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

---

Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the biochemical properties of soluble guanylate cyclase (sGC) have been extensively studied, little is known about the regulation of gene expression of sGC subunits by second messengers. cAMP analogues and elevating agents have been previously shown to alter gene expression in vascular cells. The aim of the present study was to investigate the effects of cAMP-elevating agents on sodium nitroprusside-stimulated sGC activity and to correlate activity changes with mRNA and protein levels in cultured rat aortic smooth muscle cells. Pretreatment of cells with 50 to 1000 mumol/L isobutylmethyl-xanthine or 0.01 to 10 mumol/L forskolin led to a time- and concentration-dependent decrease in sodium nitroprusside-induced cGMP accumulation, first evident after 3 hours of pretreatment with forskolin and 6 hours of pretreatment with isobutylmethylxanthine. Incubation of cells with a protein kinase A-selective inhibitor (H89 or KT 5720) partially or fully prevented the downregulation in sodium nitroprusside-induced cGMP accumulation caused by cAMP-elevating agents. Quantification of reverse transcriptase-polymerase chain reaction products by high-performance liquid chromatography revealed that mRNA for both alpha1- and beta1-subunits of sGC were decreased in cells pretreated with isobutylmethylxanthine and forskolin but not with dideoxyforskolin (inactive analogue). Moreover, protein levels for the sGC alpha1 subunit of cells pretreated with isobutylmethylxanthine and forskolin but not with dideoxyforskolin were decreased as indicated by Western blot analysis. These data indicate that cAMP-elevating agents decrease sGC activity, possibly by decreasing mRNA or protein levels or both.
...
PMID:Regulation of vascular smooth muscle soluble guanylate cyclase activity, mRNA, and protein levels by cAMP-elevating agents. 755 33

Atrial natriuretic peptide (ANP) receptors were characterized in rat uterus. The binding of [125I]ANP to uterine membranes was completely competed for by increasing concentrations of unlabeled ANP (Kd = 0.39 nM) and brain natriuretic peptide (Kd = 1.24 nM) and partially by C-type natriuretic peptide (CNP; Kd = 80.4 nM), but not by C-ANF. Also, [125I]Tyr-CNP bound to uterine membranes was completely competed by unlabeled CNP (Kd = 1.12 nM). Cross-linking of [125I]ANP to uterine membranes revealed the presence of one band of 130 kilodaltons, corresponding to the guanylyl cyclase (GC-A and/or GC-B) subtypes of natriuretic peptide receptors. The presence of messenger RNA coding for genes of both GC-A and GC-B receptors was shown by quantitative reverse transcriptase polymerase chain reaction. Furthermore, ANP and, to a lesser degree, CNP stimulated the production of cGMP in rat uterus. Autoradiographic studies localized the highest binding of [125I]ANP in the endometrium, whereas [125I]Tyr-CNP binding was distributed in the endometrium as well as in the myometrium. These results demonstrate that rat uterine ANP receptors are of the guanylyl cyclase-coupled subtypes. The uterus is a target of natriuretic peptides where ANP induces its biological effects through the production of cGMP.
...
PMID:Characterization and distribution of natriuretic peptide receptors in the rat uterus. 766 42

The mechanism for myometrial quiescence during pregnancy is unknown. cGMP plays an integral role in the relaxation of smooth muscle, and nitric oxide (NO) is the most important endogenous activator of soluble guanylate cyclase. The purpose of this study was to determine the effect of gestational age on myometrial cGMP and NO synthase (NOS) activity in the guinea pig. Myometrial cGMP content (measured by RIA) rose slowly until 0.49 (fraction of pregnancy completed) gestation before abruptly increasing to 200 times the non-pregnant control value. It then declined precipitously after 0.87 gestation. Of the known isoenzymes of NOS, the messenger RNAs coding for both endothelial and neuronal NOS could be amplified from the myometrium of pregnant and nonpregnant animals using reverse transcriptase-polymerase chain reaction, but inducible NOS messenger RNA was not found. Myometrial calcium-dependent NOS activity (measured by the conversion of L-[U-14C]arginine to [U-14C]citrulline) declined slowly with advancing gestation (r2 = 0.096; slope = -0.34; P = 0.01), but never differed significantly from the activity in nonpregnant animals [31.1 +/- 11 (term pregnancy) vs. 56.9 +/- 16 (nonpregnant) pmol/min.g; P = NS]. Calcium-independent activity declined shortly after conception, and then rose toward the nonpregnant level (r2 = 0.19; slope = 0.45; P = 0.0009). However, at no time was it significantly different from that in the nonpregnant animal. Pregnancy had no effect on myometrial L-arginine and L-citrulline content. The administration of L-nitro-arginine methyl ester (200 mg/kg) to inhibit NOS dramatically increased blood pressure and reduced fetal renal NOS activity, but had no effect on the myometrial cGMP content. Estradiol (500 micrograms/kg for 5 days) modestly increased cGMP, but in contrast to many tissues in which estradiol increases NOS, it had no effect on myometrial NOS activity. We conclude that pregnancy dramatically increases cGMP by a mechanism independent of NOS. The stimulus remains to be identified. The temporal change in cGMP concentration is consistent with the hypothesis that cGMP mediates myometrial quiescence during pregnancy.
...
PMID:Pregnancy increases guanosine 3',5'-monophosphate in the myometrium independent of nitric oxide synthesis. 798 34

