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 possible involvement of nitric oxide (NO) in the vasodilator response to parasympathetic nerve stimulation in the pig submandibular gland in vivo was studied using the NO synthase inhibitor, NG-nitro-L-arginine. The atropine-resistant vasodilation elicited by parasympathetic stimulation (10 Hz, 30 s) and the response elicited by i.v. injection of vasoactive intestinal polypeptide (VIP) were markedly reduced by NG-nitro-L-arginine. Furthermore, peptide release from the gland elicited by nerve stimulation was attenuated after NG-nitro-L-arginine administration. Addition of the NO donor, nitroprusside, reversed the NG-nitro-L-arginine evoked attenuation of the response to nerve stimulation and VIP. Also the cholinergic parasympathetic component and the vascular effect of acetylcholine were reduced by NG-nitro-L-arginine. Furthermore, the NG-nitro-L-arginine-induced attenuation of the vascular responses was partially prevented by milrinone, an inhibitor of the cyclic GMP-regulated phosphodiesterase III. The present results suggest that NO may be crucial for parasympathetic vasodilatation by regulating peptide release and second messenger systems for VIP and acetylcholine.
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PMID:Nitric oxide regulates peptide release from parasympathetic nerves and vascular reactivity to vasoactive intestinal polypeptide in vivo. 800 43

1. The relaxant responses of S-nitroso-L-cysteine (CysNO), S-nitroso-N-acetyl-D,L-penicillamine (SNAP), S-nitroso-N-acetyl-L-cysteine (SNAC) and S-nitrosoglutathione (GSNO) in the rat gastric fundus (forestomach) were studied and compared to the relaxant responses obtained in response to nitric oxide (NO) and electrical field stimulation (EFS, 10 s strains) of non-adrenergic non-cholinergic (NANC) nerves. 2. CysNO (10(-7)-3 x 10(-4) M) caused transient relaxation of the precontracted rat gastric fundus, comparable to the response to NO (10(-6)-10(-4) M) and EFS. SNAP, SNAC and GSNO elicited more sustained relaxations. 3. The cyclic GMP-specific phosphodiesterase inhibitor, zaprinast (3 x 10(-5) M) increased the relaxant effect of CysNO, SNAP and GSNO while the NO-synthase inhibitor, NG-nitro-L-arginine (L-NOARG, 3 x 10(-4) M) had no influence. 4. In the presence of LY 83583 (10(-5) M), which releases superoxide anions, the relaxant response to NO and CysNO was decreased, whereas that to all other stimuli was unaltered. The inhibitory effect of LY 83583 on CsNO-induced relaxations was prevented by superoxide dismutase (SOD, 1000 u ml-1). 5. Tissues incubated for 1 h with 5.5 x 10(-4) M nitroglycerin (GTN) became tolerant to GTN. In this condition, the relaxant response to 10(-5) M NO was maintained, while the relaxations by EFS (8 Hz) and 3 x 10(-5) M SNAP were significantly decreased. The reduction of the response to the other S-nitrosothiols was not significant. 6. The combination of nitrate tolerance and 10-5 M LY 83583 caused a significantly larger inhibition of the relaxant response to EFS (8 Hz) than nitrate tolerance alone. The combination of LY 83583 and GTN tolerance reduced the relaxant effect of 10-5 M NO to a similar extent to LY 83583 alone, while the relaxant response to 10-4 M GTN was reduced to the same extent as after 1 h exposure to 5.5 x 10-4 M GTN alone.7. It is concluded that S-nitrosothiols potently relax the rat gastric fundus, possibly by a cyclic GMP-dependent mechanism and S-nitrosothiols such as SNAC and GSNO may be involved in NANC neurotransmission.
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PMID:Influence of S-nitrosothiols and nitrate tolerance in the rat gastric fundus. 803 15

