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)

At extremely low concentrations, in the picomole and the nanomole range, bradykinin produces contraction and relaxation of smooth muscle in the gastrointestinal and the urogenital tract. At the target organ, bradykinin interacts with discriminator proteins of the plasma membranes and triggers, via changes in certain membrane functions, its biological response:--The binding to the discriminator makes specific conformative and constitutional demands on the nonapeptide. The binding results from an angular conformation which exists in the solution. The complete sequence is responsible for this specific conformation. Consequently, the biological activity of partial sequences is low. The conformational analysis of analogues used in studies on the mechanism of action showed but slight differences from bradykinin. The interaction of these analogues with the discriminator protein is disturbed to a varying extent by modifications at positions 1, 5, 8 and 9 in the side chains. The affinity for the discriminator is affected, dependently on the respective configuration, by substitution on the beta-C atom in the two phenylalanine residues.--Bradykinin is not only bound to, but also degraded at, the plasma membranes of the rat uterus and duodenum. The bradykinin-degrading enzyme has been characterized as a kininase II with the aid of various inhibitors. The conformative and configurative prerequisites decisive for enzymatic degradation are others than those decisive for binding to the discriminator.--The changes in the activities of the membrane-bound adenylate and guanylate cyclases (produced by the bradykinin-discriminator complex) that take place at the rat duodenum and uterus in the presence of extracellular calcium ions contrast with each other: At the duodenum, the ratio between these two cyclic nucleotides is changed in favour of adenylate cyclase; and at the uterus, in favour of guanylate cyclase; Substances which increase or decrease the cAMP level may also potentiate or inhibit the relaxation of the duodenum. These bradykinin-induced changes in enzyme activity must be considered in connection with other effectors, e.g. prostaglandins and calcium ions.--The calcium-ion-dependence of the effect of bradykinin on the guinea-pig ileum and the rat uterus indicates the importance of these ions as additional second messengers. Bradykinin stimulates the influx of calcium ions into the ileum; it is ineffective if no extracellular calcium ions into the ileum; it is ineffective if no extracellular calcium ions are available. It seems that intracellular and membranal calcium is mobilized in the uterus, which is evidenced by results from experiments with EGTA on the isolated organ and by the release of calcium from plasma membranes after application of bradykinin. It is assumed that the observed changes in membrane functions are induced by the peptide-discriminator complex simultaneously and not in the form of a causal chain.
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PMID:[On the mode of action of bradykinin on smooth muscle (author's transl)]. 39 90

The present studies were performed in order to examine the possible role of cyclic GMP-stimulated phosphodiesterase (cGMP-PDE) activity in the inhibitory action of the inflammatory peptide bradykinin on cyclic AMP (cAMP) accumulation in D384 cells. Bradykinin decreased the forskolin-stimulated cAMP accumulation in the presence of the phosphodiesterase inhibitor rolipram, and caused a transient 50% rise in cellular cGMP in the presence of the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). Both basal and bradykinin-stimulated cGMP accumulation were about 8 times higher in the presence of IBMX than in the presence of rolipram. Sodium nitroprusside, which caused a 20-70-fold increase in cGMP levels reduced forskolin stimulated cAMP accumulation, whereas hydroxylamine, which maximally caused a 16-fold increase in cGMP, did not. 8-bromo-cGMP or dibutyryl cGMP had no effect on cAMP accumulation induced by forskolin. The inhibitory effect of nitroprusside was totally reversed by blocking the soluble guanylate cyclase activity by methylene blue treatment; however, the inhibitory action of bradykinin on cAMP accumulation was not changed by this treatment. Additionally, inhibition of nitric oxide synthesis, which is known to be regulated by Ca2+ and in turn stimulates cGMP production, by N omega-nitro-L-arginine (L-NAME) treatment did not alter the inhibitory effect of bradykinin on forskolin-induced cAMP accumulation. These results indicate that large increases in cGMP may regulate cAMP via cGMP-PDE whereas the small increase induced by bradykinin is insufficient and that cGMP is not involved in the inhibitory action of bradykinin on cAMP levels in D384 cells.
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PMID:Bradykinin inhibition of cyclic AMP accumulation in D384 astrocytoma cells. Evidence against a role of cyclic GMP. 128 20

