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)

Compounds formed by reacting nitric oxide (NO) with various nucleophiles have been shown to dilate aortic segments with a potency that correlates strongly with the amount of NO they release spontaneously in aqueous buffers. We performed experiments aimed at confirming their mechanism of action and using the data to design improvements in their pharmacologic properties. That the vasorelaxant action these agents induce is endothelium-independent was demonstrated by exposure of denuded versus intact aortic segments to the diethylamine/NO complex (DEA/NO); denudation had no significant effect on potency. Similarly, NG-monomethyl-L-arginine, an NO synthase inhibitor, did not affect the action of DEA/NO. However, both the vasorelaxant potency of DEA/NO and the amount of cyclic guanosine monophosphate it induced were significantly diminished by the guanylate cyclase inhibitor, methylene blue. The results support the view that the NO/nucleophile adducts induce vasodilation by spontaneously releasing NO, which then activates guanylate cyclase. This mechanistic conclusion suggests that not only potency but also duration of action, a clinically relevant parameter not studied in the previous investigation, might also be controllable by structural modification. We tested this hypothesis by comparing DEA/NO and the spermine/NO adduct (SPER/NO), whose half-lives (t1/2) are 2.1 and 39 min, respectively, for persistence of their dilatory effects. The response to DEA/NO rapidly peaked (maximum at 5 min) and receded during the 60-min observation period; SPER/NO required 15 min to reach peak relaxation but maintained this level throughout the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanism of vascular relaxation induced by the nitric oxide (NO)/nucleophile complexes, a new class of NO-based vasodilators. 768 15

The aim of the present study was to investigate the effect of Cu(II) ions on soluble guanylyl cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2; sGC] and to test for a possible physiological role of this putative cofactor of the enzyme [Gerzer et al., FEBS Lett. 132: 71-74, 1981]. CuSO4 was found to inhibit NO-stimulated 5GC with an IC50 of 2.2 +/- 0.3 microM. Virtually complete inhibition of guanosine-3',5'-cyclic monophosphate (cGMP) formation was observed at 10 microM of the copper salt. Presence of CuSO4 (2 microM) did not significantly affect the potency of 2,2-diethyl-1-nitroso-oxyhydrazine (DEA/NO) but did markedly decrease maximal cyclase activity from 3.71 +/- 0.2 mumol cGMP x mg-1 x min-1 to 1.75 +/- 0.2 mumol cGMP x mg-1 x min-1. The nonstimulated enzyme was also sensitive to CuSO4 (IC50 of 6.2 +/- 1.2 microM). Addition of glutathione, which potently complexes Cu(I) ions, induced a pronounced rightward shift of the concentration-response curves for inhibition by CuSO4 of both DEA/NO-stimulated and nonstimulated guanylyl cyclase. The inhibitory effect of CuSO4 was completely antagonized by the specific Cu(I) chelator neocuproine, with a half-maximal effect at 5.9 +/- 0.2 microM. In contrast, the Cu(II) chelator cuprizone and several thiols, which do not form stable Cu(I) complexes, were far less protective. Our results suggest that inhibition of soluble guanylyl cyclase by CuSO4 is unrelated to heme-mediated enzyme stimulation and may arise from the reversible high affinity binding of Cu(I) ions to a site of the protein that is critically involved in enzyme catalysis.
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PMID:Inhibition of purified soluble guanylyl cyclase by copper ions. 883 23

Exogenous nitric oxide (NO) has been shown to modulate the contractile force of rat cardiac myocytes. We sought to determine whether endogenous NO-production in the isolated normal rat heart has an effect on myocardial contractility. Hearts of male Wistar rats were investigated using a constant flow perfused non-paced Langendorff preparation. Changes of contractile parameters such as left ventricular peak pressure, dP/dtmax and dP/dtmin, and of coronary perfusion pressure and heart rate were recorded after infusion of the NO-synthase inhibitors N(omega)-nitro-L-arginine (L-NOARG, 0.1 mM, 1.0 mM, n = 6), N(omega)-methyl-L-arginine (L-NMMA, 0.1 mM, 1.0 mM, n = 9) and methylene blue (2 microM, 20 microM, n = 6), the NO-donor sodium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolat (DEA/NO, 0.01 microM, 0.1 microM, n = 12), the specific inhibitor of soluble guanylate cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 0.1 microM, n = 7) and L-arginine (0.1 mM, 1.0 mM, n = 6). All NO-synthase inhibitors reduced the contractile function of the ventricular muscle before changes in coronary perfusion pressure were evident. The negative inotropic effect of L-NMMA was absent in the presence of an equimolar concentration of L-arginine. ODQ reduced contractile force and coronary perfusion pressure in parallel. By contrast, L-arginine and DEA/NO improved the contractile force of the left ventricle and DEA/NO decreased coronary perfusion pressure. Heart rate was reduced by L-NOARG (1 mM) and methylene blue (20 microM), while DEA/NO (0.1 microM) and L-arginine (1 mM) had a positive chronotropic effect. All these changes were significant (P < 0.05). These results suggest that endogenous NO-production exerts a positive effect on myocardial contraction that is mediated by activation of guanylate cyclase. In addition, NO might be involved in regulation of heart rate.
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PMID:Inhibition of nitric oxide synthase and soluble guanylate cyclase induces cardiodepressive effects in normal rat hearts. 936 47

