Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the effect of atrial natriuretic peptide (ANP) and its guanylyl cyclase/natriuretic peptide receptor-A (NPRA) on mitogen-activated protein kinase/extracellular signal-regulated kinase 2 (MAPK/ERK2) activity in rat mesangial cells overexpressing NPRA. Agonist hormones such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), angiotensin II (ANG II), and endothelin-1 (ET-1) stimulated 2.5- to 3.5-fold immunoreactive MAPK/ERK2 activity in these cells. ANP inhibited agonist-stimulated activity of MAPK/ERK2 by 65-75% in cells overexpressing NPRA, whereas in vector-transfected cells, its inhibitory effect was only 18-20%. NPRA antagonist A71915 and KT5823, a specific inhibitor of cGMP-dependent protein kinase (PKG) completely reversed the inhibitory effect of ANP on MAPK/ERK2 activity. ANP also inhibited the PDGF-stimulated [(3)H]thymidine uptake by almost 70% in cells overexpressing NPRA, as compared with only 20-25% inhibition in vector-transfected cells. These results demonstrate that ANP/NPRA system negatively regulates MAPK/ERK2 activity and proliferation of mesangial cells in a PKG-dependent manner.
 ...
PMID:Natriuretic peptide receptor-A negatively regulates mitogen-activated protein kinase and proliferation of mesangial cells: role of cGMP-dependent protein kinase. 1079 5

The objective of the study was to investigate the effect of endothelin-1 (ET-1) on KCl-induced contractions. Tracheal strips were obtained from 12 male rabbits, perfused with Krebs solution and aerated continuously by bubbling with a mixture of 95% O(2)-5% CO(2). Increasing concentrations of ET-1 (10(-12)-10(-7) M) additionally to KCl caused more contractions than KCl-induced (P<0.05). A total of 10(-7) M ET-1-induced 14.56% more contraction. Methylene blue (10(-5) M) decreased all the contractions induced from simultaneous use of KCl and ET-1. Methylene blue caused about 18% relaxation of contraction induced from KCl (80 mM) and ET-1 (10(-8) M). Consequently ET-1 increases the KCl-induced contractions of airway smooth muscles. This effect seem to mediate by a nitric oxide (NO)-guanylate cyclase-cGMP pathway, in which methylene blue is inactivator of guanylate cyclase.
 ...
PMID:Effects of endothelin-1 on KCl-induced contractions of airway smooth muscles. 1082 81

The vasodilator action of KRN2391 (10 nM-10 microM), a combined ATP-sensitive potassium channel (KATP) opener and organic nitrate, was investigated in human pial and omental arteries. Previous animal studies have suggested that opening of KATP and activation of guanylate cyclase may contribute to varying extents to the vasodilator action of KRN2391, depending on the origin and size of the vascular preparation. Vasodilator responses were studied in isolated vascular segments (diameter 0.4-0.8 mm) pre-contracted with endothelin-1 in the presence or absence of glibenclamide (inhibitor of KATP), LY83583 (inhibitor of guanylate cyclase), zaprinast (inhibitor of cyclic GMP phosphodiesterase V) and NG-nitro-L-arginine (inhibitor of nitric oxide synthase). KRN2391 induced concentration-dependent vasodilator responses of similar potency in arteries from the two vascular regions. While glibenclamide (1 microM) had no effect in omental arteries, this compound produced a tenfold rightwards shift of the concentration-response curve for KRN2391 in pial arteries without affecting the maximal response (Emax). LY83583 (10 microM), zaprinast (10 microM) and NG-nitro-L-arginine (0.1 mM) all failed to affect the vasodilator responses to KRN2391 significantly in either artery. However, in ring segments of rat aorta LY83583 displaced the concentration-response curve for the nitric oxide donor 3-morpholino-sydnonimin (10 nM-0.1 mM) to the right, while zaprinast produced a leftwards shift. The prototype KATP opener levcromakalim (0.01-10 microM) elicited a larger relaxation in pial (Emax 80+/-6%) than in omental (Emax 47+/-13%) arteries, whereas 3-morpholino-sydnonimin produced a smaller relaxation in pial (Emax 50+/-18%) than in omental (Emax 90+/-4%) arteries. These results suggest that the vasodilator response to KRN2391 is mediated by KATP in human cerebral arteries, but dependent on neither KATP nor guanylate cyclase in human omental arteries. The results with levcromakalim and 3-morpholino-sydnonimin indicate that opening of KATP may be a more effective mechanism of vasodilatation in pial than in omental arteries from man, whereas the reverse appears to be true for guanylate cyclase activation.
 ...
PMID:Vasodilator effects of KRN2391, levcromakalim and 3-morpholino-sydnonimin in human pial and omental arteries. 1093 35

