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

---

Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Isolated segments of porcine vena cordis magna exhibited a reproducible contractile activity upon application of prostaglandin F2 alpha (PGF2 alpha) or KCl, that was independent of the presence of intact endothelium. Substance P (3 nM) elicited strictly endothelium-dependent relaxations amounting to 46.1 +/- 1.4% (n = 206) of contractions induced by 10 microM PGF2 alpha. 2. S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a compound that spontaneously liberates nitric oxide, concentration-dependently relaxed PGF2 alpha-precontracted (50 microM) venous segments. Tolerance induction (incubation with 100 microM SNAP for 30 min) within the same segments resulted in a 3 fold attenuation of this effect, which was not further reduced after additional preincubation with glyceryl trinitrate (GTN). Removal of endothelium or the presence of N omega-nitro-L-arginine methylester (L-NAME) significantly improved the potency of SNAP before and after tolerance induction. 3. Concentration-dependent relaxations induced by GTN in non-tolerant veins were similar in the presence and absence of endothelium but much more reduced in tolerant endothelium-denuded (75 fold) compared to intact (20 fold) segments. In contrast, the presence of L-NAME significantly improved GTN-activity solely in non-tolerant veins, which, therefore, also resulted in a more pronounced attenuation of activity due to tolerance induction (100 fold). Preincubation of intact veins with SNAP also reduced GTN-activity but to a lesser extent (10 fold). 4. The more delayed but much longer, and compared to GTN somewhat weaker, acting new nitrovasodilator N-(3-nitrato-pivaloyl)-1-cysteineethylester (SPM 3672) was more potent in denuded than intact non-tolerant venous segments. Induction of tolerance by GTN resulted in a 2 fold-attenuation of potency. This effect was increased to 15 fold in denuded veins but solely due to enhanced potency of SPM 3672 caused by removal of endothelium.5. These data demonstrate that intact endothelium of porcine vena cordis magna attenuates the relaxant potency of nitrovasodilators but also probably participates in vascular bioactivation of GTN.We suggest that the reduced potency of nitrovasodilators is due to endogenous production of nitricoxide, which may affect the soluble guanylate cyclase/cyclic GMP-system or inhibit nitrate bioactivation pathways.
...
PMID:Nitrovasodilator-induced relaxation and tolerance development in porcine vena cordis magna: dependence on intact endothelium. 752 Dec 58

Development of tolerance as a consequence of organic nitrate therapy such as that which occurs with glyceryl trinitrate (GTN) appears to be associated with a depletion of free thiols in vascular smooth muscle. In this study, we investigated N-[3-nitratopivaloyl]-L-cysteineethylester (SPM 3672), a new compound containing a nitrate and a thiol moiety, in direct comparison with GTN. Liberation of nitric oxide (NO) from GTN and SPM 3672 measured in vitro was rather low and was markedly potentiated by addition of cysteine only in the case of GTN. Pronounced activation of a partially purified human soluble guanylate cyclase (sGC) by GTN was observed only after addition of cysteine, whereas a comparative activation by SPM 3672 occurred with and without addition of this thiol. In contrast, SPM 4946 (N(-)[3-hydroxypivaloyl]-L-cysteineethylester), a derivative of SPM 3672 lacking the nitrate-ester moiety, did not activate sGC. Activation of sGC by GTN and SPM 3672 was nearly abolished by oxyhemoglobin. Incubation of isolated porcine coronary artery rings with GTN or SPM 3672 resulted in a similar increase in vascular cyclic GMP levels. In rat aorta, GTN was a more potent vasorelaxant than SPM 3672 and produced a greater degree of tolerance. Vasorelaxation induced by GTN occurred with rapid onset and was brief, whereas SPM 3672 produced long-lasting relaxation with a more delayed onset. This kinetic pattern was confirmed in porcine coronary arteries, in which both nitrates exhibited marked relaxation, with GTN being slightly more potent than SPM 3672.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Nitric oxide liberating, soluble guanylate cyclase stimulating and vasorelaxing properties of the new nitrate-compound SPM 3672. 769 81