Natriuretic peptides act via receptors with intrinsic guanylate cyclase activity to stimulate cGMP production and are thought to be important regulators of neuroendocrine systems. C-Type natriuretic peptide (CNP) is of particular interest in this regard because the highest tissue concentrations of CNP occur in the anterior pituitary, where it is a highly potent stimulator of cGMP production. Here we show that pituitaries of rats and mice contain abundant CNP prohormone messenger RNA (mRNA), but no atrial natriuretic peptide or B-type natriuretic peptide prohormone mRNAs. Using reverse transcriptase-polymerase chain reaction, both A- and B-type natriuretic peptide receptor (GC-A and GC-B, respectively) transcripts were detected in rat and mouse pituitaries, although only the GC-B mRNA was measurable by Northern blotting. Immunohistochemistry revealed CNP-positive cells in the anterior, but not posterior, pituitaries of rats, and the vast majority of these cells were identified as gonadotropes by colocalization of CNP and LH immunoreactivities. Targeted toxicity using GnRH conjugated to the ricin-A chain was used to test whether gonadotropes are also direct targets for GnRH action. The conjugate dose dependently inhibited the proliferation of alpha T3-1 cells (gonadotrope-derived cells with GnRH receptors), but had no such effect on GH3 cells (which do not have GnRH receptors). Culture of rat pituitary cells with the conjugate caused comparable reductions in CNP-stimulated cGMP production, GnRH-stimulated LH release, and CA2+ ionophore (A23187)-stimulated LH release, but did not measurably alter cAMP production in response to pituitary adenylate cyclase-activating polypeptide. We conclude that CNP is synthesized in the pituitary, where it is located predominantly in gonadotropes, and GC-B receptors expressed in the pituitary mediate the direct effects of CNP in gonadotropes. Together with the recent demonstration of CNP synthesis and action in alpha T3-1 cells, the data suggest CNP to be a novel autocrine regulator of gonadotropes.
...
PMID:C-type natriuretic peptide (CNP) in the pituitary: is CNP an autocrine regulator of gonadotropes? 798 73

Expression of both particulate and soluble forms of guanylate cyclase have been identified in adult rat retina using reverse transcriptase-PCR amplification of retinal RNA and sequencing of the cloned cDNAs. Over a 267-amino acid region, the retinal particulate guanylate cyclase was found to be identical in sequence to the GC-A form of the enzyme found in many tissues. No expression of the closely related GC-B or GC alpha forms of the enzyme was found. mRNA corresponding to both subunits of the soluble form of guanylate cyclase were detected in retinal. The sequence corresponding to the 70-kDa subunit was identical to that from rat lung over a 304-amino acid region and the sequence corresponding to the 82-kDa subunit showed only one amino acid difference over a 275-amino acid region. From Northern analyses the level of expression of the soluble guanylate cyclase in retina was higher than that in lung. In situ hybridization to sections of adult retina indicated that the particulate guanylate cyclase was expressed predominantly in rod photoreceptors. Although the soluble form of the enzyme was detected in all retinal layers, the level of expression was much higher in the inner nuclear layer. The results suggest that multiple enzymes and hence multiple regulatory pathways may control cGMP levels in rod photoreceptors and that cGMP may play an important role in neurons of the inner retina.
...
PMID:Differential laminar expression of particulate and soluble guanylate cyclase genes in rat retina. 809 39

