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)

1. The formation of an S-nitrosothiol compound, S-nitroso-N-acetylcysteine (SNAC) has recently been proposed to mediate the augmentation of the anti-aggregatory and haemodynamic effects of glyceryl trinitrate observed in the presence of N-acetylcysteine. This study investigated the effects on an isolated coronary artery preparation of acute and prolonged exposure to S-nitrosothiol compounds and nitric oxide (NO). 2. Single doses of NO and of the S-nitrosothiol compounds, SNAC and S-nitroso-N-acetyl-penicillamine (SNAP), induced rapid, but transient, relaxations in U46619-contracted bovine isolated coronary artery rings. Peak relaxation responses to SNAP and NO were attenuated in the presence of N-acetylcysteine, cysteine, ascorbic acid and methylene blue. The duration of the relaxation responses to SNAC was two to three times longer than those to SNAP and NO. In the presence of N-acetylcysteine (but not cysteine, ascorbic acid or methylene blue) the duration of the relaxation responses to SNAP and NO (but not to SNAC) was markedly increased. H.p.l.c. assay confirmed that, in the presence of N-acetylcysteine, SNAP and, to a lesser degree, NO were converted to the relatively more stable and longer acting vasodilator, SNAC. 3. When compared to control rings, coronary artery rings superfused with glyceryl trinitrate were subsequently markedly less responsive to the vasodilator actions of glyceryl trinitrate, whereas responsiveness to SNAC or NO was only marginally reduced. On the other hand, coronary artery rings superfused with SNAC or NO were subsequently less responsive to glyceryl trinitrate, SNAC and NO. Thus prolonged vascular exposure to SNAC or NO induced a form of tolerance different from that induced with glyceryl trinitrate and which is possibly associated with impaired guanylate cyclase activity. 4. Coronary artery rings superfused with NO were markedly less responsive to glyceryl trinitrate and NO, whereas responses to the endothelium-dependent vasodilator A23187 and to theophylline were not significantly attenuated. 5. It is concluded that formation of the more stable vasodilator SNAC occurs on incubation of N-acetylcysteine with SNAP or NO. While coronary artery responsiveness to SNAC and NO is virtually unchanged in the presence of glyceryl trinitrate-induced tolerance, after prolonged exposure to SNAC or NO tolerance may develop to these vasodilators with cross-tolerance to glyceryl trinitrate but not A23187. Thus, formation or therapeutic utilization of SNAC may acutely circumvent the problem of glyceryl trinitrate-induced tolerance but, during prolonged vascular exposure to SNAC, attenuation of vascular responsiveness may occur to a wide range of vasodilators.
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PMID:S-nitrosothiols as vasodilators: implications regarding tolerance to nitric oxide-containing vasodilators. 251 92

A linear decapeptide, [cyclohexylalanine 106]ANP-(105-114)NH2 (1), where ANP is atrial natriuretic peptide, was prepared by solid phase synthesis and purified by reverse-phase liquid chromatography. This novel peptide was found to bind to ANP receptors in rabbit lung membranes, to stimulate cGMP production in various tissues, and to fully relax precontracted rabbit aorta in a dose-dependent fashion. The potency of 1 in the various in vitro assays varies between one-twentieth and one-eightieth of the potency of the reference peptide, the 24-mer rat ANP-(103-126). The linear decapeptide 1, which encompasses amino acid residues from the rat ANP sequence (105-114), features a cyclohexylalanine residue instead of the phenylalanine 106 residue in the hormone sequence, a free sulfhydryl function at the N-terminal cysteine 105, and a carboxamide C terminus. Its disulfide dimer 6 was active in the rabbit aorta assay while the S-methyl cysteine 7 analogue was not active in the same assay at similar concentrations. The decapeptide 1 is of particular significance because it is the shortest analogue reported to date endowed with agonistic activity at the guanylate cyclase-coupled ANP receptor. In particular, it is interesting to compare its structure to the structures of other short linear analogues of ANP which are totally devoid of the ability to stimulate particulate guanylate cyclase activity.
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PMID:A synthetic linear decapeptide binds to the atrial natriuretic peptide receptors and demonstrates cyclase activation and vasorelaxant activity. 255 53

Since the diminished vasodilatation characterizing tolerance to organic nitrates is associated with lower rises in 3', 5'-cyclic guanosine monophosphate (cGMP) levels, the possibility that nitrovasodilators desensitized guanylate cyclase (GC) when pre-incubated with coronary supernatants was studied. In the absence of cysteine, pre-incubation with nitroglycerin (NG) decreased GC-activity during subsequent incubation to 24 +/- 7% of control values, whereas six other nitrovasodilators had much smaller effects. When cysteine was present during pre-incubation, NG-stimulation of GC remained significantly higher (59 +/- 3%; P less than 0.05), whereas the effects of other nitrovasodilators were not significantly changed. We also found that GC-activity, when reduced by pre-incubation with NG could only be restored by readdition of native coronary supernatant, suggesting that the enzyme became inactivated. NG pre-incubation of GC (in contrast to coronary strips) almost completely abolished the direct and thiol-independent stimulatory effect of 3-morpholinosydnonimine (SIN-1) down to 4.5 +/- 0.2%, whereas pre-incubation with other nitrovasodilators reduced the stimulatory response to SIN-1 to only 59 to 98%. Increasing concentrations of NG during pre-incubation dose-dependently (IC50 = 0.13 mM) reduced the activating effect of SIN-1 during incubation. There was also a time dependence in NG-induced inactivation of GC which followed first order kinetics with a calculated half life of 2.5 min in the absence of a thiol. The latter was increased to 4.0 or 19.2 min, respectively, when glutathione or cysteine-methylester were present during pre-incubation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tolerance to nitroglycerin is caused by reduced guanylate cyclase activation. 256 81