Intimal thickening in arteries is considered as a site of predilection for atherosclerosis. We investigated whether oral application of the nitric oxide (NO) donors SPM-5185 (N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethylester, 10 mg/kg body weight/b.i.d.) and molsidomine (pro-drug of 3-morpholino-sydnonimine (SIN-1), 10 mg/kg body weight/day) can retard intimal thickening and changes in vascular reactivity induced by a silicone collar positioned around the carotid artery of rabbits. Intimal thickening was significantly inhibited by SPM-5185 (cross-sectional area 18 +/- 6 vs. 44 +/- 10 x 10(-3) mm2; P < 0.05), but not by molsidomine (28 +/- 6 vs. 35 +/- 9 x 10(-3) mm2), which is a donor of both NO and superoxide anions. In organ chamber studies collaring was associated with a decreased sensitivity to acetylcholine (ACh). SPM-5185 evoked a tendency towards normalization of the pD2 of ACh in collared arteries. We also investigated whether chronic nitric oxide (NO) treatment affected vascular reactivity and fatty streak development in the rabbit aorta. During 16 weeks rabbits received 150 g/day of a standard diet, or diets with 0.3% cholesterol, with 0.02% molsidomine (10 mg/kg body weight/day) or with the combination. The NO donor enhanced the area of fatty streaks, without affecting hypercholesterolemia. Moreover, it desensitized the smooth muscle cells of the rabbit aorta to vasodilators acting via the cytoplasmic guanylate cyclase and suppressed the capacity of the endothelial cells to release NO in response to muscarinic receptor stimulation. This suggested that chronic exposure to large quantities of NO caused a negative feedback, with selective decreases of both the endothelial capacity to generate NO and the responsiveness to vasodilators operating via cyclic GMP. In conclusion, we demonstrated that exogenous NO can decrease intimal hyperplasia in vivo. However, prolonged in vivo treatment with a donor of NO enhanced atherosclerosis in hypercholesterolemic rabbits.
...
PMID:The effect of chronic treatment with NO donors during intimal thickening and fatty streak formation. 926 3

We tested the hypothesis that protein kinase (PK)G activation in response to nitric oxide ((*)NO) mediates tumor necrosis factor (TNF)-alpha-induced activation of the transcription factor activating protein-1 (AP-1) in pulmonary microvessel endothelial monolayers (PEM). The DNA-binding activity of AP-1 was assessed using the electrophoretic mobility shift assay. TNF treatment (1,000 U/ml) for 4 h induced a significant increase in DNA binding of AP-1. The effects of TNF were prevented by the superoxide radical scavenger superoxide dismutase (SOD) (100 U/ml), the (*)NO synthase inhibitor aminoguanidine (100 microM), the guanylate cyclase inhibitor ODQ (100 microM), and the PKG inhibitors KT5823 (1 microM) and 8-bromo-cyclic guanosine monophosphate (cGMP)-thioate (100 microM). Spermine-NO (1 microM) and L-arginine (400 microM) prevented the aminoguanidine-induced ablation of AP-1 activation in response to TNF. Phosphorylation of H-Arg-Lys-Ile-Ser-Ala-Ser-Glu-Phe-Asp-Arg-Pro-Leu-Arg-OH (BPDEtide), a specific substrate for PKG, measured the activity of cGMP-dependent protein kinase (PKG). TNF for 0.5 h induced an increase in PKG activity that was prevented by aminoguanidine, ODQ, KT5823, and 8-bromo-cGMP-thioate; however, SOD had no effect. The PKG agonist 8-bromo-cGMP (100 microM), when given alone, increased PKG activity but induced significant DNA-binding activity of AP-1 only when given in the ODQ + TNF Group. SIN-1 (1 mM, a peroxynitrite agonist) increased DNA-binding activity of AP-1. SOD prevented SIN-1-induced AP-1 activation, a response similar to that of the SOD + TNF Group. PEM were transfected with the chloramphenicol acetyltransferase (CAT) reporter plasmid pBLCAT2, which contains a regulation sequence responsive to AP-1. The pharmacologic profile of TNF-induced CAT activity was identical to TNF-induced DNA binding by AP-1. Thus, TNF-induced AP-1-dependent gene transcription is modulated by (*)NO-dependent mediated activation of PKG.
...
PMID:Tumor necrosis factor-alpha-induced activating protein-1 activity is modulated by nitric oxide-mediated protein kinase G activation. 1061 72