The role of blood platelets in the pathogenesis of atherosclerosis, thrombosis, thromboembolism and stroke (hemorrhagic/thrombotic) is well established. In view of this recognized role played by platelets in the complications associated with coronary artery disease and cerebrovascular disease, there is considerable interest in the pharmacology of platelet activation inhibitory drugs. These drugs exert their effect by blocking several different activation signalling mechanisms. Some of the known compounds that modulate platelet function include: inhibitors of arachidonic acid metabolism (nonsteroidal anti-inflammatory drugs and thromboxane synthetase inhibitors), drugs that alter membrane phospholipid composition (omega 3 fatty acids), stimulators of adenylyl cyclase and guanylyl cyclase (PGE1, PGI2, PGD2/ERRF [nitric oxide], nitroglycerin, nitroprusside), phosphodiesterase inhibitors (dipyridamole and methylxanthines) and calcium antagonists (verapamil, nifedipine, diltiazem). Current research on the pharmacology of platelet activation inhibitory drugs is focused on the development of specific receptor antagonists (antibodies, peptides, receptor antagonists). Since platelets have multiple mechanisms for achieving activation, and the process of thrombosis involves multicellular modulation of platelet activity, it will be rather difficult to develop a compound that is capable of causing complete inhibition of activation mechanisms. Therefore, future research will be devoted to development of designer drugs that will be used for preventing discrete platelet responses. This approach may be useful as total inhibition of platelet activation, although it may prevent thrombotic events, may possibly precipitate hemorrhagic conditions. A better understanding of cell signalling pathways and the mechanisms involved in the pathogenesis of cardiovascular cerebrovascular disease will facilitate the development of efficient antiplatelet drugs.
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PMID:Pharmacology of platelet activation-inhibitory drugs. 806 66

1. The use of pharmacological inhibitors of nitric oxide (NO) synthesis to treat patients with septic shock is limited by the observation that they cause a fall in cardiac output in some subjects. The aim of this work was to investigate this fall and to test whether it was reversible by subsequent administration of nicardipine, theophylline or the cyclic GMP-selective phosphodiesterase inhibitor, zaprinast (M&B 22948). 2. In pentobarbitone-anaesthetized pigs, haemodynamic indices were measured before and after intravenous administration of NG-nitro-L-arginine methyl ester (L-NAME) in a dose-response protocol (0.2-20 mg kg-1; n = 6) and as a single bolus of 10 mg kg-1 either alone or followed by increasing doses of nicardipine, theophylline or zaprinast (n = 8 in each group). 3. L-NAME caused a dose-dependent rise in systemic vascular resistance and mean systemic arterial pressure and a dose-dependent fall in cardiac output. A single bolus of L-NAME (10 mg kg-1) produced these effects within 15 min. 4. Subsequent administration of nicardipine (0.05-0.2 mg kg-1) caused complete reversal of systemic vasoconstriction and hypertension and in doing so completely restored cardiac output. Theophylline (7.5-10 mg kg-1) partially reversed the rise in systemic vascular resistance and partially restored cardiac output but the effect was small compared to that of nicardipine. Zaprinast (1-5 mg kg-1) had no significant effect on any of these variables. 5. These results suggest that reduced cardiac output following inhibition of NO synthesis is an effect of increased afterload on the heart and is reversible by nicardipine and to a lesser extent by theophylline.These findings may have potential value for those using NO synthase inhibitors to treat patients with septic shock.
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PMID:Comparison of the ability of nicardipine, theophylline and zaprinast to restore cardiovascular haemodynamics following inhibition of nitric oxide synthesis. 807 60

Electrical field stimulation (EFS) induced a relaxation response in female rabbit urethral smooth muscle strips precontracted with phenylephrine. The relaxation response was inhibited by tetrodotoxin, but not by atropine, propranolol, or hexamethonium. Thus, the relaxation response results from stimulation of inhibitory non-adrenergic, non-cholinergic nerves. The EFS induced relaxation response was inhibited by an inhibitor of nitric oxide biosynthesis, NG-nitro-L-arginine. This inhibition was overcome by addition of a precursor of nitric oxide, L-arginine. An inhibitor of soluble guanylate cyclase, methylene blue, but not an inhibitor of soluble adenylate cyclase, SQ22536 reduced the relaxation response. And a selective cyclic GMP phosphodiesterase inhibitor, M & B 22948 and also a non selective phosphodiesterase inhibitor, 3-isobutyl-1-methyl xanthine, potentiated the relaxation response. Cyclic GMP, but not cyclic AMP contents were significantly elevated by EFS in urethral smooth muscle strips. These data demonstrate that agents which affect the biosynthesis of nitric oxide are associated with the urethral relaxation evoked by EFS, and that cyclic GMP but not cyclic AMP mediates the relaxation response.
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PMID:[Roles of cAMP and cGMP on non-adrenergic, non-cholinergic relaxation in rabbit urethral smooth muscle]. 812 Nov 15

