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)

Isatin (indole-2,3-dione) is an endogenous compound with anxiogenic properties. In the brain, highest levels (0.1 microgram/g) have been found in the rat hippocampus. In the present study, we show that isatin has little effect on a wide range of neurotransmitter and hormonal receptors but that it acts as an inhibitor of atrial natriuretic peptide (ANP) binding, with an IC50 of 4x 10(-7) M. It also inhibits ANP-activated particulate guanylate cyclase from rat kidney, heart and brain membranes in dose-dependent fashion, varying also with ANP concentration. These findings suggest that isatin is a new endogenous regulator of mammalian ANP activity, with potential implications for the control of both anxiety and natriuresis.
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PMID:Isatin is a potent endogenous antagonist of guanylate cyclase-coupled atrial natriuretic peptide receptors. 747 58

Isatin is an endogenous indole with a distinctive distribution in brain and tissues. In the brain, the highest levels have been found in the hippocampus (0.1 microgram/g), and an immunocytochemical stain has shown specific localization within particular cells. In vitro, its most potent known actions are as an inhibitor of monoamine oxidase B (IC50 approximately 3 microM), and of atrial natriuretic peptide (ANP) receptor binding and ANP-induced guanylate cyclase (both with an IC50 approximately 0.4 microM). In vivo, isatin administration (10-200 mg/kg) causes an increase of monoamine neurotransmitter levels in the brain. Isatin is anxiogenic in animal models at doses of 10-20 mg/kg and sedative at higher doses. Its anxiogenic effects are unlikely to be due to inhibition of monoamine oxidase, but may possibly stem from interaction with the ANP system. Isatin may mediate a link between monoamines and the natriuretic peptide system, and its analogues may provide new pharmacological tools.
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PMID:Isatin: a link between natriuretic peptides and monoamines? 868 91

The effect of isatin on rat brain particulate guanylate cyclase (GC) was investigated. The enzyme was stimulated by atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and urodilatin, but not by C-type natriuretic peptide (CNP). Their effects were not additive, pointing to action via the GC-A receptor. Isatin, in dose-dependent manner, abolished this stimulation. The non-hydrolysable ATP analogue, adenylylimidodiphosphate, potentiated the effects of submaximal doses of ANP, BNP and urodilatin on this particulate GC-A, and attenuated or abolished sensitivity to isatin. These results suggest that isatin antagonises the generation of second messenger by GC-A; this sensitivity might be regulated at an ATP binding site, possibly a protein kinase-like domain.
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PMID:Interaction of isatin with type-A natriuretic peptide receptor: possible mechanism. 965 Nov 5

Isatin is an endogenous indole and an inhibitor of atrial natriuretic peptide (ANP) receptors coupled with particulate guanylyl cyclase (GC). In this study, several isatin analogues were tested as inhibitors of ANP-stimulated GC in rat brain and heart membranes. None of these analogues affected activity in the absence of ANP, or stimulated ANP-induced activity. In both tissues, some 5-substituted isatins (5-hydroxyisatin, 5-methylisatin, and 5-aminoisatin) exhibited more effective inhibitory activity than isatin itself, with IC50 values in the range 1.3-20 microM. The efficacy of other analogues varied and was not consistent between the two tissues, raising the possibility of receptor heterogeneity and relative selectivity of inhibition. Some substituted isatins may have a role as pharmacological tools for investigating the physiological roles of natriuretic peptides and their receptors.
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PMID:Efficacy of isatin analogues as antagonists of rat brain and heart atrial natriuretic peptide receptors coupled to particulate guanylyl cyclase. 1008 25

Monoamine oxidase (MAO) catalyzes the biological degradation of the neurotransmitters monoamines. The altered substrate specificity of MAO may be of pathogenic importance in some cases and MAO inhibitors showed a therapeutical effect in the experimental setting. Analyzing the efficacy of various compounds in inhibiting MAO A and B revealed new approaches to designing new-generation MAO inhibitors. Tribulin is a fraction of endogenous MAO inhibitors that are present in human and animal tissues and biological fluids. Isatin is an endogenous indole which was initially derived from a tribulin fraction. An investigation of the biological properties of tribulin revealed its heterogeneity and some chemical components were identified. It was shown that deficiency of tribulin components that selectively inhibited MAO A long with a larger number of molecules of this enzyme might be of great importance for the development of alcoholism. In addition to MAO inhibition, the physiological concentrations of isatin inhibited the receptor-binding of atrial natriuretic peptides and ANP-stimulated guanylate cyclase (GC). The sensitivity of ANP-GC to isatin might be allosterically regulated. Selective antagonists of natriuretic peptide receptors were found among isatin analogues which may be an effective pharmacological tool for further studies of the role of natriuretic peptides in the body.
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PMID:[Monoamine oxidase, tribulin, isatin: basic and applied medical aspects]. 1057 64