In rat pulmonary artery pre-contracted with phenylephrine, the mechanisms of relaxation to the nitric oxide (NO) donor, spermine NONOate, were investigated. Responses to spermine NONOate were only partially blocked by the soluble guanylate cyclase inhibitor, ODQ (1H:-[1,2,4]Oxadiazolo-[4,3,-a]quinoxalin-1-one) at concentrations up to 30 microM. Ten microM ODQ gave maximal inhibition. Endothelium removal had no effect on the potency of spermine NONOate or its inhibition by ODQ. The protein kinase G inhibitor, Rp-8-Br-cGMPS (100 microM), caused minimal inhibition of spermine NONOate despite causing marked inhibition of glyceryl trinitrate and isosorbide dinitrate. Spermine NONOate (100 microM) caused a 35 fold increase in guanosine 3'5' cyclic monophosphate (cyclic GMP) above basal levels in pulmonary artery rings. ODQ (3 microM) abolished this cyclic GMP production but did not inhibit corresponding relaxant responses. Similar results were seen with another NONOate (MAHMA NONOate; 10 microM). ODQ-resistant relaxation to spermine NONOate (i. e. relaxation seen in the presence of 10 microM ODQ) was inhibited by potassium (80 mM), charybdotoxin (300 nM), iberiotoxin (300 nM), apamin (100 nM), ouabain (1 mM) or thapsigargin (100 nM) but not by 4-aminopyridine (3 mM), glybenclamide (10 microM) or diltiazem (10 microM). Potassium, charybdotoxin, ouabain and thapsigargin also inhibited ODQ-resistant relaxation to FK409 ((+/-)-E:-4-ethyl-2-[E:-hydroxyimino]-5-nitro-3-hexenamide). We conclude that, on rat pulmonary artery, spermine NONOate can produce cyclic GMP-independent relaxation that involves, at least in part, activation of Na(+)/K(+)-ATPase, sarco-endoplasmic reticulum Ca(2+)-ATPase and calcium-activated potassium channels.
...
PMID:Cyclic GMP-independent relaxation of rat pulmonary artery by spermine NONOate, a diazeniumdiolate nitric oxide donor. 1103 Jul 15

We coexpressed the human large-conductance, calcium-activated K (K(Ca)) channel (alpha- and beta-subunits) and rat atrial natriuretic peptide (ANP) receptor genes in Xenopus oocytes to examine the mechanism of guanylyl cyclase stimulatory coupling to the channel. Exposure of oocytes to ANP stimulated whole cell K(Ca) currents by 21 +/- 3% (at 60 mV), without altering current kinetics. Similarly, spermine NONOate, a nitric oxide donor, increased K(Ca) currents (20 +/- 4% at 60 mV) in oocytes expressing the channel subunits alone. Stimulation of K(Ca) currents by ANP was inhibited in a concentration-dependent manner by a peptide inhibitor of cGMP-dependent protein kinase (PKG). Receptor/channel stimulatory coupling was not completely abolished by mutating the cAMP-dependent protein kinase phosphorylation site on the alpha-subunit (S869; Nars M, Dhulipals PD, Wang YX, and Kotlikoff MI. J Biol Chem 273: 14920-14924, 1998) or by mutating a neighboring consensus PKG site (S855), but mutation of both residues virtually abolished coupling. Spermine NONOate also failed to stimulate channels expressed from the double mutant cRNAs. These data indicate that nitric oxide donors stimulate K(Ca) channels through cGMP-dependent phosphorylation and that two serine residues (855 and 869) underlie this stimulatory coupling.
...
PMID:Guanylyl cyclase stimulatory coupling to K(Ca) channels. 1107 9

1. Vasorelaxant properties of three nitric oxide (NO) donor drugs (glyceryl trinitrate, sodium nitroprusside and spermine NONOate) in mouse aorta (phenylephrine pre-contracted) were compared with those of endothelium-derived NO (generated with acetylcholine), NO free radical (NO*; NO gas solution) and nitroxyl ion (NO(-); from Angeli's salt). 2. The soluble guanylate cyclase inhibitor, ODQ (1H-(1,2,4-)oxadiazolo(4,3-a)-quinoxalin-1-one; 0.3, 1 and 10 microM), concentration-dependently inhibited responses to all agents. 10 microM ODQ abolished responses to acetylcholine and glyceryl trinitrate, almost abolished responses to sodium nitroprusside but produced parallel shifts (to a higher concentration range; no depression in maxima) in the concentration-response curves for NO gas solution, Angeli's salt and spermine NONOate. 3. The NO* scavengers, carboxy-PTIO, (2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide; 100 microM) and hydroxocobalamin (100 microM), both inhibited responses to NO gas solution and to the three NO donor drugs, but not Angeli's salt. Hydroxocobalamin, but not carboxy-PTIO, also inhibited responses to acetylcholine. 4. The NO(-) inhibitor, L-cysteine (3 mM), inhibited responses to Angeli's salt, acetylcholine and the three NO donor drugs, but not NO gas solution. 5. The data suggest that, in mouse aorta, responses to all three NO donors involve (i) activation of soluble guanylate cyclase, but to differing degrees and (ii) generation of both NO* and NO(-). Glyceryl trinitrate and sodium nitroprusside, which generate NO following tissue bioactivation, have profiles resembling the profile of endothelium-derived NO more than that of exogenous NO. Spermine NONOate, which generates NO spontaneously outside the tissue, was the drug that most closely resembled (but was not identical to) exogenous NO.
...
PMID:Vascular smooth muscle relaxation mediated by nitric oxide donors: a comparison with acetylcholine, nitric oxide and nitroxyl ion. 1158