Various thiols exert non-specific effects on the activity of soluble guanylate cyclase under aerobic conditions. We studied the effects of thiols under anaerobic conditions (pO2 less than 6 Torr) on soluble guanylate cyclase, purified from bovine lung. Reduced glutathione stimulated the enzyme concentration-dependently with half-maximal enzyme stimulation at a concentration of about 0.5 mM. The extend of maximal enzyme stimulation (up to 80-fold) was comparable with the activation by NO-containing substances. The activation by glutathione was additive with the effect of sodium nitroprusside. Cysteine and various other thiols increased the enzyme activity 20-fold and 2- to 5-fold, respectively. The stimulatory effect of these thiols was not related to their reducing potency. Activation of soluble guanylate cyclase by glutathione was dose-dependently reduced in the presence of other thiols (cysteine greater than oxidized glutathione greater than S-methyl glutathione). Under aerobic conditions or with Mn-GTP as substrate, the effect of glutathione on soluble guanylate cyclase was suppressed. The results suggest a specific role for glutathione in the regulation of soluble guanylate cyclase activity and a modulation of this effect by redox reactions and other intracellular thiols.
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PMID:Under anaerobic conditions, soluble guanylate cyclase is specifically stimulated by glutathione. 256 67

The major class of atrial natriuretic peptide (ANP) receptors was isolated from cultured vascular smooth muscle cells, and a partial amino acid sequence was obtained. This allowed the isolation of cDNA clones from which the entire amino acid sequence was established. The smooth muscle cell ANP receptor appears to be synthesized as a 537-amino acid precursor with an N-terminal membrane translocation signal. The mature form consists of 496 amino acids with a single potential transmembrane domain predicting a 37-amino acid cytoplasmic domain and a large, acidic, extracellular domain low in cysteine and probably containing attached carbohydrate. The receptor is therefore similar in structure to the growth factor receptors but notably lacks repetitive cysteine-rich domains and has a relatively small intracellular domain. Expression of the cloned receptor in Xenopus oocytes elicited high affinity, membrane-associated binding sites for ANP and for truncated and internally deleted analogs of ANP. These results reflect the ligand binding specificity found for the major class of ANP receptors on smooth muscle cells and thus provide additional evidence that two distinct ANP receptors exist since ANP receptor-coupled guanylate cyclase activity exhibits a very different ANP analog specificity.
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PMID:Atrial natriuretic peptide clearance receptor. Complete sequence and functional expression of cDNA clones. 283 87

Since there is evidence suggesting that nicorandil (SG-75) relaxes coronary arterial smooth muscle by increasing cGMP levels, the effects of this vasodilator on soluble guanylate cyclase from bovine coronary arteries were studied more closely. It was found that nicorandil stimulated guanylate cyclase dose-dependently (3-30 mM) up to 100-fold the control value. Similar to nitroglycerin but in contrast to sodium nitroprusside, cysteine (0.5-20 mM) was required to obtain this stimulation. All other investigated thiols, except thiosalicylic acid which was partially able to mimic the cysteine effect, were ineffective. As evident from time course studies, nicorandil induced stimulation of guanylate cyclase was characterized by a lag-phase which could be avoided by preincubating the enzyme with nicorandil. The stimulatory effect of nicorandil was diminished in the presence of methylene blue, ferricyanide or hydroquinone. These results give further evidence that a) nicorandil exerts its vasodilating effect via stimulation of guanylate cyclase and b) nitrate esters, such as nitroglycerin or nicorandil, stimulate the enzyme, at least in vitro, only in the presence of cysteine or, to a lesser extent, thiosalicylic acid.
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PMID:Stimulation of coronary guanylate cyclase by nicorandil (SG-75) as a mechanism of its vasodilating action. 285 1