The mechanism underlying smooth muscle relaxations of cerebral arteries in response to nitric oxide is still not completely understood. The present study was designed to determine the role of soluble guanylate cyclase in the relaxations to a nitric oxide/nucleophile complex, diethylaminodiazen-1-ium-1,2-dioate (DEA-NONOate). Rings of canine middle cerebral arteries without endothelium were suspended in Krebs-Ringer bicarbonate solution for isometric tension recording. The levels of guanosine 3',5'-cyclic monophosphate (cyclic GMP) were measured by radioimmunoassay technique. During contractions to uridine 5'-triphosphate (UTP), DEA-NONOate (10(-10) to 10(-5) M) caused concentration-dependent relaxations. Measurements of cyclic GMP levels in cerebral arterial wall demonstrated that DEA-NONOate is a potent stimulator of guanylate cyclase and subsequent formation of cyclic GMP. Increasing concentrations of a selective soluble guanylate cyclase inhibitor, 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), caused concentration-dependent reduction of both cyclic GMP production and relaxations to DEA-NONOate. Interestingly, in the presence of the highest concentration (3 x 10(-6) M) of ODQ, production of cyclic GMP in response to 10(-6) M of DEA-NONOate was abolished, whereas the same concentration of DEA-NONOate caused almost complete relaxation, suggesting that mechanisms independent of cyclic GMP production may mediate relaxing effect of high concentration of a nitric oxide donor. A selective Ca2+-activated potassium channel blocker charybdotoxin (CTX) significantly reduced relaxations to DEA-NONOate resistant to ODQ, supporting the idea that in cerebral arteries nitric oxide may activate potassium channels independently of cyclic GMP. The results of our study suggest that under physiological conditions, guanylate cyclase is a key mediator of cerebral arterial relaxations to nitric oxide. However, under pathological conditions associated with induction of nitric oxide synthase and increased biosynthesis of nitric oxide (e.g., cerebral ischemia, inflammation, sepsis), mechanisms other than formation of cyclic GMP may be activated.
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PMID:The effect of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and charybdotoxin (CTX) on relaxations of isolated cerebral arteries to nitric oxide. 952 59

The present study was undertaken to assess the effects of sodium nitroprusside (SNP) and diethylamine NO (C2H5)2N[N(O)NO]-Na+ (DEA/NO), NO donors, on an acetylcholine (ACh)-induced Cl- current in identified Onchidium neurons using voltage-clamp and pressure ejection techniques. Bath-applied SNP (10 microM) and DEA/NO (5-10 microM) reduced the ACh-induced Cl- current in the neurons without affecting the resting membrane conductance and holding current. The suppressing effect of NO donors were concentration-dependent and completely reversible. Pretreatment with 1H-[1,2,4]oxadiazolo-[4,3-a] quinoxalin-1-one (1 micro M), a specific inhibitor of NO-stimulated guanylate cyclase, and hemoglobin (50 micro M), a nitric oxide scavenger, decreased the SNP-induced inhibition of the ACh-induced current. Intracellular injection of guanosine 3',5'-cyclic monophosphate (cGMP) or bath-application of 3-isobutyl-1-methylxanthine (50 micro M), a non-specific phosphodiesterase inhibitor, inhibited the ACh-induced current, mimicking the effect of NO donors. These results suggest that SNP and DEA/NO inhibit the ACh-induced Cl- current and that this effect is mediated by an increase in intracellular cGMP.
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PMID:Nitric oxide donors inhibit the acetylcholine-induced Cl- current in identified Onchidium neurons. 962 21

