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

The effects of sodium nitroprusside (SNP) on dopamine synthesis in a porcine renal epithelial cell line (LLC-PK1) were evaluated. Subsequent studies examined the actions of the degradation products of SNP (cyanide, ferrous ion and nitric oxide) on aromatic amino acid decarboxylase (AAAD) activity in tissue supernatants from LLC-PK1 cells and rat renal cortex. SNP (10-500 mumol/l) significantly inhibited dopamine production in LLC-PK1 cells in a dose-related manner. The activation of guanylate cyclase by nitric oxide was not found to be the mechanism whereby SNP inhibited dopamine synthesis in LLC-PK1 nor did the antioxidant glutathione attenuate the actions of SNP. Ferrous sulfate (0.5 mmol/l) and SNP (0.5 mmol/l) were found to inhibit dopamine synthesis in LLC-PK1 cells and to directly inhibit cytosolic AAAD activity from LLC-PK1 cells. A series of studies were conducted using AAAD from rat renal cortex and confirmed that SNP could directly inhibit the conversion of L-dopa to dopamine by AAAD. Furthermore, potassium ferricyanide (1 mmol/l) and potassium cyanide (1 mmol/l) could produce greater than 80% reductions in AAAD activity. Iron (0.5-1 mmol/l) was found to increase rat kidney AAAD activity. Kinetic analysis revealed that potassium cyanide was a potent (Ki = 40-50 mumol/l) noncompetitive/mixed noncompetitive inhibitor of AAAD. SNP was also found to be a noncompetitive inhibitor of AAAD with a Ki of approximately 300-500 mumol/l. In contrast, ferrous sulfate (0.5 mmol/l) was a competitive inhibitor (Ki = approximately 650 mumol/l) that actually increased the Vmax of AAAD. The results of these studies support that cyanide released from SNP can potently inhibit AAAD, although SNP has somewhat more complex interactions with AAAD due to the presence of ferrous ion.
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PMID:Mechanism of sodium nitroprusside-mediated inhibition of aromatic amino acid decarboxylase activity. 771 78

Nitric oxide (.NO) is a recently discovered signaling agent which plays a role in many biological processes such as vasodilation and neuronal synaptic transmission. The only receptor characterized thus far for .NO is the soluble form of guanylate cyclase (sGC). .NO increases the Vmax of sGC by 100-200-fold, probably by interacting with a heme moiety on the enzyme. Although several procedures exist for purifying sGC, these procedures result in preparations with low heme contents. Using a novel procedure, the enzyme has been purified to homogeneity from bovine lung with a heme content of approximately 1 heme/heterodimer. The UV-visible spectrum of the enzyme contains a Soret peak centered at 431 nm and a single broad alpha/beta peak at 555 nm indicative of a 5-coordinate ferrous heme with histidine as the axial ligand. The heme moiety does not bind oxygen but will readily bind .NO to form a 5-coordinate complex or carbon monoxide (CO) to form a 6-coordinate complex. Oxidation of the heme with ferricyanide shifts the Soret to 393 nm, due most likely to the formation of a 5-coordinate ferric heme. In the ferric state, the heme will apparently not bind water but will bind cyanide with reduced affinity compared to methemoglobin and metmyoglobin. Purified enzyme containing 1 heme/heterodimer is activated 130-fold by .NO and 4.4-fold by CO.
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PMID:Soluble guanylate cyclase from bovine lung: activation with nitric oxide and carbon monoxide and spectral characterization of the ferrous and ferric states. 791 35

Hydroxylamine (0.01-30 mM), a nitric oxide (NO) generator, produced a concentration-dependent release of [3H]dopamine ([3H]DA) from rat striatal slices. Hemoglobin (10 microM), a NO scavenger, reduced basal [3H]DA release and blocked hydroxylamine (100 microM)-stimulated [3H]DA efflux. Tetrodotoxin (0.5 microM) had no significant effect. Sodium cyanide was used as a model compound to test the possibility that NO acted through blockade of mitochondrial electron transport. Calcium-free experimental buffer (1 mM EGTA) reduced basal release and the hydroxylamine response, while sodium cyanide-induced release did not change under these experimental conditions. Cadmium (200 microM), a non-selective inhibitor of voltage-dependent calcium channels, reduced the hydroxylamine response by 69%. Methylene blue (10 microM), an inhibitor of guanylate cyclase, produced a 3-fold increase in the basal release but had no significant effect on the hydroxylamine response. These data suggest that NO induces calcium-dependent [3H]DA release from the striatum via a mechanism which is independent of blockade of electron transport or activation of guanylate cyclase.
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PMID:Nitric oxide induces calcium-dependent [3H]dopamine release from striatal slices. 810 May 88