A series of six beta-adrenergic blocking drugs including propranolol, bufetolol, bunitrolol, pindolol, labetalol and acebutolol were examined for effects on adenylate cyclase, guanylate cyclase and calmodulin-dependent phosphodiesterase from heart. The adrenergic blocking agents had no apparent effects on basal activities of adenylate cyclase, guanylate cyclase and phosphodiesterase. The drugs blocked the enhancement of adenylate cyclase activity by isoproterenol, but not by guanine nucleotide or fluoride. The inhibitory effects of beta-antagonists were overcome by sufficiently large doses of isoproterenol. Sodium azide specifically required catalase whereas NaNO2 required cysteine to activate myocardial guanylate cyclase. Among beta-adrenergic blocking drugs tested, both pindolol and acebutolol inhibited the stimulation of guanylate cyclase by NaNo2 or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). However, other beta-blocking drugs did not significantly affect the activation by NaN3, NaNO2 and MNNG. Several beta-antagonists, such as labetalol, bunitrolol, pindolol and acebutolol were also effective in blocking the activation of phosphodiesterase by calmodulin. The inhibitory effects of beta-adrenergic blocking drugs, i.e. pindolol and acebutolol upon either nitroso compound-stimulated guanylate cyclase or calmodulin-activated phosphodiesterase display little correlation with their potency as beta-adrenergic blocking agents. These data suggest that beta-antagonists may have another site of action which is not directly related to the control of catecholamine metabolism.
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PMID:Different effects of various beta-adrenoceptor antagonists on adenylate cyclase, guanylate cyclase and calmodulin-dependent phosphodiesterase in heart. 286 Sep 6

According to our present understanding organic nitrates like glycerine trinitrate mediate their pharmacological effect by an intracellular stimulation of the enzyme guanylate cyclase (E.C. 4.6.1.2.) [1, 10]. The exact molecular mechanism underlying the process of enzyme activation is still a matter of controversial discussion. But there is general agreement in literature about the fact that organic nitrate compounds are able to activate the enzyme guanylate cyclase only in the presence or by the interaction of the amino acid cysteine [3, 5]. The stimulatory activity of nitric oxide-containing compounds may be due, at least in part, to the formation of active, unstable intermediate S-nitrosothiols, i.e. S-nitrosocysteine in case of the organic nitrates [7]. According to Craven and DeRubertis [2], the active intermediates of guanylate cyclase stimulation are represented by nitric oxide-heme complexes. There is, however, substantial evidence that the organic nitrates have to be cleaved before they become biologically active. During the transformation which takes place in the presence of cysteine or by means of enzymatic catalysis, nitric oxide radicals are reductively split off the molecule from which (via the intermediate formation of salpetric acid) the nitric oxide is liberated as the essential stimulatory agent. In this study we examined the transformation of glycerine trinitrate and other organic nitrates under the influence of different thiols and a purified soluble rat liver guanylate cyclase preparation. At the same time the stimulation of guanylate cyclase in the presence of the thiols mentioned was quantitatively estimated. Only in case of cysteine did we find a strict correlation between the liberation of nitric oxide from different organic nitrates and the degree of enzyme activation. Several other thiols were also able to liberate nitric oxide, but surprisingly enough, there was no equivalent stimulation of guanylate cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Evidence for a correlation between nitric oxide formation by cleavage of organic nitrates and activation of guanylate cyclase. 286 57

SIN-1, a metabolite of the vasodilating drug molsidomine, was found to stimulate dose dependently (0.01-1 mM) soluble guanylate cyclase from bovine coronary arteries up to 100-fold the control value. The stimulatory effect of SIN-1 increased with rising concentrations of MnC1(2) or MgC1(2) and was diminished in the presence of methylene blue or ferricyanide. The time course of SIN-1-induced guanylate cyclase stimulation was characterized by a lag phase which was not observed after preincubation of the enzyme with SIN-1. In contrast to nitroglycerin and sodium nitroprusside, SIN-1 did not require the presence of cysteine or other thiols to stimulate guanylate cyclase. The results presented in this study provide further evidence that SIN-1 exerts its dilating effect on coronary vessels via direct stimulation of guanylate cyclase.
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PMID:Stimulation of soluble coronary arterial guanylate cyclase by SIN-1. 286 62

Organic nitrates produce their pharmacological effect by an intracellular stimulation of the enzyme guanylate cyclase (E. C. 4.6.1.2). We could show that the stimulatory effect of organic nitrates on the activity of guanylate cyclase is strongly dependent on the number of nitrate residues per molecule. The EC50 values found for the tetra-, tri- di-, and mononitrates differed from each other by the factor 4. In contrast to investigations carried out with the perfused isolated Langendorff heart there was no correlation between the lipophilicity of these substances and the EC50 in our guanylate cyclase preparation, as penetration of cell membranes is not required. Other authors have found that organic nitrates are able to activate the enzyme guanylate cyclase only in the presence of cysteine. There is general agreement in the literature that organic nitrates have to be cleaved before they become biologically active. During the transformation which takes place in the presence of cysteine or by means of enzymatic catalysis the nitric oxide radical is liberated as the essential stimulatory agent. We found a strict correlation between the liberation of nitric oxide from different organic nitrates (GTN, IMDN, IIDN, ISDN, IS-2-N, IS-5-N) and the degree of enzyme activation. The Ec50 values of the organic nitrates were calculated from the concentration response curves which were obtained with a guanylate cyclase preparation from rat liver in the presence of cysteine. The degradation of the organic nitrates was measured under the same conditions by means of HPLC. The amount of nitric oxide set free was calculated by using the velocity constants k of organic nitrate degradation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Thiol-dependent activation of guanylate cyclase by organic nitrates]. 287 91


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