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)

Cyclic AMP accumulation has been measured in whole human sweat glands. The mean rate in glands from 19 subjects was 0.519 +/- 0.316 pmol of cyclic AMP formed 5 min-1 micrograms-1 of DNA, which is comparable with that reported for other tissues. Cyclic AMP accumulation in the sweat gland is stimulated fourfold by prostaglandin (PG) E1 and fivefold by PGE2 (0.1 mmol/l), in accord with stimulation in renal tubules and medullary membranes. Bradykinin (10 micrograms/ml) increases the rate threefold and this is substantially prevented by indomethacin (1.5 X 10(-5) mol/l), as also is a fivefold stimulation by cyclic GMP (10(-5) mol/l). Mecholyl (10(-2) mol/l) and isoprenaline (6 X 10(-6) mol/l) increase the rate five- and four-fold respectively, and these agonist effects are largely abolished by atropine and propranolol. The stimulation and inhibition pattern suggests a direct action of PGE, enhancement of prostaglandin synthetase by cyclic GMP and stimulation of guanylate cyclase by mecholyl and bradykinin. Isoprenaline presumably stimulates adenylate cyclase directly. This complex chain of events, from cholinergic stimulation to an enhancement of adenylate cyclase, demonstrated in vitro, constitutes a potential for flexible and fine control of sweat gland function.
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PMID:The human eccrine sweat gland adenylate cyclase system: response to agonists. 285 3

The objective of this study was to examine the relationship between responses of bovine intrapulmonary artery and vein to arachidonic acid and cyclic nucleotide levels in order to better understand the mechanism of relaxation elicited by arachidonic acid and acetylcholine. Arachidonic acid relaxed phenylephrine-precontracted arterial rings and elevated both cyclic GMP and cyclic AMP levels in arteries with intact endothelium. In contrast, endothelium-damaged arterial rings contracted to arachidonic acid without demonstrating significant changes in cyclic nucleotide levels. Indomethacin partially inhibited endothelium-dependent relaxation and abolished cyclic AMP accumulation whereas methylene blue, a guanylate cyclase inhibitor, partially inhibited relaxation and abolished cyclic GMP accumulation in response to arachidonic acid. All vessel responses were blocked by a combination of the two inhibitors. Prostaglandin (PG) I2 relaxed arterial rings and elevated cyclic AMP levels whereas PGE2 and PGF2 alpha caused contraction, suggesting that the indomethacin-sensitive component of arachidonic acid-elicited relaxation is due to PGI2 formation and cyclic AMP accumulation. The methylene blue-sensitive component is attributed to an endothelium-dependent but cyclooxygenase-independent generation of a substance causing cyclic GMP accumulation. Intrapulmonary veins contracted to arachidonic acid with no changes in cyclic nucleotide levels and PGI2 was without effect. Homogenates of intrapulmonary artery and vein formed 6-keto-PGF1 alpha, PGF2 alpha and PGE2 from [14C]arachidonic acid, which was inhibited by indomethacin. Thus, bovine intrapulmonary vein may not possess receptors for PGI2. The failure of endothelium-intact vein to relax to acetylcholine may be related to the lack of a relaxant effect by arachidonic acid, perhaps attributed to the absence of generation of an endothelium-derived relaxing factor.
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PMID:Differences in responsiveness of intrapulmonary artery and vein to arachidonic acid: mechanism of arterial relaxation involves cyclic guanosine 3':5'-monophosphate and cyclic adenosine 3':5'-monophosphate. 298 87

The effect of the acidic phospholipase A2 (PLA2) from Vipera russelli venom on the rat aortic ring was studied and compared with that of acetylcholine (ACh). PLA2 induced relaxation of the aortic ring precontracted with noradrenaline (NA) in a dose-dependent manner. Removal of the endothelium did not reduce the relaxant effect of PLA2. Replacement of Ca2+ by Sr2+ in the medium to inhibit the PLA2 enzyme activity reduced the relaxant effect. Atropine, a muscarinic receptor antagonist, did not affect the relaxant response. The cyclooxygenase inhibitor indomethacin, when equilibrated for 50 min, potentiated the relaxation. The lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) partially reduced the relaxation. This relaxation was also partially reduced by the guanylate cyclase inhibitor methylene blue. In contrast, the relaxation elicited by ACh was abolished by de-endothelialization, atropine, NDGA or methylene blue. 6-keto-PGF1 alpha (degradation product of prostacyclin) and PGE2 produced by aortic rings were measured by radioimmunoassay. PLA2 (3 X 10(-6) g/ml) increased the output of 6-keto-PGF1 alpha about 10-fold. The production of PGE2 was also increased but to a lesser extent. ACh also increased the output of 6-keto-PGF1 alpha and PGE2. However, prostacyclin released by PLA2 and ACh appears not to contribute to the relaxant effect, since prostacyclin does not relax the rat aorta. It is concluded that the relaxation elicited by PLA2 in the rat aorta is endothelium-independent and partially mediated by lipoxygenase product(s) and cyclic GMP whereas the relaxation induced by ACh was endothelium-dependent, mediated by lipoxygenase product(s) and cyclic GMP, and blocked by atropine.
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PMID:Relaxant effect of phospholipase A2 from Vipera russelli snake venom on rat aorta. 408 46