Previous studies in our laboratory have shown that nitric oxide (NO) gas enhances NMDA-stimulated release of preloaded tritiated norepinephrine ([3H]NA) from rat brain slices in a dose-dependent, oxygen-sensitive, and cyclic GMP-independent manner. In this study we have attempted to determine the mechanism for the enhancement of neurotransmitter release seen with NO. No-enhanced transmitter release was not due to buffer acidification or generation of NO degradation products, since reducing buffer pH below 7.3 inhibited NMDA-stimulated [3H]NA release and nitrite or nitrate ions (3-100 microM) had no significant effect on release. Carbon monoxide (CO, 10-300 microM), another diatomic gas with properties similar to NO including heme binding and guanylate cyclase activation, had no significant effect on depolarization-induced [3H]NA release. The NO effect was probably not due to mono-ADP-ribosylation of cellular proteins, since the ADP-ribosyltransferase (ADPRT) inhibitors nicotinamide (10 microM-10 microM) and luminol (1 microM-1mM) did not diminish the enhancement of transmitter release seen with NO. The NA reuptake inhibitor desmethylimipramine (DMI, 10 nM-10 microM) neither mimicked nor blocked the effect of NO, suggesting that NO was not acting via inhibition or reversal of the NA transporter. Similar to NO, the metabolic inhibitors sodium azide (NaN3, 0.1-3 mM), potassium cyanide (KCN, 0.1-3 mM), and 2,4-dinitrophenol (2,4-DNP, 10-300 microM) also dose-dependently enhanced NMDA-stimulated [3H]NA release. These results suggest that NO may enhance neurotransmitter release by inhibiting cellular respiration and perhaps ultimately via altering calcium homeostasis.
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PMID:Mechanism for nitric oxide's enhancement of NMDA-stimulated [3H]norepinephrine release from rat hippocampal slices. 853 39

The soluble form of guanylate cyclase (sGC) is a hemoprotein which serves as the only known receptor for the signaling agent nitric oxide (.NO). The enzyme is a heterodimer in which each subunit binds 1 equiv of 5-coordinate high-spin type b heme. .NO increases the Vmax of sGC up to 400-fold by binding to the heme to form a 5-coordinate ferrous nitrosyl complex. The electron paramagnetic resonance spectrum of the ferric form of the enzyme has been obtained. The spectrum displays rhombic symmetry and is indicative of a high-spin heme. Computer simulation of the EPR spectrum yields g values of 6.36, 5.16, and 2.0 with linewidths of 3.3, 4.1, and 3.3 mT, respectively. Using electronic absorption spectroscopy, it was observed that the ferric heme binds cyanide to form a 6-coordinate low-spin complex. The rate constants for association (k(on)) and dissociation (k(off)) of cyanide at 10 degrees C have been determined to be (7.8 +/- 0.3) x 10(-2) M(-1) s(- 1) and (7.2 +/- 0.2) x 10(-5) s(-1), respectively. Unlike the ferrous form of the enzyme, which has a low affinity for ligands that form 6-coordinate complexes due to an unusually fast off-rate, the ferric form of the enzyme appears to have a low affinity for ligands due to a slow on-rate. The ferric heme binds azide with a Kd of 26 +/- 4 mM to form a high-spin complex. The ferric form of the enzyme has a specific activity of approximately 57% that of the nonactivated ferrous form of the enzyme. However, in contrast to the mild activation of the ferrous enzyme by carbon monoxide, the ferric enzyme is not activated by cyanide. These results indicate that there may be a significant structural change in the protein upon the oxidation of the heme iron.
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PMID:Spectral and ligand-binding properties of an unusual hemoprotein, the ferric form of soluble guanylate cyclase. 860 61

