its functional consequences. We used the nitric oxide donor 3-morpholino-sydnonimine (SIN-1) or the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME) in 12 control and 12 LVH anesthetized open-chest mongrel dogs. L-NAME (6 mg/kg) or SIN-1 (1 microgram/kg per min) was infused into the left anterior descending coronary artery and regional segment work and cyclic GMP levels were determined. In vitro myocardial guanylate cyclase sensitivity (0.43 +/- 0.04 to 0.28 +/- 0.04 mM [EC50]) and maximal activity (10.1 +/- 2.9 to 25.5 +/- 6.5 pmol/mg protein per min) were significantly increased in LVH as compared with control animals in response to nitroprusside stimulation, but cyclic GMP-phosphodiesterase activity was similar. In LVH dogs, basal cyclic GMP was significantly elevated in vivo when compared with controls. Treatment of dogs with SIN-1 resulted in a significant increase in cyclic GMP in control (1.09 +/- 0.12 to 1.48 +/- 0.19 pmol/gram) and a greater increase in the LVH group (1.78 +/- 0.16 to 3.58 +/- 0.71 pmol/g). L-NAME had no effect on myocardial cyclic GMP levels in control or LVH dogs. Segment work decreased in the control group after SIN-1 (1,573 +/- 290 to 855 +/- 211 grams x mm/min). LVH dogs showed no decrement in work as a result of treatment with SIN-1. L-NAME did not cause significant changes in myocardial cyclic GMP, O2 consumption, or work in either control or LVH dogs, but vascular effects were evident. SIN-1 increased cyclic GMP, and with greater effect on LVH; however, this resulted in a decrement in function only in the control group. The greater increased cyclic GMP in LVH dogs is not related to increased NO production, but is related to significantly higher sensitivity and maximal activity of soluble myocardial guanylate cyclase.
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PMID:Increased guanylate cyclase activity is associated with an increase in cyclic guanosine 3',5'-monophosphate in left ventricular hypertrophy. 869 76

1. The modulation of the guanosine 3':5'-cyclic monophosphate (cyclic GMP)- and adenosine 3':5'-cyclic monophosphate (cyclic AMP)-dependent protein kinase activities by the diastereomers of 8-bromo-beta phenyl-1, N2-ethenoguanosine 3':5'-cyclic monophosphorothioate, ((Rp)- and (Sp)-8-bromo-PET-cyclic GMPS) was investigated by use of purified protein kinases. In addition, the effects of (Rp)-8-bromo-PET-cyclic GMPS on protein phosphorylation in intact human platelets and on [3H]-noradrenaline release and neurogenic vasoconstriction in electrical field stimulated rat tail arteries were also studied. 2. Kinetic analysis with purified cyclic GMP-dependent protein kinase (PKG) type I alpha and I beta, which are expressed in the rat tail artery, revealed that (Rp)-8-bromo-PET-cyclic GMPS is a competitive inhibitor with an apparent Ki of 0.03 microM. The activation of purified cyclic AMP-dependent protein kinase (PKA) type II was antagonized with an apparent Ki of 10 microM. 3. In human platelets, (Rp)-8-bromo-PET-cyclic GMPS (0.1 mM) antagonized the activation of the PKG by the selective activator 8-(4-chlorophenylthio)-guanosine 3':5'-cyclic monophosphate (8-pCPT-cyclic GMP; 0.2 mM) without affecting the activation of PKA by (Sp)-5, 6-dichloro-1-beta-D-ribofurano-sylbenzimidazole- 3':5'-cyclic monophosphorothioate ((Sp)-5,6-DCl-cyclic BiMPS; 0.1 mM). 4. (Rp)-8-bromo-PET-cyclic GMPS was not hydrolysed by the cyclic GMP specific phosphodiesterase (PDE) type V from bovine aorta but potently inhibited this PDE. 5. The corresponding sulphur free cyclic nucleotide of the two studied phosphorothioate derivatives, 8-bromo-beta-phenyl-1, N2-ethenoguanosine-3':5'-cyclic monophosphate (8-bromo-PET-cyclic GMP), had no effect on electrically-induced [3H]-noradrenaline release but concentration-dependently decreased the stimulation-induced vasoconstriction. (Rp)-8-bromo-PET-cyclic GMPS (3 microM) shifted the vasoconstriction response to the right without affecting stimulation evoked tritium overflow. 6. The NO donor, 3-morpholinosydnonimine (SIN-1) relaxed rat tail arteries precontracted with phenylephrine (1 microM). The SIN-1 concentration-relaxation curve was shifted in a parallel manner to the right by (Rp)-8-bromo-PET-cyclic GMPS, suggesting that the relaxation was mediated by a cyclic GMP/PKG-dependent mechanism. 7. The [3H]-noradrenaline release-enhancing effect and stimulation-induced decrease in vasoconstriction of forskolin were unaffected by (Rp)-8-bromo-PET-cyclic GMPS. Moreover, the forskolin concentration-relaxation curve was not changed in the presence of the PKG inhibitor, suggesting a high selectivity in intact cells for PKG- over PKA-mediated effects. 8. The results obtained indicate that (Rp)-8-bromo-PET-cyclic GMPS presently is the most potent and selective inhibitor of PKG and is helpful in distinguishing between cyclic GMP and cyclic AMP messenger pathways activation. Therefore, this phosphorothioate stereomer may be a useful tool for studying the role of cyclic GMP in vitro.
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PMID:Inhibition of cyclic GMP-dependent protein kinase-mediated effects by (Rp)-8-bromo-PET-cyclic GMPS. 871 84

1. The nitric oxide (NO)-releasing properties of two new mesoionic 3-aryl substituted oxatriazole-5-imine derivatives (GEA 3162 and GEA 3175) were characterized and compared with the known NO-donors 3-morpholino-sydnonimine (SIN-1) and S-nitroso-N-acetylpenicillamine (SNAP). 2. GEA 3162, GEA 3175, SIN-1 and SNAP inhibited adenosine 5'-diphosphate-induced platelet aggregation (IC50 values 0.18, 0.39, 3.73 and 2.12 microM, respectively). All four compounds induced a dose-dependent and more than 4 fold increase in cyclic GMP in platelets. The increase in cyclic GMP concentration was potentiated more than 1.5 fold by a phosphodiesterase inhibitor, zaprinast (10 microM) and inhibited 38-97% by oxyhaemoglobin (10-45 microM). 3. All of the four compounds studied converted oxyhaemoglobin to methaemoglobin and formed a paramagnetic NO-haemoglobin complex. All but GEA 3175 formed nitrite and nitrate in phosphate buffer. During a 40 min incubation, GEA 3162, SIN-1 and SNAP (100 microM) produced 50-70 microM NO2- + NO3- as determined by high performance liquid chromatography. The release of NO and NO2 by GEA 3175 was increased 140 fold in the presence of human plasma (0.14 and 19.7 ppb in the absence and presence of 1% human plasma, respectively) as analyzed by ozone chemiluminescence. 4. The results suggest that the mesoionic 3-aryl substituted oxatriazole-5-imine derivatives GEA 3162 and GEA 3175 as well as SIN-1 and SNAP release nitric oxide.
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PMID:Nitric oxide-donating properties of mesoionic 3-aryl substituted oxatriazole-5-imine derivatives. 882 26


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