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)

Prazosin (25 microM) was found to increase 125I-labeled rat atrial natriuretic peptide ([125I]rANP) receptor binding by 50% (SC50) in bovine adrenal zona glomerulosa membranes. A series of 2,4-disubstituted quinazolines was prepared in order to identify more potent analogues for additional in vitro testing. Compound 7 (N-[3-[[2-(diethyl-amino)-4-quinazolinyl]amino]propyl] guanidine dinitrate) from this series (3 microM) significantly decreased the EC50 for rANP-mediated inhibition of ACTH-stimulated aldosterone synthesis in rat adrenal glomerulosa cells. At a higher concentration (20 microM), compound 7 had no effect on particulate guanylate cyclase from rabbit glomeruli in either the presence or absence of rANP.
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PMID:Atrial natriuretic peptide receptor modulators: effects of disubstituted quinazolines on receptor binding and in vitro biological activity. 196 15

Human neutrophils were incubated with granulocyte-macrophage (GM)-CSF and examined for changes in second messenger systems. Twofold increases in cGMP but not cAMP were measured after 5 to 20 min with 100 U/ml GM-CSF. Guanylate cyclase activities in membrane and cytosol fractions were increased to the same extent whether measured in the presence of Mg2+ or Mn2+, or in the cytosol with Mg2+ + N-methyl-N'-nitro-N-nitroso-guanidine. Kinetic studies of the cytosol enzyme showed no changes in the Km values for Mg2+ and Mn2+dependent guanylate cyclase activities (0.91 and 0.022 mM, respectively), whereas Vm values were increased after treating intact cells with GM-CSF. Two peaks of guanylate cyclase activity were observed, one at 10 and another at 60 min after adding 100 U/ml GM-CSF, whereas only one peak at 5 min occurred with 1 U/ml. Adenylate cyclase activity was reduced by nearly 50% after adding 100 U/ml GM-CSF for 10 to 30 min. These effects were also seen in the presence of several hormonal and nonhormonal adenylate cyclase stimulators. In contrast, small increases in adenylate cyclase activity occurred after adding 1 U/ml GM-CSF. In experiments to examine the pathway of guanylate cyclase activation by GM-CSF, we observed no changes in inositol phosphates, intracellular calcium ion, or cytosolic protein kinase C. The augmentation of chemotactic peptide-induced superoxide production by GM-CSF concentrations, may be related to the effects of the higher levels of GM-CSF to stimulate late increases in guanylate cyclase or decreases in adenylate cyclase.
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PMID:Stimulation of guanylate cyclase activity and reduction of adenylate cyclase activity by granulocyte-macrophage colony-stimulating factor in human blood neutrophils. 289 92

The acetylcholine (ACh) stores of cholinergic neurons of the myenteric plexus of guinea-pig ileum were labelled by preincubation with 3H-(methyl)-choline. The secretion of labelled transmitter evoked by electrical field stimulation at 1 Hz in the presence of eserine increased by 55% after addition of 0.5 mM 8-Br adenosine 3', 5'-cyclic monophosphate (8-Br cAMP). Atropine further enhanced the secretory response, but not more than in the absence of 8-Br cAMP. 8-Br guanosine 3', 5'-cyclic monophosphate (8-Br cGMP, 0.5 mM) did not change the secretory response to 0.5 or 1 Hz stimulation, either at 1.8 mM or at 0.6 mM calcium, in the absence of eserine. Nor did 1 mM 8-Br cGMP alter the effects of atropine or of oxotremorine. Activation of guanylate cyclase by 0.1 mM N-methyl-N'-nit-ro-N-nitroso guanidine failed to alter the secretory response to 0.5 Hz stimulation in the absence of eserine, or to influence the depression of the secretion caused by oxotremorine. The phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine (a mM) neither altered the secretory response in the presence of eserine, nor the enhancing effect of atropine. The results suggest that cyclic nucleotides are probably not critically involved as "second messengers" in the muscarinic "autoinhibition" of ACh secretion from cholinergic myenteric neurons of guinea-pig ileum.
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PMID:Secretion of 3H-acetylcholine from guinea-pig ileum myenteric plexus is enhanced by 8-Br adenosine 3', 5'-cyclic monophosphate but not changed by 8-Br guanosine 3', 5'-cyclic monophosphate. 618 55

