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)

Seminal plasma (porcine) was shown to elevate cyclic GMP in Balb/3T3 cells (235-fold), NIH/3T3, Rat-2, but not in human T84 cells. Seminal plasma and C-type natriuretic peptide (CNP) markedly elevated cyclic GMP of 293 cells stably transfected with the guanylyl cyclase-B (GC-B) receptor, but failed to elevate cyclic GMP concentrations of 293 cells stably transfected with the guanylyl cyclase-A receptor. The seminal plasma activity was analyzed by reverse-phase high performance liquid chromatography; two major fractions were obtained and the amino acid sequence of one matched that of proCNP-103. For the second peak of activity, sequence could not be obtained but the purified material bound to antibody specific for CNP. CNP concentrations in seminal plasma and seminal vesicle fluid were shown to be 2,000- and 100,000-fold greater than those found in porcine brain, respectively. Significant amounts of immunoreactive CNP also were detected in tracheal mucosa and uterus suggesting a general signaling role for the peptide. That seminal plasma CNP serves a function during fertilization was suggested by finding expression of GC-B mRNA in the uterus/oviduct and CNP-stimulatable GC-B in the intact uterus. Therefore, some or all of the GC-B receptor appears to exist on the apical membrane of uterine epithelial cells.
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PMID:Seminal plasma factors that cause large elevations in cellular cyclic GMP are C-type natriuretic peptides. 809 83

Nitric Oxide mediates various biological phenomena, including vascular smooth muscle relaxation. In the present study, we sought to determine if an L-arginine nitric oxide-relaxation system is present in the uterus and if it modulates contractility during pregnancy. The substrate and a donor of nitric oxide and nitric oxide gas caused substantial relaxation of the spontaneous contractility of tissues from the rat uterus in vitro during pregnancy. Inhibitors of nitric oxide synthase and soluble guanylate cyclase reversed the relaxation effects of L-arginine. Nitric oxide was produced by the uterus in organ culture. Relaxation effects of L-arginine on the pregnant rat uterus were diminished at the time of spontaneous labor and postpartum. Nitric oxide production was also substantially reduced during labor. These results show that an L-arginine-nitric oxide-relaxation system is present in the uterus and it inhibits contractility during pregnancy but not during labor.
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PMID:Nitric oxide inhibits uterine contractility during pregnancy but not during delivery. 840 32

1. The role of nitric oxide (NO) in the regulation of uterine contractility has yet to be clearly defined. We evaluated the effect of NO (in the form of S-nitroso-cysteine, CysNO) upon uterine contractility and guanosine 3',5'-cyclic monophosphate (cyclic GMP) accumulation in pregnant and nonpregnant guinea-pig myometrium. 2. While CysNO had no effect upon spontaneous contractile activity in either pregnant or nonpregnant uterine tissues, addition of CysNO resulted in an immediate and reversible relaxation of oxytocin- or acetylcholine (ACh)-evoked contractions. 3. Relaxation of agonist-evoked contractions in response to CysNO was associated with significant elevations in intracellular cyclic GMP concentrations ([cyclic GMP]i). 4. Elevations in [cyclic GMP]i were not required for relaxation, as inhibition of guanylyl cyclase by methylene blue prevented [cyclic GMP]i accumulation while having no effect upon the ability of CysNO to relax agonist-evoked contractions. 5. Addition of the cyclic GMP-analogues, 8-Br-cyclic GMP and PET-cyclic GMP, only at high concentrations, produced partial relaxation of agonist-contracted tissues, suggesting the possibility that cyclic GMP may be sufficient but not necessary for myometrial relaxation. 6. Our studies not only provide evidence for a functional role for NO-modulation of agonist-evoked contractions in the pregnant and nonpregnant guinea-pig uterus, but also that these occur by a mechanism which is not dependent upon guanylyl cyclase activity.
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PMID:Cyclic GMP-independent effects of nitric oxide on guinea-pig uterine contractility. 890 49