The mechanism of activation of intestinal guanylate cyclase by Escherichia coli heat-stable enterotoxin (STa) has been studied by using isolated rat intestinal epithelial cells and purified brush border membrane (BBM) preparations. Inhibitors of prostaglandin biosynthesis, quinacrine and 5,8,11,14-eicosatetraynoic acid (ETYA), significantly reduced intracellular levels of cyclic guanosine 3', 5'-monophosphate in isolated cells treated with STa. Although these data suggested that activation of phospholipase A2 and metabolism of arachidonic acid are involved in the mechanism of action of STa, other data ruled out such a mechanism. (i) The rate of release of [3H]arachidonic acid by prelabeled intestinal cells incubated with STa was the same as control cells not treated with STa. (ii) Thin-layer chromatography of lipid extracts of intestinal cells treated with STa and untreated cells did not reveal any quantitative or qualitative differences in free fatty acids, neutral lipids, and phospholipids. (iii) Amounts of prostaglandin PGE2, prostaglandin PGF2 alpha, and thromboxane B2 in intestinal cells and BBM incubated with STa did not increase compared with controls not incubated with STa. When purified BBM preparations were incubated with phospholipase A2 inhibitors (p-bromophenacyl bromide and quinacrine) or cyclooxygenase inhibitors (ETYA and indomethacin), basal and STa-induced guanylate cyclase activities were significantly reduced. Inhibitors of calcium-calmodulin-mediated reactions (EGTA [ethylene glycol-bis(beta-aminoethyl ether)-N,N-tetraacetic acid], trifluoperazine, and chlorpromazine) and calcium channel blockers (verapamil and nifedipine) also nonspecifically inhibited both basal and STa-stimulated guanylate cyclase in BBM preparations. Lanthanum, a competitive inhibitor of membrane-bound calcium, did not affect either basal or STa-stimulated guanylate cyclase of BBM preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the mechanism of action of Escherichia coli heat-stable enterotoxin. 614 30

Samples of blood, urine and ovarian tissues of non-pregnant cycling guinea-pigs were obtained from day 3 before until day 2 after oestrus. In addition placental specimens were obtained from 49- to 62-day pregnant guinea-pigs. In a separate series of experiments blood samples of normally menstruating and dysmenorrhoeic women were collected daily during the last one week preceding and the first two days of the menstrual cycle. Plasma and tissue samples were analyzed simultaneously for ascorbic acid (AA) and prostaglandins (PGs) E2 and F2 alpha. The urine and leukocyte samples were estimated for AA only. The results demonstrate that the ovarian AA depletion at ovulation is not associated with a rise in urinary, plasma or leukocyte levels. From about the 8th week of pregnancy in the guinea-pig the placental levels of AA start to decline, while the concentrations of PGs start to rise. During the late luteal phase, the plasma of normally cycling women has a PGD2 alpha/PGE2 ratio of about 0.6. In the dysmenorrhoeic women this ratio varies from 0.9 to 1.3. In addition, the plasma and leukocyte levels of AA in the dysmenorrhoeic women are lower than the levels found in the normally cycling women. The results of both animal and human studies indicate that an inverse relationship exists between the levels of AA and the amount of PGF2 alpha synthesized and/or released in the body tissues. It is suggested that AA acts to control the ratio between PGF2 alpha and PGE2 and therefore forms an integral part of the adenyl/guanylate cyclase system. The mechanism for the fall in tissue ascorbic acid is however not known. The results suggest that this is due to increased break-down and/or rapid consumption of AA in the body tissues. In addition the reduction in placental tissue levels of AA near term could be due to its redistribution from maternal to foetal tissues.
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PMID:Interactions of ascorbic acid with prostaglandins. 681 84