Effect of sodium cyanide on the relaxing response (decrease of intraluminal pressure) to sodium nitroprusside, sodium nitrite, nitric oxide and human atrial natriuretic peptide (HANP) was investigated in isolated rabbit aortic preparations in vitro. Cyanide 1 microM approximately 1 mM produced relaxation in norepinephrine (NE) 1 microM-contracted aortic preparation in a concentration dependent manner. Cyanide 100 microM, which was administered approximately 8 min before NE addition, depressed the relaxing response to nitroprusside 0.1 microM in NE 1 microM-contracted aortic preparation. The relaxing responses to nitric oxide 0.3 and 3.3 microM were slightly, but concentration-dependently depressed by cyanide 1-100 microM, which was administered 6-10 min before nitric oxide addition, in NE 1 microM-contracted aortic preparations. Cyanide 100 microM and 1 mM, which was administered 4-10 min after nitroprusside 0.1 microM, reversed the nitroprusside-induced relaxation in NE 1 microM contracted aortic preparation. Namely, relaxing response of NE-contracted aortic preparation to cyanide was converted into contractile response in the presence of nitroprusside. Similar reversal phenomena of the responses to cyanide 100 microM and 1 mM were also observed in the presence of sodium nitrite 0.1 microM or nitric oxide 3.3 microM, but those were less extent than that of nitroprusside 0.1 microM. On the contrary, the relaxing response to cyanide 100 microM was unaffected by pretreatment with HANP 0.37 nM. These findings may indicate that cyanide inhibits soluble guanylate cyclase activated by nitroprusside, sodium nitrite or nitric oxide through interaction with nitric oxide and heme binding site of the enzyme.
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PMID:Antagonism of relaxing responses to nitrovasodilators by cyanide in rabbit isolated aortic preparation. 882 92

ATP receptors and ATP-sensitive potassium channels (KATP) are expressed in vascular smooth muscle (VSM) and endothelial cells (EC). In isolated penetrating vessels, ATP caused a dilatation when applied intraluminally but not extraluminally. The actions of ATP were blocked by the nitric oxide (NO) synthesis inhibitor N omega-nitro-L-arginine (0.1 mM) but were only reduced by N-monomethyl-L-arginine (0.1 mM); responses to intraluminal ATP were also prevented by thapsigargin. The KATP opener (KCO) nicorandil (1 microM) caused an NO-independent vasodilatation when applied extraluminally and an NO-dependent response when applied intraluminally. Both responses were blocked by glibenclamide. EC-mediated responses to nicroandil were prevented by blockade of guanylate cyclase by LY-83583 (10 microM). The effects of nicorandil were mimicked by pinacidil (1-10 microM). Exposure of the endothelium to 500 microM cyanide and 0 mM glucose ("in vitro ischemia") caused a vasodilatation that was reduced by exposure to glibenclamide (5 microM). Blockade of NO synthase produced similar effects, suggesting that the ischemic dilation is mediated by KATP and NO. Our results suggest that both VSM and EC mediate the vascular responses induced by KCOs, whereas the dilatation induced by intraluminal ATP is mediated by the endothelium. The endothelium-dependent component of the in vitro ischemic vasodilatation is mediated by opening of endothelial KATP and subsequent release of NO.
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PMID:Endothelium-dependent regulation of cerebrovascular tone by extracellular and intracellular ATP. 927 6

1. We used whole-cell patch clamp to investigate the currents activated by nicorandil in smooth muscle cells isolated from rat small mesenteric arteries, and studied the relaxant effect of nicorandil using myography. 2. Nicorandil (300 microM) activated currents with near-linear current-voltage relationships and reversal potentials near to the equilibrium potential for K+. 3. The nicorandil-activated current was blocked by glibenclamide (10 microM), but unaffected by iberiotoxin (100 nM) and the guanylyl cyclase inhibitor LY 83583 (1 microM). During current activation by nicorandil, openings of channels with a unitary conductance of 31 pS were detected. 4. One hundred microM nicorandil had no effect on currents through Ca2+ channels recorded in response to depolarizing voltage steps using 10 mM Ba2+ as a charge carrier. A small reduction in current amplitude was seen in 300 microM nicorandil, though this was not statistically significant. 5. In arterial rings contracted with 20 mM K+ Krebs solution containing 200 nM BAYK 8644, nicorandil produced a concentration-dependent relaxation with mean pD2 = 4.77+/-0.06. Glibenclamide (10 microM) shifted the curve to the right (pD2 = 4.32+/-0.05), as did 60 mM K+. LY 83583 caused a dose-dependent inhibition of the relaxant effect of nicorandil, while LY 83583 and glibenclamide together produced greater inhibition than either alone. 6. Metabolic inhibition with carbonyl cyanide m-chlorophenyl hydrazone (30 nM), or by reduction of extracellular glucose to 0.5 mM, increased the potency of nicorandil. 7. We conclude that nicorandil activates KATP channels in these vessels and also acts through guanylyl cyclase to cause vasorelaxation, and that the potency of nicorandil is increased during metabolic inhibition.
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PMID:Potassium channel activation and relaxation by nicorandil in rat small mesenteric arteries. 988 63