The effect of intracellular cyclic AMP (cAMP) on N-methyl-D-aspartate (NMDA) receptor-mediated stimulation of nitric oxide (NO) formation was investigated in rat cerebellar slices. Forskolin (30-120 microM), while lacking any direct effect on NO production, elicited a concentration-dependent enhancement of the response to 10 microM NMDA. Dideoxyforskolin, which does not activate adenylyl cyclase did not influence the NMDA response. Increasing intracellular cAMP directly by incubation with the membrane-permeant analogue of cAMP, 2'-o-dibutyryladenosine 3'5'-cyclic monophosphate (dibutyryl cAMP) (1 mM), similarly enhanced NO formation, as did prevention of cAMP degradation with the phosphodiesterase inhibitor theophylline. The enhancement of NMDA activity appeared to involve protein phosphorylation (possibly of the receptor itself) since the protein kinase A inhibitor H-89, abolished the enhancements with both forskolin and dibutyryl cAMP. Thus cAMP may have a physiological role in the modulation of NMDA receptor-stimulated synthesis of NO.
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PMID:NMDA receptor-mediated stimulation of rat cerebellar nitric oxide formation is modulated by cyclic AMP. 813 85

1. Platelet activation in vivo occurs in healthy pregnancy and is more pronounced in pre-eclampsia. 2. This study has investigated: (i) the inhibitory potency of the nitric oxide donors 3-morpholinosydnonimine and sodium nitroprusside, on the platelet release reaction in vitro in non-pregnant, healthy pregnant and pre-eclamptic women; (ii) the concentration of cyclic GMP during incubation of washed platelets with sodium nitroprusside in a separate group of non-pregnant, healthy pregnant and pre-eclamptic women. 3. The half-maximal inhibitory concentration of sodium nitroprusside, in the presence of a phosphodiesterase inhibitor, for inhibition of the platelet release reaction was lower in the pre-eclamptic subjects than in the non-pregnant subjects (P < 0.05). 4. Several of the pre-eclamptic women were studied again postnatally. The half-maximal inhibitory concentrations of sodium nitroprusside and 3-morpholinosydnonimine were higher in the postnatal than in the antenatal sample (P < 0.02). 5. Peak platelet cyclic GMP responses to sodium nitroprusside were significantly higher in the pre-eclamptic women than in the healthy pregnant and non-pregnant women. 6. These results suggest that platelets are more sensitive to the inhibitory effects of nitric oxide donors in pre-eclampsia.
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PMID:Effects of nitric oxide donors in vitro on the arachidonic acid-induced platelet release reaction and platelet cyclic GMP concentration in pre-eclampsia. 814 30

To elucidate the sequence of events between the release of neurotransmitters and cavernous smooth muscle relaxation in erection, we studied the role of the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) systems. In a well-established simian model, the effects of specific agonists and antagonists of the intracellular sequence for smooth muscle relaxation and potassium channel openers on the intracavernous pressure were examined. Sodium nitroprusside (10(-3) M), a nitric oxide releaser and thus a stimulant of the cGMP system, caused an increase in the intracavernous pressure from 82 to 115 cm H2O for 7 to 19 min and penile diameter from 24.8 +/- 2.28 to 43 +/- 4.87 mm. When nitroprusside was injected after methylene blue (10(-3) M), a specific antagonist of the enzyme guanylate cyclase, intracavernous pressure rise decreased significantly, but cromakalin, a potassium channel opener, provoked excellent increases after the block. A smaller dose of sodium nitroprusside (10(-4) M) caused an increase in intracavernous pressure from 35 to 85 cm H2O for 7 to 11.5 min. When nitroprusside was injected after zaprinast, a phosphodiesterase inhibitor, the increase in pressure ranged from 80 to 116 cm H2O for 15 to 30 min. Prostaglandin E1, an activator of the cAMP system, caused an increase in the intracavernous pressure of 20-80 cm H2O for 5 to 10 min, and an increase in penile diameter from 25 +/- 2.22 to 35 +/- 3.48 mm. The erectile response to PGE1, but not to cromakalin, was nearly abolished by ethylmaleimide, an adenylate cyclase blocker. The response to nitroprusside was significantly greater (P < 0.05) than to PGE1. Both systems, cAMP and cGMP, may be involved in cavernous smooth muscle relaxation, and cGMP is probably the predominant intracellular second messenger in penile erection in monkeys. Stimulants of the cGMP system, such as nitric oxide releasers, could represent a more physiological and effective approach in the treatment of erectile dysfunction.
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PMID:Intracellular mechanism of penile erection in monkeys. 815 77