Endothelium-dependent relaxations are inhibited during chronic vasospasm after subarachnoid hemorrhage in the canine basilar artery, although the luminal release of endothelium-derived relaxing factor (EDRF) is maintained. The present study investigated the mechanisms underlying the impaired vascular reactivity and in particular whether the loss of responsiveness of the smooth muscle to EDRF is due to an impaired production of cGMP. Bradykinin and nitric oxide evoked concentration-dependent relaxations in isolated canine basilar arteries with and without endothelium, respectively, which were reduced in the subarachnoid hemorrhage group. Relaxations evoked by M&B22,948 (an inhibitor of cGMP phosphodiesterases) were smaller, but those evoked by the lipophilic cGMP analogue 8-bromo-cGMP were potentiated slightly in the subarachnoid hemorrhage group. The resting levels of cGMP in rings with endothelium (reflecting the effect of spontaneous release of EDRF) and those evoked by bradykinin in rings with endothelium and by nitric oxide in rings without endothelium were diminished in the subarachnoid hemorrhage group. These data indicate that the altered endothelium-mediated relaxations of the smooth muscle after subarachnoid hemorrhage is due, at least in part, to an impaired activation of soluble guanylate cyclase leading to a reduced production of cGMP in the smooth muscle.
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PMID:Reduced production of cGMP underlies the loss of endothelium-dependent relaxations in the canine basilar artery after subarachnoid hemorrhage. 131 Apr 45

Endothelial cells (ECs) from brain microvessels respond to exogenous nitric oxide (NO) donor molecules (N-ethoxycarbonyl-3-morpholinosydnonimine and sodium nitroprusside) with large (greater than 15-fold) increases in cyclic GMP (cGMP) levels. Comparable actions of sodium nitroprusside were observed in vascular smooth muscle cells and in neuroblastoma cells. Coculturing brain capillary ECs in the presence of N1E-115 neuroblastoma cells increased their cGMP levels fourfold. A further increase was observed in the presence of 50 nM neurotensin, although brain capillary ECs lack receptor sites for neurotensin. The neuroblastoma cell-dependent formation of cGMP was suppressed by 0.1 mM L-NG-monomethylarginine, indicating that NO, produced by N1E-115 cells in response to neurotensin, activated guanylate cyclase in brain capillary ECs. Similarly, culturing brain capillary ECs in the presence of aortic ECs increased their cGMP content in a manner that was amplified by bradykinin and that was inhibited by L-NG-monomethylarginine. Bradykinin had no action in pure cultures of brain capillary ECs. It is concluded that brain capillary ECs express high levels of guanylate cyclase activity that could be activated by exogenous NO donor molecules and by NO produced by neuroblastoma cells and by aortic ECs in response to specific agonists. Brain capillary ECs are thus potential target cells for brain-derived NO.
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PMID:Activation by nitric oxide of guanylate cyclase in endothelial cells from brain capillaries. 135 91

Guanosine 3',5'-cyclic monophosphate (cGMP) accumulation in single and cocultures of calf pulmonary arterial endothelial (CPAE) and rabbit pulmonary arterial smooth muscle cells (RPASM) was investigated to discover whether endothelial cGMP is involved in the feedback regulation of basally released endothelium-derived relaxing factor (EDRF). Endothelial cell-induced increases in smooth muscle cGMP levels were inhibited by competitive inhibitors of endothelial nitric oxide synthesis, NG-monomethyl-L-arginine and N omega-nitro-L-arginine, in both long-term cocultures and short-term bioassay. Such treatment had no effect on endothelial content of cGMP. Coculture cGMP accumulation was stimulated (twofold increases) by endothelium-dependent vasodilators, bradykinin and acetylcholine. Bradykinin and acetylcholine did not elicit cGMP accumulation in single cultures of either smooth muscle or endothelial cells. To investigate the underlying mechanism(s) of dissociation in cGMP accumulation between cocultures and single endothelial cell cultures, the distribution profile of guanylate cyclase isoforms was determined by stimulating CPAE and RPASM cells with vasodilators activating selectively the soluble or particulate isoenzymes. Both nitrovasodilators, sodium nitroprusside and a putative EDRF, S-nitroso-L-cysteine, produced a 20-fold increase in cGMP content of RPASM cells only, having no effect on endothelial cells. Conversely, atriopeptin II caused 80-fold increases in endothelial cells. Exposure of the short-term bioassay system to 100 nM atriopeptin II, which caused 60-fold increases in CPAE cGMP levels, did not affect basal EDRF-induced smooth muscle cell cGMP accumulation, suggesting that a cGMP-mediated negative feedback mechanism does not appear to be involved in the regulation of basally released EDRF in culture.
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PMID:Endothelial cGMP does not regulate basal release of endothelium-derived relaxing factor in culture. 137 1