Nitric oxide generates slow electrical oscillations (SEOs) in cells near the myenteric edge of the circular muscle layer, which resemble slow waves generated by interstitial cells of Cajal (ICCs) at the submucosal edge of this muscle. The properties of SEOs were studied to determine whether these events are similar to slow waves. Rapid frequency membrane potential oscillations (MPOs; 16 +/- 1 cycles/min and 9.6 +/- 0.2 mV) were recorded from control muscles near the myenteric edge. Sodium nitroprusside (0.3 microM) reduced MPOs and initiated SEOs (1.3 +/- 0.3 cycles/min and 13.4 +/- 1.4 mV amplitude). SEOs were abolished by the guanylate cyclase inhibitor 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxaline-1-one (10 microM). MPOs were abolished by nifedipine (1 microM), whereas SEO frequency increased and the amount of depolarization decreased. BAY K 8644 (1 microM) prolonged SEOs and reduced their frequency. SEOs were abolished by Ni(2+) (0.5 mM), low Ca(2+) solution (0.1 mM Ca(2+)), cyclopiazonic acid (10 microM), and the mitochondrial uncouplers antimycin (10 microM) and carbonyl cyanide p-trifluoromethoxyphenylhydrazone (1 microM). Oligomycin (10 microM) was without effect. These effects are similar to those described for colonic slow waves. Our results suggest that nitric oxide-induced SEOs are similar in mechanism to slow waves, an activity not previously thought to be generated by myenteric pacemakers.
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PMID:Electrical activity induced by nitric oxide in canine colonic circular muscle. 1175 Nov 65

In the guinea pig gastric antrum, the effects of sodium nitroprusside (SNP), an NO donor, on pacemaker potentials were investigated in the presence of nifedipine. The pacemaker potentials consisted of primary and plateau components; SNP (> 1 microM) increased the frequency of occurrence of these pacemaker potentials, while inhibiting the plateau component. 1H-[1,2,4]-Oxadiazole [4,3-a] quinoxalin-1-one, an inhibitor of guanylate cyclase, had no effect on the excitatory actions of SNP on the frequency of pacemaker potentials. Other types of NO donor, (+/-)-S-nitroso-N-acetylpenicillamine, 3-morpholino-sydnonimine and 8-bromoguanosine 3'5'-cyclic monophosphate had no excitatory effect on pacemaker activity. Forskolin, an activator of adenylate cyclase, or 4,4'-diisothiocyano-stilbene-2,2'-disulphonic acid, an inhibitor of the Ca(2+)-activated Cl(-) channel, strongly attenuated the generation of pacemaker potentials, and SNP added in the presence of these chemicals restored the generation of pacemaker potentials. The pacemaker potentials evoked by SNP were abolished in low-Ca(2+) solution or by membrane depolarization with high-K(+) solution. The SNP-induced generation of pacemaker potentials was not prevented by cyclopiazonic acid, an inhibitor of internal Ca(2+)-ATPase, but was limited to a transient burst by iodoacetic acid, an inhibitor of glycolysis, carbonyl cyanide m-chlorophenyl-hydrazone, a mitochondrial protonophore, or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, an intracellular Ca(2+) chelator. These results suggest that the SNP-induced increase in the frequency of pacemaker potentials is related to the elevated intracellular Ca(2+) concentrations due to release from mitochondria, and these actions may be independent of the activation of guanylate cyclase.
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PMID:Pacemaker frequency is increased by sodium nitroprusside in the guinea pig gastric antrum. 1250 88


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