Uterine natriuretic peptides may be involved in the alterations that occur in the uterus during the estrous cycle through its role in hydromineral balance. The following studies were performed to determine whether uterine natriuretic peptides and receptors follow a cyclic pattern during the estrous cycle. The results obtained show that atrial natriuretic peptide (ANP) content in rat uterine tissue was low in proestrus (8.5 +/- 2.6 pg/g) and significantly increased (P < 0.001) in estrus (71.5 +/- 16.6 pg/g), metestrus (82.6 +/- 19.7 pg/g) and diestrus (91.0 +/- 19.4 pg/g), whereas plasma ANP was not altered during the cycle. Similarly, measurement of uterine ANP mRNA by reverse transcribed polymerase chain reaction (RT-PCR) indicated lowest levels of ANP mRNA at proestrus. Measurement of C-type natriuretic peptide (CNP) by a specific and sensitive radioimmunoassay revealed that uterine CNP also varies with the estrous cycle. Uterine CNP was low in diestrus (143.2 +/- 22.4 pg/mg protein) as compared with proestrus, estrus and metestrus (305.3 +/- 51.5, 267.5 +/- 44.9, 291 +/- 41.2 pg/mg protein respectively, P < 0.05). Autoradiography performed on uterine tissue slices localized natriuretic peptide receptors to myometrial smooth muscle layers and to endometrial uterine glands. High binding of 125I-ANP was observed in proestrus and estrus with 60-75% decreases during metestrus and diestrus. Binding of 125I-tyr0CNP to uterine slices was also high during proestrus, but declined by 35% at estrus, metestrus and diestrus. The alterations in the receptors were also observed at the level of synthesis. RT-PCR detection of guanylyl cyclase A (GC-A) receptor mRNA and guanylyl cyclase B (GC-B) mRNA showed high signals at proestrus but 4- and 2-fold reductions respectively at metestrus and diestrus. In conclusion, variations in uterine ANP and CNP and their receptors during the rat estrous cycle imply the involvement of the natriuretic peptides in uterine hydromineral balance and myometrial motor activity.
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PMID:Regulation of the natriuretic peptide system in rat uterus during the estrous cycle. 920 88

1. We evaluated the effect of the nitric oxide (NO) donor CysNO (S-nitroso-L-cysteine) and endogenous NO upon spontaneous contractility in non-pregnant cynomolgus monkeys. We also assessed the role of intracellular guanosine 3',5'-cyclic monophosphate ([cyclic GMP]i) as a second messenger for NO in monkey uterine smooth muscle. 2. CysNO reduced spontaneous contractility by 84% (P < 0.05) at maximal concentrations, and significantly elevated [cyclic GMP]i (P < 0.05). However, increases in [cyclic GMP]i were not required for CysNO-induced relaxations; CysNO inhibited contractile activity despite the complete inhibition of guanylyl cyclase by methylene blue or LY83,583. 3. Analogues of cyclic GMP had no significant effect upon spontaneous contractile activity. L-arginine produced a 62% reduction in spontaneous activity (P < 0.05) while D-arginine had no effect. The competitive nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine (L-NOARG) not only blocked L-arginine-induced relaxations, but also significantly increased spontaneous contractile activity when added alone (P < 0.05); the inactive D-enantiomer of NOARG had no such effect. 4. While both endogenous NO and the NO donor CysNO relax monkey myometrium, this effect is not causally related to CysNO-induced elevations in [cyclic GMP]i. The failure of cyclic GMP analogues to alter monkey uterine smooth muscle tension also argues against a role for [cyclic GMP]i in the regulation of uterine contractility. Not only do these findings argue for the existence of a functionally-relevant NOS in the monkey uterus, but increases in contractile activity seen in the presence of NOS inhibitors suggest a role for NO in the moment-to-moment regulation of contractile activity in this organ.
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PMID:Nitric oxide regulation of monkey myometrial contractility. 963 Mar 44