Effects of aminoethylisothiuronium bromide (AET), known as radioprotector, on human platelet soluble guanylate cyclase and on ADP-induced human platelets aggregation were studied. It was shown that AET - in Tris buffer and at certain pH values - is converted, via transguanidine rearrangement, to mercaptoethylguanidine. The latter contains in its molecule both the guanidine and SH groups which act as donor and acceptor of nitric oxide (NO), respectively. It was demonstrated that AET, after its rearrangement to mercaptoethylguanidine, is able to activate human platelet soluble guanylate cyclase, as well as to inhibit ADP-induced human stimulatory effect of AET is dependent on the effectiveness of its transguanidine rearrangement to mercaptoethylguanidine. The molecular mechanism of the hypotensive by - effect of AET is proposed.
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PMID:Guanidine thiol--a new activator of soluble guanylate cyclase with antihypertensive and antiaggregatory properties. 852 55

The effects of aminoethylisothiuronium bromide known as a radioprotector on the activity of human platelet soluble guanylate cyclase and on ADP-induced aggregation of human platelets have been studied. It has been shown that in Tris-buffer and at definite pH values aminoethylisothiuronium bromide is converted into mercaptoethylguanidine as a result of a transguanidine rearrangement. The latter contains in its molecule both guanidine and SH-groups which appear to be the donor and acceptor of nitric oxide, respectively. It was found that after its rearrangement into mercaptoethylguanidine, aminoethylisothiuronium bromide activates human platelet soluble guanylate cyclase, inhibits ADP-induced aggregation of human platelets and accelerates their spontaneous disaggregation. The stimulating effect of aminoethylisothiuronium bromide depends on the effectiveness of its transguanidine rearrangement into mercaptoethylguanidine. A molecular mechanism of the hypotensive side effect of aminoethylisothiuronium bromide is proposed.
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PMID:[A new activator of soluble guanylate cyclase generated by nitric oxide and having antihypertensive and anti-aggregation properties]. 856 54

Guanidine thiol derivatives--a new class of soluble guanylate cyclase activators--have been studied. Guanidine thiols contain in their molecule both the guanidine and thiol groups which act as donors acceptors of nitric oxide (NO), respectively. The role of the guanidine thiol SH-groups in the mechanism of soluble guanylate cyclase activation has been evaluated. The effect of three guanidine thiol derivatives: mercaptoethylguanidine (MEG), mercaptoethylguanidine disulfide (MEG disulfide) and S-methyl mercaptoethylguanidine (S-methyl MEG) on human platelet guanylate cyclase activity, has been examined. It was found that all the compounds tested in this study were substrates for NO-synthase and guanylate cyclase activators. The stimulatory effects of MEG and MEG disulfide surpassed the L-arginine-induced activation of guanylate cyclase-2- and 4-fold, respectively. The enzyme stimulation by S-methyl MEG was of the same order as that of L-arginine. The important role of S-acceptor groups of guanidine thiols in the mechanism of directed increase of guanylate cyclase activation was established. This mechanism explains the nature of differences in the intensity of guanylate cyclase activation by the guanidine thiols under study. The NO-acceptor properties of disulfide bond of guanidine thiols in the case of the NO-synthase mechanism of NO formation have been established.
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PMID:[The role of SH-groups in guanidine thiols--new substrates for NO-synthase--in stimulating the activity of guanylate cyclase]. 867 71

Protein folding continues to be an important biophysical topic in molecular biology. We report the parameters for successfully refolding the guanylyl cyclase core of the ANP receptor, an allosteric homodimeric enzyme. Urea was a better chaotropic solvent than guanidine HCl, and physiological salt concentrations and pH were needed for optimal recovery of enzymatic activity. Renaturation was more sensitive to alkaline compared to acidic deviations in solvent conditions. The time course of refolding was sigmoidal producing an enzyme with a specific activity of 16,000 pmol cGMP/min/mg using 60 microM concentration of substrate. Additional factors are described in this unusual case of renaturing an allosteric homodimeric enzyme in vitro.
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PMID:Refolding parameters for the allosteric homodimeric guanylyl cyclase catalytic core from the atrial natriuretic peptide receptor. 871 20