1. The aim of the present study was to determine the effect of nitric oxide (NO) on angiotensin-converting enzyme (ACE) activity. 2. A biochemical study was performed in order to analyse the effect of the NO-donors, SIN-1 and diethylamine/NO (DEA/NO), and of an aqueous solution of nitric oxide on the ACE activity in plasma from 3-month old male Sprague-Dawley rats and on ACE purified from rabbit lung. SIN-1 significantly inhibited the activity of both enzymes in a concentration-dependent way between 1 and 100 microM. DEA/NO inhibited the activity of purified ACE from 0.1 microM to 10 microM and plasma ACE, with a lower potency, between 1 and 100 microM. An aqueous solution of NO (100 and 150 microM) also inhibited significantly the activity of both enzymes. Lineweaver-Burk plots indicated an apparent competitive inhibition of Hip-His-Leu hydrolysis by NO-donors. 3. Modulation of ACE activity by NO was also assessed in the rat carotid artery by comparing contractions elicited by angiotensin I (AI) and AII. Concentration-response curves to both peptides were performed in arteries with endothelium in the presence of the guanylyl cyclase inhibitor, ODQ (10 microM), and the inhibitor of NO formation, L-NAME (0.1 mM). NO, which is still released from endothelium in the presence of 10 microM ODQ, elicited a significant inhibition of AI contractions at low concentrations (1 and 5 nM). In the absence of endothelium, 1 microM SIN-1 plus 10 microM ODQ, as well as 10 microM DEA/NO plus 10 microM ODQ induced a significant inhibition on AI-induced contractions at 1 and 5 nM and at 1-100 nM, respectively. 4. In conclusion, we demonstrated that (i) NO and NO-releasing compounds inhibit ACE activity in a concentration-dependent and competitive way and that (ii) NO release from endothelium physiologically reduces conversion of AI to AII.
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PMID:Modulation of angiotensin-converting enzyme by nitric oxide. 964 45

The effects of sodium nitroprusside (SNP) on Ca2+-dependent K+ (KCa) channels in cultured bovine adrenal chromaffin cells were investigated using single channel recording patch-clamp techniques. KCa channels were activated by application of 100 microM SNP to the extracellular side of cell-attached patches. Methylene blue (300 microM), an inhibitor of soluble guanylate cyclase, or H-8 (1 microM), a protein kinase inhibitor with relative specificity for cGMP-dependent protein kinase, diminished but did not completely abolish the SNP-induced KCa channel activation. Diethylamine/NO complex (DEA/NO), an NO donor, also activated KCa channels in cell-attached patches. Furthermore, application of 100 microM SNP or 100 nM DEA/NO to the intracellular surface of excised inside-out patches also activated KCa channels in the bath solution which contained 1 microM Ca2+. These results indicate that SNP is capable of activating the KCa channel via cGMP-dependent and -independent mechanisms. These studies demonstrate that NO may serve as an important regulatory mechanism for catecholamine secretion in chromaffin cells via the activation of KCa channels.
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PMID:Nitric oxide activates Ca2+-activated K+ channels in cultured bovine adrenal chromaffin cells. 965 59

NO as produced by NO-synthases (NOS) contributes to the regulation of cardiovascular functions. In hypertension, there is a reduced production and/or activity of endogenous NO in the vasculature. We investigated if hypertension alters the NO-sensitivity of soluble guanylate cyclase (sGC) in blood vessels and heart muscle isolated from 15 month old spontaneously hypertensive rats (SHR15) and normal Wistar rats (WIS). Inhibition of NOS by 1 mM N omega-nitro-L-arginine decreased dP/dtmax in WIS (-27.6 +/- 3.4%) and SHR15 (-26.0 +/- 4.4%), while stimulation of NOS with 1 mM L-arginine increased dP/dtmax in WIS (9.9 +/- 0.7%) and SHR15 (8.9 +/- 2.3%). The positive inotropic response to 0.1 microM glyceryl trinitrate (GTN) was comparable in WIS (dP/dtmax: 4.5 +/- 1.7%) and SHR15 (dP/dtmax: 3.75 +/- 0.7%) as was the positive inotropic response to the NO-donor sodium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolat (DEA/NO, 1 microM) in WIS (dP/dtmax: 10.7 +/- 2.9%) and SHR15 (dP/dtmax: 5.1 +/- 1.5%, P = 0.1873). In aortas of SHR15 we found an increased superoxide production of 19.4 +/- 1.7 nM/mg/min (WIS: 6.1 +/- 0.6 nM/mg/min) in the smooth muscle and the endothelial layer. Endothelium-dependent relaxation by acetylcholine was markedly impaired in SHR15 as was the vasorelaxant activity of S-nitroso-N-acetyl-D,L-penicillamine (SNAP), pentaerythritol tetranitrate and GTN. Maximal cGMP-production by sGC isolated from the lung and stimulated with SNAP (0.5 mM) was much lower in SHR15 (115 +/- 14 pmol/mg/min) than in WIS (348 +/- 36 pmol/mg/min). We suggest that hypertension is associated with a reduced activity of the sGC/cGMP-system in the vasculature but not in the heart muscle. Our results provide the first evidence that excess superoxide production in hypertension may trigger a desensitization of vascular sGC.
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PMID:Alterations of the vascular and the myocardial guanylate cyclase/cGMP-system induced by long-term hypertension in rats. 970 36