Gene expression of soluble guanylate cyclase (sGC) and cGMP accumulation in response to sodium nitroprusside (SNP) were studied in cultured human vascular cells and freshly harvested vascular tissue. As revealed by reverse transcriptase-polymerase chain reaction, cultured smooth muscle and endothelial cells, as well as freshly isolated human vascular tissue, express mRNA for the alpha 3 and beta 3 subunits but not for the alpha 2 and beta 3 subunits is evident even in the absence of increased cGMP accumulation in response to SNP. cGMP accumulation in human cells cultured from different vascular beds typically increased two- to five-fold (maximum of 11.4-fold) over baseline following stimulation with 100 microM SNP. Bovine, murine, canine, and avian vascular smooth muscle cells accumulated similar or lower amounts of cGMP than human cells, whereas porcine, rat, and rabbit smooth muscle cells accumulated greater amounts of cGMP. In freshly harvested human vessels, cGMP accumulation in response to SNP was found to increase fifteen-fold over baseline. In contrast to the SNP-induced cGMP accumulation, cGMP levels in response to particulate guanylate cyclase activator atriopeptin II were equal to or greater in cultured human cells than in fresh human vascular tissue. We conclude that human vascular cells (fresh and cultured) express the mRNA for both a large (alpha 3) and a small (beta 3) sGC subunit and that fresh human cells are more sensitive to SNP stimulation.
...
PMID:cGMP accumulation and gene expression of soluble guanylate cyclase in human vascular tissue. 861 61

Previous studies [Czyzyk-Krzeska et al.: J Neurochem 1992;58:1538] demonstrated the relationship between low O2 breathing and tyrosine hydroxylase (TH) gene expression in chemosensory type I cells of the carotid body. In the present study, we have exposed carotid bodies in vitro to hypoxic superfusion media, and subsequently used the reverse transcriptase-polymerase chain reaction technique to measure relative changes in the TH transcript in an effort to elucidate the cellular mechanisms which regulate TH gene expression. Carotid bodies and superior cervical ganglia (SCG) were exposed for 3 h to superfusion media equilibrated with either 10% O2 or 100% O2 and then rapidly frozen on dry ice prior to extraction of total RNA. Hypoxia elevated TH mRNA in the carotid body 3.63 +/- 0.84-fold (mean +/- SEM), while in contrast, these parameters were unchanged in SCG similarly exposed to hypoxic media. Incubation of carotid bodies in zero Ca2+ superfusates greatly attenuated the increase in TH mRNA evoked by hypoxia (1.39 +/- 0.34-fold increase; p < 0.025 compared to normal Ca2+ group). Likewise, exposure to the guanylate cyclase activator, atriopeptin III (100 nM), attenuated the TH mRNA hypoxic response (p < 0.005), while activation of adenylate cyclase with forskolin (10 microM) tended to elevate the response to low O2. Our data suggest that hypoxia, independent of circulating hormones, induces TH gene expression in the carotid body, and that multiple factors, including [Ca2+] and cyclic nucleotides, may be important components of the signal transduction pathway.
...
PMID:Second messenger regulation of tyrosine hydroxylase gene expression in rat carotid body. 870 28

The hemodynamic effects of sepsis have been attributed in part to increased nitric oxide (NO) production and activation of guanylate cyclase, resulting in increased cGMP and relaxation of vascular smooth muscle. Heme oxygenase-1 (HO-1), a heat shock protein, has been shown to increase intracellular cGMP levels by formation of carbon monoxide (CO). We hypothesized that HO may be an important mediator of the hepatic response to infection. Male Swiss Webster mice underwent standard cecal ligation and puncture (CLP, 18 gauge 2X) or sham operation, and received either normal saline (NS) or Zn protoporphyrin IX (ZN PP IX), a competitive HO inhibitor (n = 6-8/group). Hepatic tissue samples were collected at 3, 6, 12, and 24 hr from separate mice. Serum was collected at 3 and 24 hr. A semiquantitative reverse transcriptase polymerase chain reaction method was used to measure HO-1 mRNA levels. Hepatic cGMP levels were measured by ELISA. Groups were repeated (n = 10/group) to assess mortality. Serum was collected at 3 and 24 hr to measure serum aspartate aminotransferase (AST) levels. HO-1 mRNA expression increased significantly by 3 hr after CLP and with HO inhibition alone (P < 0.05 vs sham + NS). HO-1 mRNA remained elevated through 24 hr. CLP animals with HO inhibition showed a significant reduction of hepatic cGMP following CLP compared with CLP + saline at 24 hr (P < 0.05). Mortality was significantly increased in the CLP + ZN PP group at 24 hr (P < 0.05 CLP NS vs CLP ZN PP). CLP caused a marked increase in AST activity, which was increased further with HO inhibition. HO-1 mRNA expression was induced by CLP. AST levels following CLP were markedly increased with HO inhibition. HO-1 function appeared to contribute to elevation of hepatic cGMP during peritonitis and may be an important hepatic adaptive response to infection.
...
PMID:Heme oxygenase-dependent carbon monoxide production is a hepatic adaptive response to sepsis. 927 Dec 71