The study is concerned with the mechanism of activation of soluble guanylate cycla-se by guanidine thiol derivatives-a new class of enzyme activators. Guanidine thiols contain both the guanidine and SH group which act, respectively, as donor and acceptor of nitric oxide (NO). The role of guanidine thiol SH group in the mechanism of soluble guanylate cyclase activation was studied. Three guanidine thiol derivatives were tested: mercaptoethylguanidine, its disulfide and S-methyl mercaptoethylguani-dine. All three compounds proved to be NO-synthase substrates and, simultaneously, guanylate cyclase activators. The degrees of guanylate cyclase activation by mercaptoethylguanidine and its disulfide were, respectively, two and four times higher than that by L-arginine. The stimulatory effects of S-methyl mercaptoethylguanidine and L-arginine were evaluated and found to be of the same order. The important role of S-acceptor group of guanidine thiols in the mechanism of guanylate cyclase activation increase provides an explanation for different intensities of guanylate cyclase activation by the compounds tested. NO-acceptor properties of guanidine thiols disulfide bonds in the synthase mechanism of NO generation were first reported.
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PMID:Mechanism of activation of soluble guanylate cyclase by guanidine thiols--a new class of enzyme activators. 882 10

Antiaggregatory properties of guanidine thiol derivatives and their effect on human platelet guanylate cyclase activity were studied. The molecules of guanidine thiols contain guanidine and thiol groups which are the donor and acceptor of nitric oxide (NO), respectively. Three synthetic guanidine thiol derivatives were studied including mercaptoethylguanidine (MEG), mercaptoethylguanidine disulfide (MEG-disulfide), and mercaptoethylguanidine methylated at SH-group (S-methylmercaptoethylguanidine (S-methyl MEG)). All compounds are the substrates of NO-synthase and activators of human platelet guanylate cyclase. The stimulatory effects of MEG and MEG-disulfide on guanylate cyclase activity were 2- and 4-fold higher, respectively, than the effect of L-arginine. Stimulation of the enzyme by S-methyl MEG is similar to L-arginine. Antiaggregatory properties of these compounds correspond to the extent of guanylate cyclase activation. Extent of guanylate cyclase activation (S-methyl MEG < MEG < MEG-disulfide) significantly correlates with inhibition of ADP-induced platelet aggregation and with acceleration of spontaneous disaggregation of platelets. The mechanism of directed enhancement of antiaggregatory properties of the compounds can depend on their chemical structure and extent of guanylate cyclase activation.
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PMID:[Inhibition of ADP-induced platelet aggregation by guanidine thiols--a novel class of guanylate cyclase activators and NO-synthase substrates]. 915 56

Human and rat plasma and rat hypothalamus contain a cytochemically detectable substance, the concentration of which rises with an increase in salt intake. The plasma concentration of this material is also raised in essential hypertension and in the spontaneously hypertensive rat (SHR), the Milan hypertensive rat, and the reduced renal mass (RRM) hypertensive rat. In the normal rat, the greatest concentration is found in the hypothalamus of the SHR and the RRM hypertensive rat. The physicochemical characteristics of this cytochemically detectable hypothalamic hypertensive factor (HHF), including chromatographic behavior and molecular weight range, suggest that it may share features common to a substituted guanidine that is present in established nitric oxide synthase (NOS) inhibitors. It was therefore decided to determine the effect on NOS activity of the HHF obtained from mature SHR. The ability of HHF to inhibit NOS activity was studied on (1) NOS extracted from bovine aorta, rat brain, and human platelets by measuring the conversion of radiolabeled L-arginine to L-citrulline and (2) rat liver NOS measured indirectly with a cytochemical technique based on the stimulation of soluble guanylate cyclase activity in hepatocytes by NO. HHF showed a biphasic inhibitory action on platelet NOS activity that was greater with HHF obtained from SHR than from Wistar-Kyoto rats. HHF also had a biphasic inhibitory effect on hepatocyte NOS activity that was more potent when obtained from SHR. It is proposed that the increase in HHF, a novel form of NOS inhibitor that is elevated in SHR, may be involved in the rise in arterial pressure.
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PMID:Hypothalamic hypertensive factor: an inhibitor of nitric oxide synthase activity. 940 72


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