The role of intracellular guanosine 3',5'-cyclic monophosphate concentration ([cGMP]i) in nitric oxide (NO)-mediated relaxations in the uterus has become controversial. We found the NO donor S-nitroso-L-cysteine (CysNO) to potently (IC50 = 30 nM) inhibit spontaneous contractions in the nonpregnant human myometrium. CysNO treatment increased [cGMP]i significantly (P < 0.001), and this increase was blocked by the guanylyl cyclase inhibitors methylene blue (10 microM) or LY-83583 (1 microM); however, pretreatment with these guanylyl cyclase inhibitors failed to block CysNO-mediated relaxations. Intracellular cAMP concentrations were not altered by treatment of tissues with 10 microM CysNO. Incubation with the cGMP analogs 8-bromo-cGMP or beta-phenyl-1,N2-etheno-cGMP did not significantly affect spontaneous contractility. Pretreatment of tissues with charybdotoxin [a calcium-dependent potassium channel (BK) blocker] completely reversed CysNO-induced relaxations. We conclude that NO is a potent inhibitor of spontaneous contractile activity in the nonpregnant human uterus and that, although guanylyl cyclase and BK activities are increased by NO, increases in [cGMP]i are not required for NO-induced relaxations in this tissue.
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PMID:Nitric oxide relaxes human myometrium by a cGMP-independent mechanism. 984 29

Soluble guanylate cyclase (sGC) is an important component of the NO signaling pathway. Human sGC isoforms alpha(1), alpha(2), and beta(1) show differential mRNA tissue distributions. alpha(1) and beta(1) are expressed in most tissues; however, the alpha(2) isoform shows a more restricted expression pattern with high levels in brain, placenta, spleen, and uterus only. Both alpha subunits exist as multiple transcripts whereas beta(1) exists as a single message. This study reports for the first time the tissue distribution of human sGC message and demonstrates that sGC isoforms are nonuniformly expressed which may be useful if the enzyme is to be exploited as a therapeutic target.
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PMID:Tissue distribution of the human soluble guanylate cyclases. 1051 42

1. In myometrial strips from near-term non-labouring human uterus, addition of oxytocin (OT) evoked dose-dependent (10 - 3000 nM) phasic contractions that were antagonized by atosiban (1 microM) and relaxed by addition of the nitric oxide donor S-nitroso L-cysteine (Cys-NO). In near-term labouring myometrium, however, addition of OT was ineffective at raising additional tone. 2. In both labouring and non-labouring tissue, Cys-NO mediated relaxation of spontaneous or OT-induced contractions (IC(50)=1 microM) was unaffected by prior addition of the guanylyl cyclase (GC) inhibitors ODQ (1H-[1,2,4]oxadiazolo[4,3,-alpha]quinoxalin-1-one; 1 microM), or methylene blue (MB; 10 microM). 3. Elevation of intracellular cyclic GMP accompanying 30 microM Cys-NO addition in non-labouring tissue (7.5 fold) or in labouring tissues (2.5 fold) was completely blocked in tissues that had been pre-treated with ODQ or MB. 4. Charybdotoxin (ChTx), iberiotoxin (IbTx) and kaliotoxin (KalTx) all shifted the Cys-NO inhibition curve to the right and reduced the degree of relaxation produced by maximal Cys-NO treatment (100 microM in non-labouring tissue; in labouring tissue, KalTx prevented Cys-NO mediated relaxation in both stimulated and unstimulated tissue. 5. Addition of the NO-donor S-nitroso N-acetyl penicillamine (SNAP) produced a dose-dependent relaxation of pregnant myometrium while 3-morpholinosyndonimine (SIN-1) did not. The failure of SIN-1 to relax OT-induced contractions was not due to a failure of the donor to stimulate myometrial GC. 6. We demonstrate that despite the ability of NO to stimulate myometrial GC in pregnant uterine muscle, relaxations are independent of cyclic GMP action. Effects of K(+)-channel inhibitors suggests that NO-induced relaxation in human uterine smooth muscle may be subserved by direct or indirect activation of one or more calcium-activated K(+)-channels.
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PMID:NO-induced relaxation of labouring and non-labouring human myometrium is not mediated by cyclic GMP. 1152 13