The induction in vitro of inducible nitric oxide synthase (iNOS) in intact gastric circular (CM) and longitudinal (LM) smooth muscle preparations was evaluated 1) pharmacologically, by the appearance of 1 mM L-arginine (L-Arg)-induced relaxation in a precontracted tissue; 2) biochemically, according to the appearance of iNOS mRNA using a reverse transcriptase-polymerase chain reaction; and 3) immunohistochemically, using an iNOS-specific antibody. Functionally, iNOS induction affected the contractile properties of the CM but not the LM preparation. The time course of iNOS induction monitored pharmacologically paralleled exactly the appearance of iNOS mRNA. The relaxant response to L-Arg in iNOS-induced CM tissues was blocked by the iNOS inhibitor aminoguanidine and by the guanylyl cyclase inhibitor LY-83583. The addition of oxyhemoglobin to the organ bath also attenuated the relaxant response, but tetrodotoxin had no effect. The transcriptional inhibitor actinomycin D completely blocked iNOS induction as assessed by both pharmacological and biochemical criteria. In iNOS-induced preparations the iNOS immunoreactivity was not detected in the smooth muscle elements but was localized in a layer of macrophage-related cells that were in apposition to the CM smooth muscle elements. We conclude that the spontaneous induction of iNOS in rat gastric tissue can affect the pharmacomechanical reactivity of the CM elements and that this regulation of the CM contractility is due to the induction of iNOS in a set of macrophage-related cells that are closely apposed to the CM elements so that they selectively affect only the contractility of the CM preparation.
...
PMID:Induction of nitric oxide synthase in rat gastric smooth muscle preparations. 937 8

We hypothesized that nitric oxide (NO) production by the fetal ductus arteriosus is limited because of low fetal PO2, but that at neonatal PO2, NO might be an important regulator of ductus arteriosus tone. We exposed isolated rings of fetal lamb ductus arteriosus to elevated PO2. L-NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), and methylene blue and 6-anilino-5,8-quinolinedione (LY83583), inhibitors of guanylate cyclase, produced constriction of the ductus arteriosus. When ductus arteriosus rings were exposed to low PO2, L-NAME had no effect, and methylene blue and LY83583 had only a small effect on ductus arteriosus tone. Sodium nitroprusside and calcium ionophore A23187 relaxed ductus arteriosus rings more than aortic rings, and relaxed ductus arteriosus rings from immature fetuses more than those from late gestation fetuses. In contrast, ductus arteriosus rings from both early and late gestation were equally sensitive to 8-bromo-cGMP. By both reverse transcriptase-polymerase chain reaction and immunohistochemistry, endothelial cell NOS and inducible calcium-independent NOS, but not nerve cell NOS, were detected in the ductus arteriosus. Inducible NOS was expressed only by endothelial cells lining the ductus arteriosus lumen; in contrast, endothelial cell NOS was expressed by both luminal and vasa vasorum endothelial cells. The role of inducible NOS in the ductus arteriosus is uncertain because the potency of a specific inducible NOS inhibitor in constricting the ductus arteriosus was negligible compared with that of an endothelial cell NOS inhibitor. We speculate that NO may be an important regulator of ductus arteriosus tone at high but not low PO2. The endothelial cell NOS isoform found in vasa vasorum may be an important source of NO because removal of ductus arteriosus luminal endothelium only partially blocks the effects of L-NAME, methylene blue, and LY83583.
...
PMID:Regulation of ductus arteriosus patency by nitric oxide in fetal lambs: the role of gestation, oxygen tension, and vasa vasorum. 958 10


1 2 Next >>

---