In atrial myocytes, an initial exposure to isoproterenol (ISO) acts via cAMP to mediate a subsequent acetylcholine (ACh)-induced activation of ATP-sensitive K(+) current (I(K,ATP)). In addition, beta-adrenergic receptor (beta-AR) stimulation activates nitric oxide (NO) release. The present study determined whether the conditioning effect of beta-AR stimulation acts via beta(1)- and/or beta(2)-ARs and whether it is mediated via NO signaling. 0.1 microM ISO plus ICI 118,551 (ISO-beta(1)-AR stimulation) or ISO plus atenolol (ISO-beta(2)-AR stimulation) both increased L-type Ca(2+) current (I(Ca,L)) markedly, but only ISO-beta(2)-AR stimulation mediated ACh-induced activation of I(K,ATP). 1 microM zinterol (beta(2)-AR agonist) also increased I(Ca,L) and mediated ACh-activated I(K,ATP). Inhibition of NO synthase (10 microM L-NIO), guanylate cyclase (10 microM ODQ), or cAMP-PKA (50 microM Rp-cAMPs) attenuated zinterol-induced stimulation of I(Ca,L) and abolished ACh-activated I(K,ATP). Spermine-NO (100 microM; an NO donor) mimicked beta(2)-AR stimulation, and its effects were abolished by Rp-cAMPs. Intracellular dialysis of 20 microM protein kinase inhibitory peptide (PKI) abolished zinterol-induced stimulation of I(Ca,L). Measurements of intracellular NO ([NO](i)) using the fluorescent indicator DAF-2 showed that ISO-beta(2)-AR stimulation or zinterol increased [NO](i). L-NIO (10 microM) blocked ISO- and zinterol-induced increases in [NO](i). ISO-beta(1)-AR stimulation failed to increase [NO](i). Inhibition of G(i)-protein by pertussis toxin significantly inhibited zinterol-mediated increases in [NO](i). Wortmannin (0.2 microM) or LY294002 (10 microM), inhibitors of phosphatidylinositol 3'-kinase (PI-3K), abolished the effects of zinterol to both mediate ACh-activated I(K,ATP) and stimulate [NO](i). We conclude that both beta(1)- and beta(2)-ARs stimulate cAMP. beta(2)-ARs act via two signaling pathways to stimulate cAMP, one of which is mediated via G(i)-protein and PI-3K coupled to NO-cGMP signaling. Only beta(2)-ARs acting exclusively via NO signaling mediate ACh-induced activation of I(K,ATP). NO signaling also contributes to beta(2)-AR stimulation of I(Ca,L). The differential effects of beta(1)- and beta(2)-ARs can be explained by the coupling of these two beta-ARs to different effector signaling pathways.
...
PMID:Beta 2-adrenergic receptor signaling acts via NO release to mediate ACh-induced activation of ATP-sensitive K+ current in cat atrial myocytes. 1177 39