The cyclic GMP (cGMP) content was rapidly (greater than 30 s) increased by serotonin [5-hydroxytryptamine (5-HT)] (EC50 = 10 microM), and the increase lasted for greater than 10 min in NG108-15 cells. The 5-HT-induced elevation of cGMP level (EC50 = 10 microM) at 20 s ("fast" elevation) was inhibited by ICS 205-930 or MDL 72,222 and by Ca2+ deficiency in the reaction medium but not by organic Ca2+ antagonists. The 5-HT effect at 10 min ("slow" elevation) was not inhibited by several antagonists for 5-HT receptors of the 1A, 1B, 1C, 1D, 2, and 3 subtypes and was independent from external Ca2+ concentration. The fast and slow effects of 5-HT were similar to the effects of bradykinin and atrial natriuretic peptide (ANP), respectively, in aspects of both Ca2+ dependency and time course of the effects. Bradykinin transiently stimulated formation of inositol phosphates as well as accumulation of cGMP, a finding suggesting that intracellular Ca2+ is involved in bradykinin-induced cGMP accumulation as shown in the fast response to 5-HT. ANP, an activator of membrane-associated guanylate cyclase (mGC), slowly (approximately 60 s) increased the cGMP content (EC50 = 10 nM), a result lasting for greater than 10 min, and the effects were independent from external Ca2+, as shown in the slow response to 5-HT. 5-HT and ANP did not induce formation of inositol phosphates.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serotonin stimulates both cytosolic and membrane-bound guanylate cyclase in NG108-15 cells. 197 61

Endothelial cells regulate vascular tone through the release of nitric oxide and other relaxing factors. The role of these substances was studied in isolated intramyocardial porcine coronary resistance arteries suspended in myographs for isometric tension recording. The inhibitor of nitric oxide formation NG-monomethyl-L-arginine (L-NMMA; 10(-7)-10(-4)M), but not D-NMMA, caused endothelium-dependent contractions that could be reversed by L-arginine but not by D-arginine. In preparations with endothelium, L-NMMA potentiated the contractions induced by acetylcholine and the relaxations to 3-morpholino-sydnonimine. Under both conditions, the effect of endothelial removal was slightly more pronounced than that of L-NMMA. Bradykinin, serotonin, and the alpha 2-adrenergic agonist clonidine evoked endothelium-dependent relaxations. L-NMMA as well as the inhibitor of guanylate cyclase methylene blue (10(-5) M) prevented the relaxations induced by clonidine, reduced those to serotonin, but hardly affected those to bradykinin. Thus, in porcine coronary resistance arteries, endothelium-derived nitric oxide is continuously produced from L-arginine. Endothelium-dependent relaxations to clonidine are fully mediated and those to serotonin partially mediated by nitric oxide; its release does not involve a Gi protein. An endothelium-derived relaxing factor different from nitric oxide must mediate the relaxations to bradykinin and contribute to those evoked by serotonin.
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PMID:Importance of endothelium-derived nitric oxide in porcine coronary resistance arteries. 199 90

The responses of small (60-100 microns), medium (101-190 microns), and large (191-300 microns) porcine coronary microvessels to nitroglycerin were examined in vitro using a video-imaging apparatus. Large coronary microvessels, preconstricted with acetylcholine, relaxed by 90% in response to nitroglycerin, whereas small microvessels relaxed only 20% to nitroglycerin. Responses to putative metabolites of nitroglycerin, S-nitrosocysteine, and nitric oxide, were also examined. S-Nitrosocysteine produced equal relaxations in all sizes of coronary microvessels. Nitric oxide was 10 times more potent in large coronary arteries than in small but produced greater than 90% relaxation of all sizes of coronary microvessels at the highest concentrations. Bradykinin and the calcium ionophore A23187, which release endothelium-derived relaxing factor (EDRF), produced similar relaxation in small, medium, and large microvessels. The compound LY 83583 (which depletes vascular guanylate cyclase) reduced responses to nitroglycerin, nitric oxide, S-nitrosocysteine, bradykinin, and the calcium ionophore A23187 in microvessels of all sizes. Our data are compatible with the concept that nitroglycerin must undergo reductive processing to exert its vasodilator effect, likely through the formation of nitrosothiols. In small coronary microvessels, this biotransformation of nitroglycerin is diminished compared with larger coronary arteries. This may be caused by a relative deficiency of available sulfhydryl groups or a lack of enzymes necessary for conversion of nitroglycerin to its active metabolites in small coronary resistance vessels.
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PMID:Influence of vessel size on the sensitivity of porcine coronary microvessels to nitroglycerin. 210 98