We assessed the role of cyclic nucleotides in modulating lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) generation in human peripheral blood monocytes. Exposure of monocytes to LPS (3 ng/ml) evoked a delayed, time-dependent generation of TNF-alpha that reached a maximum level 5-6 hr after LPS challenge and remained constant for up to 24 hr. This effect was concentration dependent and resulted in a 20-40-fold increase in the release of TNF-alpha that was sensitive to actinomycin D and cycloheximide. Treatment of monocytes with agents reputed to activate the cAMP/cAMP-dependent protein kinase (PKA) cascade in general inhibited LPS-induced TNF-alpha generation. Thus, the beta 2-adrenoceptor agonists albuterol and procaterol partially (approximately 40%) suppressed TNF-alpha generation in a propranolol-sensitive manner. Furthermore, 8-bromo-cAMP, cholera toxin, prostaglandin E2, and a number of drugs (i.e., rolipram (ZK 62711), denbufylline (BRL 30892), Ro 20-1724, benafentrine (AH 21-132), that inhibit the phosphodiesterase (PDE) 4 isoenzyme family abolished cytokine generation. In contrast, forskolin, inhibitors of PDE3 and PDE5, and activators of soluble and particulate guanylyl cyclase were essentially inactive. Interestingly, rolipram failed to potentiate the inhibitory effect of albuterol on LPS-induced TNF-alpha biosynthesis but, paradoxically, synergized with albuterol in the generation of cAMP and in the activation of PKA. When PGE2 was used to activate adenylyl cyclase, however, rolipram potentiated cAMP accumulation, PKA activation, and inhibition of TNF-alpha generation. In contrast, forskolin did not increase the cAMP content of monocytes in the absence or presence of rolipram. Collectively, these data suggest that LPS-induced TNF-alpha generation by human peripheral blood monocytes is due to increased transcription and subsequent translation of the TNF-alpha gene and that these effects are suppressed by a range of agents that activate the cAMP/PKA cascade. However, the failure of rolipram to potentiate the inhibitory effect of albuterol and procaterol on TNF-alpha generation suggests that beta 2-adrenoceptor agonists may affect gene expression and/or post-transcriptional regulatory processes by, at least in part, a cAMP-independent mechanism(s).
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PMID:Suppression of lipopolysaccharide-induced tumor necrosis factor-alpha generation from human peripheral blood monocytes by inhibitors of phosphodiesterase 4: interaction with stimulants of adenylyl cyclase. 747 3

The role of the L-arginine-NO pathway on the formation of PGE2 by cultured astroglial cells incubated with the HIV coating glycoprotein gp120 was investigated. Preincubation of human cultured T 67 astrocytoma cells with gp 120 (100-500 nM) produced a significant increase of nitrite (the breakdown product of NO) and PGE2 in cell supernatants. The effect of gp 120 on both nitrite and PGE2 production was antagonized by inhibition of NO synthase by L-NAME (20-300 microM). The inhibition of gp120-induced PGE2 production by L-NAME was reverted by addition of arachidonic acid (30 microM), an effect antagonized by the cyclo-oxygenase inhibitor indomethacin (10 microM). Methylen bleu, an inhibitor of the biological activity of NO acting at the guanylate cyclase level failed to affect gp 120-mediated PGE2 release showing that the increase of cGMP subsequent to NO production was not involved in the modulatory activity of NO on arachidonic acid cascade. On the basis of present experiments we conclude that gp-120-induced release of PGE2 by astroglial cells is driven by NO, thereby contributing in the involvement of glial cells in HIV-related cerebral disorders.
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PMID:HIV coating gp 120 glycoprotein-dependent prostaglandin E2 release by human cultured astrocytoma cells is regulated by nitric oxide formation. 752 Nov 67