We have previously demonstrated that isatin (indole-2,3 dione), an endogenous compound widely distributed in mammalian tissues and body fluids, effectively inhibits atrial natriuretic peptide (ANP) receptor binding and ANP-stimulated guanylyl cyclase activity of rat membrane preparations. In the present study the effects of isatin on ANP-mediated accumulation of cGMP and guanylyl cyclase (GC) activity of PC12 cells were studied. Isatin (0.1 mM) effectively inhibited ANP-stimulated GC-activity of broken cells but was nearly inactive in attenuating ANP-dependent accumulation of cGMP in intact PC12 cells. The ATP-analogue adenylylimidodiphosphate (AMP-PNP) slightly potentiated the ANP effect on GC activity in broken cell preparations and significantly reduced GC sensitivity to isatin. Isatin caused a more pronounced reduction of ANP-dependent cGMP accumulation in cells grown in the presence of 10% embryonal calf serum (ECS) than in 0.5% ECS. The data obtained suggest that, in intact cells, the manifestation of the isatin effect on ANP-mediated signal transduction may depend on intracellular factor(s), possibly interacting at the kinase domain.
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PMID:Effects of isatin on atrial natriuretic peptide-mediated accumulation of cGMP and guanylyl cyclase activity of PC12 cells. 1166 40

Isatin, an endogenous indole, has previously been shown to inhibit atrial natriuretic peptide (ANP)-stimulated particulate guanylate cyclase activity. Here, it was shown that it can be transported to human platelets where it inhibited nitric oxide (NO)-stimulated soluble guanylate cyclase activity obtained from human platelets. The effect was most pronounced at 10(-8)M isatin and is the most potent effect of isatin yet observed. The dose response curve was bell shaped with higher doses becoming less effective. The maximal inhibition observed was of 40%. Isatin had no effect on protoporphyrin IX-stimulated guanylate cyclase. Isatin-dependent regulation of ligand-stimulated guanylate cyclases is suggested to promote a stress-induced switch in metabolism.
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PMID:Effect of isatin on nitric oxide-stimulated soluble guanylate cyclase from human platelets. 1199 46

Isatin is an endogenous indole, which has a distinct and discontinuous distribution in the brain and exhibits a wide range of physiological and pharmacological effects. In the present study, we have demonstrated that atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) inhibited [3H]isatin binding to rat brain sections and isolated membrane fractions. Isatin itself antagonised not only natriuretic peptide receptor type A (NPR-A) (ANP-stimulation of guanylyl cyclase) but also NPR-C (ANP and CNP mediated inhibition of adenylyl cyclase) signalling. These results suggest that some [3H]isatin binding in the brain may be to NPR-A and NPR-C. Competitive interactions between isatin and natriuretic peptides and their receptors give a possible explanation of the known anxiogenic effect of low doses of isatin, interacting at NPR-A, and the sedative effects of higher doses, antagonising respectively the anxiolytic effect of ANP and the anxiogenic effect of CNP.
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PMID:Natriuretic peptide interaction with [3H]isatin binding sites in rat brain. 1585 83

Isatin is an endogenous indole widely distributed in mammalian tissues and body fluids. The presence of isatin-binding proteins has been recognised in particulate and soluble fractions of various organs and tissues. However, identified targets of isatin action (monoamine oxidase, natriuretic peptide receptor type A and soluble NO-stimulated guanylate cyclase) cannot account for all biological activity of this compound. Highly purified glycerol-3-phosphate dehydrogenase (GPDH) from rabbit muscle effectively interacts with the isatin analogue immobilised on the cuvette of IAsys optical biosensor. This effect was specific because the other NAD-dependent cytosolic enzyme purified from rabbit muscle, lactate dehydrogenase failed to interact with the immobilised isatin analogue. Replacement of the cuvette medium for washing buffer did not cause total dissociation of GPDH-isatin complexes. This suggests involvement of several types of enzyme-isatin interaction including tight binding. Low (10 microM) and high (100 microM) concentrations of isatin caused different effects on GPDH activity: the former significantly increased apparent Km for NAD, whereas the latter decreased apparent Vmax and increased Km.
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PMID:[Glycerol-3-phosphate dehydrogenase--cytosolic isatin-binding protein]. 1611 92

Isatin (1H-indole-2,3 dione) is an endogenous compound that may act as a physiological regulator of muscle contraction by reducing cGMP production by inhibition of guanylyl cyclase (GC) activity. Intracellular cGMP levels can regulate the contractile response of smooth muscle. Therefore, in the present study we investigated the effects of seven novel carbamate derivatives of isatin, namely C1-C7, on the contractility of aortic rings from Wistar rats. Carbamates C1 and C6 most effectively promoted endothelium-dependent relaxation of aortic rings pretreated with 10 micromol/L phenylephrine (PE) to induce contraction. The concentration of the C1 and C6 carbamates necessary to reduce PE-induced aortic contraction by 50% (IC(50)) was 5.6 +/- 1.0 and 48.4 +/- 3.4 micromol/L, respectively. Carbamate derivative-induced vasodilation required an intact endothelium, which is responsible for nitric oxide (NO) release. Pretreatment of rings with 100 micromol/L naloxone or 10 micromol/L atropine prevented the C1- and C6-mediated vascular relaxation, indicating that the vasodilatory activity was dependent on the activation of opioid or muscarinic receptors, respectively. The results of our studies provide insights into the role of novel carbamates in the regulation of vascular tone. Carbamates could stimulate NO synthesis, which induces vasodilation primarily by stimulation of GC and cGMP production. Taken together, our findings suggest that carbamate derivative-induced vasodilation may be considered an alternative treatment for primary and/or secondary hypertension.
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PMID:Vasodilatory activity of novel carbamate derivatives of isatin. 1850 49


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