Rat calcitonin gene-related peptide (rCGRP) causes endothelium-dependent vasorelaxations via a dual signal transduction mechanism involving elevations of both cyclic AMP and cyclic GMP levels in rat aorta. These responses are all dependent on de novo synthesis of nitric oxide (NO) in endothelial cells and appear to involve a mechanistic link between cyclic GMP and cyclic AMP responses in smooth muscle cells. The present study determined whether NO from an exogenous source (i.e. added nitroglycerin) could substitute for endogenous NO in rCGRP-induced responses in endothelium-denuded aorta. Nitroglycerin (1 microM) significantly elevated cyclic GMP levels by 20-fold and 3.3-fold and cyclic AMP levels by 26% and 22% at 1 and 2 min, respectively. By itself, rCGRP (100 nM) did not significantly elevate cyclic AMP levels. In combination, however, nitroglycerin and rCGRP caused more-than-additive cyclic AMP elevations (41% above basal at 1 and 2 min). Nitroglycerin also potentiated rCGRP-induced vasorelaxations in endothelium-denuded rings, thus uncovering a direct (endothelium-independent) relaxant effect of rCGRP in rat aorta. The data indicate that exogenous NO can substitute for endogenous NO in rCGRP-induced relaxant and cyclic AMP responses in aorta. This nitroglycerin-induced potentiation of CGRP effects likely involves inhibition of cyclic-GMP-inhibited-phosphodiesterase in smooth muscle cells, thus allowing cyclic AMP to accumulate and mediate the direct vasodilator effects of rCGRP.
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PMID:Nitroglycerin (exogenous nitric oxide) substitutes for endothelium-derived nitric oxide in potentiating vasorelaxations and cyclic AMP elevations induced by calcitonin gene-related peptide (CGRP) in rat aorta. 817 May 22

Vascular smooth muscle contraction is modulated by an increase in cyclic guanosine monophosphate (cyclic GMP) subsequent to nitric oxide production by endothelial cells. The participation in this vasodilatation of specific cyclic adenosine monophosphate (cyclic AMP) phosphodiesterase (PDE) forms differentially sensitive to cyclic GMP is unclear. Chromatographic separation and pharmacological characterization show that the specific cyclic AMP PDE of endothelial cells is of the PDE IV subtype, known to be insensitive to cyclic GMP, whereas cyclic AMP PDEs of vascular smooth muscle are both cyclic GMP-sensitive and -insensitive (subtypes PDE III and PDE IV, respectively). The role of these PDE forms in the modulation of vascular contraction was investigated in rat aorta with and without endothelium by using specific inhibitors of PDE III and PDE IV as relaxing agents. PDE III inhibitors (milrinone, CI 930, SK&F 94120 and LY 195115) similarly relax rat aorta with and without endothelium and their potencies are not modified by NG-monomethyl-L-arginine (L-NMMA, 300 microM) or L-arginine (1 mM). However, PDE IV inhibitors (rolipram and denbufylline) only induce relaxation of aorta with endothelium, this relaxation being reversed by addition of L-NMMA and restored by addition of L-arginine. Relaxation studies performed with PDE IV inhibitors in the presence of low concentration of agents that increase cyclic AMP or cyclic GMP, clearly show that PDE IV inhibitor potencies are markedly increased by cyclic GMP elevating agents, by PDE III inhibitors and by the presence of functional endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of vascular cyclic nucleotide phosphodiesterases by cyclic GMP: role in vasodilatation. 829 65


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