Interleukin 1 (IL-1) is a pro-inflammatory cytokine which has direct vasorelaxant effects on vascular smooth muscle cells (VSMC). In the present study, IL-1 markedly increased intracellular levels of the vasodilatory mediator, cAMP, in human saphenous and human aortic VSMC. IL-1-induced cAMP was associated with a marked increase in prostacyclin (PGI2) production, and was reversed by indomethacin and tranylcypromine, inhibitors of cyclooxygenase and PGI2 synthetase respectively. Furthermore, PGI2, but not PGE2, was a potent inducer of cAMP production in HSVSMC, implicating a role for PGI2 in mediating IL-1-induced cAMP production. In previous studies, IL-1 increased immunoreactive cGMP production in human saphenous VSMC through a pathway inhibitable by soluble guanylate cyclase inhibitors, methylene blue and LY83583, but not by nitric oxide (NO) synthase inhibitors, suggesting a role of NO-independent activation of soluble guanylate cyclase. However, in the present study, it was found that cAMP cross-reacted significantly in cGMP radioimmunoassays employing three out of four commercial antisera, that IL-1 did not affect cGMP production in human saphenous or human aortic VSMC as determined by an RIA having low cAMP cross-reactivity, and that both LY83583 and methylene blue inhibited IL-1-induced increases in cAMP. The results implicate prostacyclin-dependent cAMP production as a mediator of the vasodilatory effects of IL-1 in humans.
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PMID:Interleukin 1 induces prostacyclin-dependent increases in cyclic AMP production and does not affect cyclic GMP production in human vascular smooth muscle cells. 757 79

Prostaglandin E2 (PGE2) has a cytoprotective role in the gastric parietal cell. PGE2 opened a housekeeping basolateral Cl- channel of rabbit gastric parietal cells, the single channel conductance of which was about 0.3 picosiemens. In the present patch-clamp and Fura 2 fluorescence studies, we found that PGE2 increased the intracellular free Ca2+ concentration ([Ca2+]i) and that PGE2-induced opening of the Cl- channel depended on the increase of [Ca2+]i. A novel bifunctional prostaglandin EP3 agonist/EP1 antagonist, 5(Z)-7-[1S, 2S, 3S, 5R)-3-(trans-beta-styren) sulfonamido-6,6-dimethylbicyclo- (3.1.1)hept-2-yl]-5-heptenoic acid, also increased both [Ca2+]i and channel opening. The PGE2-induced effect was mediated via production of nitric oxide (NO); that is, NG-monomethyl-L-arginine, an inhibitor of NO production, markedly inhibited the PGE2-induced channel opening, and nitroprusside, a NO donor, induced the channel opening in the absence of PGE2. Both PGE2 and A23187, Ca2+ ionophore, elevated the cGMP content of isolated parietal cells. The A23187-induced channel opening was abolished by methylene blue, a guanylate cyclase inhibitor. In conclusion, we found that the PGE2-induced opening of the housekeeping Cl- channel in the parietal cell involves the EP3 receptor-mediated increase in [Ca2+]i via a pertussis toxin-sensitive GTP-binding protein, resulting in successive production of NO and cGMP.
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PMID:A gastric housekeeping Cl- channel activated via prostaglandin EP3 receptor-mediated Ca2+/nitric oxide/cGMP pathway. 764 28

We recently reported that intrathecal (i.t.) administration of prostaglandin (PG) E2 or PGF2 alpha in conscious mice induced allodynia through a pathway that includes the glutamate receptor system. Allodynia induced by PGE2 and PGF2 alpha was blocked by antagonists for NMDA and metabotropic glutamate receptor subtypes, respectively. In the present study, we examined the possibility for the involvement of nitric oxide (NO) in the PG-evoked allodynia. Allodynia was assessed once every 5 min by light stroking of the flank of mice with a paintbrush. Intrathecal administration of L-arginine, a substrate of nitric oxide synthase (NOS), in conscious mice resulted in allodynia. Dose dependency of L-arginine for allodynia showed a bell-shaped pattern (1-10 micrograms/mouse). The maximal allodynic effect was observed with 5.0 micrograms at 10-15 min after i.t. injection, similar in time course and magnitude to that induced by L-glutamate. L-Arginine-induced allodynia was dose-dependently reduced by the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) and the soluble guanylate cyclase inhibitor methylene blue with IC50 values of 7.68 and 8.70 pg/mouse, respectively. PGE2-induced allodynia was also dose-dependently inhibited by L-NAME and methylene blue with IC50 values of 94.7 and 74.9 pg/mouse. PGF2 alpha-induced allodynia was inhibited by methylene blue with an IC50 value of 40.6 pg/mouse, but not by L-NAME at doses up to 1.0 ng.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide mediates allodynia induced by intrathecal administration of prostaglandin E2 or prostaglandin F2 alpha in conscious mice. 765 39


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