Receptor desensitization of G protein-coupled receptors (GPCRs), which occurs during short-term (seconds to minutes) exposure of cells to agonists, is mediated by phosphorylation and receptor endocytosis. Recycling of the receptors is a requisite for resensitization of the response. The mechanisms that attenuate signaling by GPCRs are of considerable importance to regulation of intercellular signaling and maintenance of their ability to respond to agonists over time. This study evaluates the effect of nitric oxide (NO) on P2Y nucleotide receptor resensitization in cultured rat glomerular mesangial cells. The NO production in cultured mesangial cells was measured by using confocal microscopy and the fluorescence NO indicator 4,5-diaminofluorescein diacetate (DAF-2 DA). L-arginine increased and Nomega-nitro-L-arginine methyl ester (L-NAME) decreased NO production significantly (P < 0.05). Calcium responses to ATP were measured with fura-2 and imaging techniques. Repeated stimulation with ATP results in receptor desensitization that is characterized by lower calcium peak amplitude. Desensitization was induced by challenging mesangial cells with four consecutive 2-min pulses of ATP (0.1 mM) separated by 4.5-min control perfusions. Intracellular calcium concentration ([Ca2+]i) increase evoked by second, third, and fourth ATP challenges were about 40%, 26%, and 18% of the first one. The NO precursor, L-arginine (10 mM), and the NO donors, spermine-NONOate (500 microM) and sodium nitroprusside (SNP) (1 mM), were added before and during a fourth ATP challenge. Spermine-NONOate and L-arginine induced a recovery of the [Ca2+]i response to the fourth ATP challenge (P < 0.01 and 0.05, respectively). The NO synthase inhibitor, L-NAME (5 mM), applied along with ATP, was shown to enhance desensitization. 1H-(1,2,4)oxadiazolo(4,3-alpha)quinoxalin-1-one (ODQ, 30 microM), an inhibitor of guanylate cyclase, was used along with L-arginine, SNP, or spermine-NONOate. There was no significant difference with or without ODQ. Neither ODQ nor 8-Br-cGMP, an analog of cGMP, at different concentrations showed effects on ATP-stimulated [Ca2+]i. There was no elevation of [Ca2+]i when the cells were challenged by different concentrations (1 microM, 100 microM, 1 mM, 20 mM, and 30 mM) of caffeine, caffeine plus ATP (0.1 mM), and 4-chloro-3-ethylphenol (100 microM, 500 microM, and 1 mM), a new agonist of ryanodine receptors. The results indicate that NO can increase the P2Y receptor resensitization in rat glomerular mesangial cells by acting through a cGMP-independent pathway. No evidence was found for the existence of ryanodine-sensitive intracellular calcium stores in rat mesangial cells.
...
PMID:Nitric oxide induces resensitization of P2Y nucleotide receptors in cultured rat mesangial cells. 1180 58

Although both nitric oxide (NO) and glutamate within the rostral ventrolateral medulla (RVLM) are important mediators of the central cardiovascular regulation, little is known about the functional interactions between these two mediators. Herein, we investigated the possible role of NO on the glutamatergic transmission of RVLM neurons. Whole-cell patch-clamp recordings were performed on visualized RVLM neurons in the brainstem slice preparation of rats. We found that bath application of l-arginine, the substrate for NO production, significantly increased the amplitude of excitatory postsynaptic currents (EPSCs). This enhancement was completely abolished by coadministration of the NO synthase inhibitor 7-nitroindazole and mimicked by the NO donors 3-morpholinylsydnoneimine and spermine NONOate. Bath application of a NO-sensitive guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, or a protein kinase G (PKG) inhibitor, Rp-8-bromo-guanosine 3',5'-cyclic monophosphorothioate, fully prevented the l-arginine-, 3-morpholinylsydnoneimine-, and N-[4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino]-butyl]-1,3-propanediamin (spermine NONOate)-induced synaptic potentiation. Direct activation of PKG with 8-(4-chlorophenylthio)-cGMP mimicked the action of NO donors. Furthermore, the augmentation by spermine NONOate of EPSC was accompanied by a reduction of the paired-pulse facilitation and synaptic failure rate of EPSCs. Spermine NONOate also significantly increased the frequency of both spontaneous and miniature EPSCs without altering their amplitude distribution. Pretreatment with the N-type Ca2+ channel blocker omega-conotoxin GVIA selectively blocked the spermine NONOate-induced synaptic potentiation. These results suggest that NO acts presynaptically to elicit a synaptic potentiation on the RVLM neurons through an enhancement of presynaptic N-type Ca2+ channel activity leading to facilitating glutamate release. The presynaptic action of NO is mediated by a cGMP/PKG-coupled signaling pathway.
...
PMID:cGMP/protein kinase G-dependent potentiation of glutamatergic transmission induced by nitric oxide in immature rat rostral ventrolateral medulla neurons in vitro. 1286 58


1 2 Next >>

---