Among marsupials, the control of birth is best understood in the tammar wallaby. The young is tiny relative to the mother and is highly altricial. Adult female tammar wallabies weigh 5 kg, whereas the neonate weighs about 400 mg. However, despite this small size, there is clear evidence that the fetus provides the signal that sets the timing of birth through several mechanisms. A fetal signal activates a nitric oxide-guanylate cyclase system in the myometrium that may maintain myometrial inactivity, and this is down-regulated at term. There is also up-regulation of prostaglandin (PG) production in the gravid endometrium during the last two days of gestation that parallels increased placental PG synthesis, and a pregnancy-specific up-regulation of oxytocin receptors in the gravid myometrium that increases the responsiveness of the gravid uterus to mesotocin. These changes facilitate parturition, but an acute fetus-derived signal appears to trigger parturition. The fetal signal is probably related to glucocorticoid production. The fetal adrenal matures and is able to synthesize cortisol by Day 22 of the 26-day gestation. The fetal adrenals double in size between Day 24 and term, and their cortisol content increases over 10-fold. The pituitary of the neonate contains presumptive corticotrophs, and the adrenals increase cortisol production in response to adrenocorticotrophin. Prostaglandin E2, which is produced by the placenta, is also a potent stimulant of fetal adrenal cortisol synthesis. Treatment of tammars in late gestation with the cortisol agonist, dexamethasone, triggers birth around 23 h later. There is thus a strong case that fetal adrenal cortisol plays a key role in the preparation for birth and the timing of it. Further studies are in progress to more clearly define the mechanisms behind these actions of cortisol.
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PMID:Fetal control of parturition in marsupials. 1199 17

Na(+)-dependent and -independent transport sites were elucidated for glycine and L-leucine, respectively, in Chang liver cells, a human culture cell line. Findings of acceleration of the L-leucine uptake by the cells in the acidic medium and synchronized acidification within the cell membrane vesicles with the uptake by them all suggested contransport of L-leucine and proton and the uptake of L-leucine dependent on the inward proton gradient in Chang liver cells. Cotransport of L-leucine and proton was also demonstrated in human peripheral lymphocytes and accelerated by the addition of concanavalin A, probably accompanied by membrane hyperpolarization. It was shown that the Na(+)-gradient-dependent uptake of glycine can be regulated by insulin and 17 beta-estradiol in the rat uterus and by Ca(2+)-calmodulin and membrane potential in Chang liver cells. D-Aspartate uptake as a model of glutamate transport was characterized in rat hippocampal slices and found to consist of Na(+)-dependent (higher-affinity) and -independent (lower-affinity) components. The vulnerability of hippocampal neurons to the Alzheimer beta-amyloid protein was confirmed in vitro with primary cultured rat hippocampal neurons in the presence of the amyloid protein beta 1-42 or its core fragments. The toxicity of the amyloid protein could be blocked by the addition of insulin and several other growth factors to the medium. The addition of genipin, a plant-derived iridoid, was demonstrated to prevent the toxicity of a synthetic fragment of beta 1-42, beta 25-35. Genipin had a neuritogenic activity in PC12h cells, a rat pheochromocytoma cell line, an activity extremely sensitive to inhibitors of the nitrogen oxide (NO) synthase and soluble guanylate cyclase and an NO scavenger. It was also demonstrated in PC12h cells that the activation of the MAP kinase cascade was essential for the neuritogenesis of genipin. These properties of genipin are very comparable to those of nerve growth factor in the cells. It is considered likely that various useful, neurotrophic substances and their extracts will be found in plants in future.
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PMID:[Studies on the cytological function of the biomembrane and the neurons]. 1240 Jan 54


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