The effect of two nitric oxide (NO) donors, SIN-1 and DEA/NO, as well as of the inactive SIN-1 derivative molsidomin, was studied on locus coeruleus (LC) neurons in a slice preparation using intracellular recordings. In addition, the effect of the guanylate cyclase inhibitor ODQ was analysed. Furthermore, the effect of NO donors on cyclic guanosine monophosphate (GMP) levels in the LC was studied using the indirect immunofluorescence technique, and the expression of soluble guanylyl cyclase with in situ hybridization. In 36 of 66 LC neurons extracellular application of SIN-1 and DEA/NO caused a hyperpolarization and a decrease in apparent input resistance. In almost 20% of neurons SIN-1 increased the firing rate. No effect could be recorded with the brain-inactive SIN-1 derivative molsidomin. The membrane permeable cGMP analogue 8-bromo-cGMP imitated the action of SIN-1. The hyperpolarizing effect of SIN-1 and DEA/NO was attenuated by preincubation with the guanylyl cyclase inhibitor ODQ. The immunohistochemical analysis revealed lack of cGMP immunostaining in non-stimulated slices, whereas SIN-1 dramatically increased this staining in about 40% of the LC neurons, and these neurons were all tyrosine hydroxylase positive, that is noradrenergic. A large proportion of the LC neurons expressed soluble guanylyl cyclase mRNA. The present and previous results suggest that NO, released from a small number of non-noradrenergic neurons in the LC, mainly has an inhibitory influence on many noradrenergic neurons, by upregulating cGMP levels via stimulation of soluble guanylyl cyclase. As nitric oxide synthase is present only in a small number of non-noradrenergic neurons (Xu et al., 1994), a few neurons may influence a large population of noradrenergic LC neurons, which in turn may control activity in many regions of the central nervous system.
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PMID:The NO-cGMP pathway in the rat locus coeruleus: electrophysiological, immunohistochemical and in situ hybridization studies. 982 64

1. Sodium nitroprusside (SNP, 10(-9)-3x10(-4) M), diethylamine/NO complex (DEA/NO, 10(-9)-10(-4) M) and spermine/NO complex (SPER/NO, 10(-8)-3x10(-4) M) induced concentration-dependent relaxation of isolated rabbit carotid arteries precontracted with KCl (50 mM) or with histamine (3x10(-6) M). 2. In KCl-precontracted arteries the order of potency was SNP=DEA/NO>SPER/NO, and in histamine-precontracted arteries the order of potency was SNP>DEA/NO>SPER/NO. Relaxations to the three NO donors were significantly higher in histamine-precontracted arteries than in KCl-precontracted arteries. 3. The guanylyl cyclase inhibitor methylene blue (10(-5) M) significantly inhibited relaxations to the three NO donors in histamine-precontracted arteries and, to a lesser extent, in KCl-precontracted arteries. 4. In conclusion, the NO donors SNP, DEA/NO and SPER/NO induce quantitatively different relaxation of rabbit carotid artery. Both, lower relaxant effects in depolarized arteries and inhibition of relaxation by methylene blue indicate the mediation of cGMP formation in the relaxant effects of the three NO donors.
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PMID:Comparative relaxant effects of the NO donors sodium nitroprusside, DEA/NO and SPER/NO in rabbit carotid arteries. 988 58


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