The production of endothelium-derived relaxing factor(s) in response to kinins was investigated in cultured porcine aortic endothelial cells. The production was estimated by the measurement of the accumulation of cyclic GMP, a response which can be attributed to activation of the soluble guanylate cyclase of the endothelial cells by endothelium-derived relaxing factor(s). Bradykinin increased markedly the levels of cyclic GMP in endothelial cells without affecting those of cyclic AMP. The bradykinin-stimulated production of cyclic GMP was transient and concentration-dependent. Kallidin (an agonist at B2-kinin receptors) but not des-Arg9 bradykinin and des-Arg10 kallidin (agonists at B1 kinin receptors) also increased, in a concentration-dependent manner, the content of cyclic GMP. The B2 kinin receptor antagonist, D-Arg0 [Hyp3, D-Phe7]bradykinin but not the B1 kinin receptor antagonists Leu8-des-Arg9 bradykinin and Leu9-des-Arg10 kallidin inhibited the production of cyclic GMP upon stimulation of the endothelial cells with either bradykinin or kallidin. Both the basal and kinin (bradykinin and kallidin)-stimulated productions of cyclic GMP were reduced by hemoglobin and potentiated by superoxide dismutase. Methylene blue also reduced kinin-stimulated production of cyclic GMP. These findings suggest that cultured porcine aortic endothelial cells possess B2 kinin receptors which are associated with the production and/or release of endothelium-derived relaxing factor(s). The endothelium-derived relaxing factor(s) produced in turn enhances the activity of soluble guanylate cyclase and induces the accumulation of cyclic GMP.
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PMID:Bradykinin stimulates the production of cyclic GMP via activation of B2 kinin receptors in cultured porcine aortic endothelial cells. 215 53

1. The effects of bradykinin, adenosine diphosphate, calcium ionophore A23187 and nitric oxide on the production of adenosine 3':5'-cyclic monophosphate (cyclic AMP) and guanosine 3':5'-cyclic monophosphate (cyclic GMP) were investigated in cultured aortic endothelial cells of the pig. 2. Bradykinin (10(-7) M), adenosine diphosphate (3 x 10(-5) M), nitric oxide (2 x 10(-6) M) and A23187 (10(-6) M) stimulated the production of cyclic GMP. This stimulation reached a maximum within 1 min and declined rapidly with the first three agonists whereas that induced by A23187 was long-lasting. 3. These concentrations of bradykinin, A23187 and nitric oxide had no effect on cyclic AMP production. However, adenosine diphosphate (3 x 10(-5) M) slightly but significantly enhanced its production by about 1.7 fold. 4. The basal content of cyclic GMP in endothelial cells was significantly reduced by haemoglobin (10(-5) M, a scavenger of endothelium-derived relaxing factor(s] and methylene blue (10(-5) M, an inhibitor of the activation of soluble guanylate cyclase) and was significantly enhanced by superoxide dismutase (500 u ml-1, a scavenger of superoxide anions). The basal content of cyclic GMP was not affected by NG-monomethyl-L-arginine (10(-5) M, a specific inhibitor of the formation of nitric oxide from L-arginine) and was slightly but significantly increased by its D-enantiomer, NG-monomethyl-D-arginine. 5. The production of cyclic GMP stimulated by bradykinin, adenosine diphosphate, A23187 and nitric oxide was inhibited by haemoglobin (10 5M) and methylene blue (10- M) but was unaffected by superoxide dismutase (500 u ml 1)- 6. The production of cyclic GMP stimulated by bradykinin, adenosine diphosphate or A23187, but not that stimulated by nitric oxide, was significantly reduced by N0-monomethyl-L-arginine (10-M). The production of cyclic GMP evoked by nitric oxide, but not that induced by the other three agents, was enhanced significantly by N0-monomethyl-D-arginine by about 1.5 fold. 7. These data indicate that the endothelium-dependent vasodilators bradykinin, adenosine diphosphate and A23187 activate the production of cyclic GMP in endothelial cells via the synthesis of nitric oxide, which in turn stimulates the soluble guanylate cyclase.
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PMID:Stimulation of cyclic GMP production in cultured endothelial cells of the pig by bradykinin, adenosine diphosphate, calcium ionophore A23187 and nitric oxide. 217 13


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