1. We studied the ability of nitric oxide (NO) to physiologically antagonize endothelin-1 (ET-1) induced constrictions in human internal mammary artery (IMA). We also investigated the hypothesis that NO interacts directly with ET-receptor binding in human heart and aorta. 2. ET-1 potently contracted IMA (EC(50) 6.86 nM, 95% CI: 3.5 - 13.4 nM; n=12). The constrictor response to 10 nM ET-1 was fully reversed by the NO-donor diethylamine NONOate (DEA/NO; EC(50) 2.0 microM, 95% CI: 0.8 - 4.8 microM; n=5). The guanylate cyclase inhibitor ODQ (100 microM) reduced the response to DEA/NO but did not abolish it (E(MAX) 50.9+/-8.5% in the presence of ODQ; 113.0+/-8.4%, control). 3. The increase in cyclic GMP by 30 microM DEA/NO was abolished in the presence of 100 microM ODQ (n=6). 4. In saturation binding experiments the NO-donor Diethyltriamine NONOate (DETA/NO; 1 mM) caused a 90% reduction in maximum binding of [(125)I]-ET-1 in human heart, without affecting the affinity. This reduction in binding was abolished by haemoglobin. Pre-incubating either the radiolabel or the tissue with NO-donors did not reduce binding. A similar effect was observed in aortic smooth muscle. 5. We have shown that DEA/NO is able to reverse ET-1-induced contractions in the human vasculature. The binding studies suggest a direct interaction between NO and the ET receptor or receptor-ligand complex in human ventricular and aortic tissue. NO is released continuously in vivo, thus this apparent modification of ET-receptor binding may provide an additional mechanism by which NO counter-balances the effects of ET.
 ...
PMID:Nitric oxide-mediated modulation of the endothelin-1 signalling pathway in the human cardiovascular system. 1115 80

Portal hypertension is associated with a wide range of pulmonary pathophysiologies, ranging from portopulmonary hypertension to hepatopulmonary syndrome. Although the clinical and pathological features of pulmonary dysfunction in this setting have been extensively characterized, the underlying biology is not well understood. Specifically, the role of mediators that regulate mesenteric vascular hemodynamics in portal hypertension, such as nitric oxide and endothelin, have not been studied in the lung. Using a rat model of prehepatic portal hypertension with preserved hepatic function, we examined pulmonary elaboration of endothelial nitric oxide synthase (NOS), inducible NOS, heme oxygenase- 1 (HO-1), heme oxygenase-2 (HO-2), endothelin-1 mRNA, and protein. In comparison to sham controls, portal hypertensive animals exhibited significantly increased pulmonary iNOS and HO-1 mRNA and protein. Cyclic GMP was significantly increased in portal hypertensive lung tissue, suggesting activation of guanylyl cyclase by the endproducts of iNOS and/or HO-1 activity. Using immunohistochemical analysis, iNOS expression was localized to the vascular endothelium, while HO-1 localized to bronchiolar epithelium and macrophages. These results suggest that production of nitric oxide and carbon monoxide may contribute to the pulmonary pathology associated with portal hypertension.
 ...
PMID:Pulmonary expression of iNOS and HO-1 protein is upregulated in a rat model of prehepatic portal hypertension. 1125 66

The ability of four endogenous vasodilators, nitric oxide (NO; 0.01 - 30 microM), atrial (ANP), brain (BNP) and C-type (CNP) natriuretic peptide (0.1 - 300 nM), to reverse endothelin-1 (ET-1; 10 nM) constrictions in human resistance and conductance coronary arteries (CA) in vitro was investigated. ET-1 (0.1 - 300 nM) constricted resistance CA more potently than conductance CA (P<0.05; EC(50) values 2.98 nM (95% CI: 1.49 - 5.95 nM and 8.58 (4.72 - 15.6 nM) respectively)). The NO-donor diethylamine NONOate fully reversed the ET-1 constriction in conductance CA (E(MAX) 127+/-9.16%), however only partial reversal was observed in resistance CA (E(MAX) 78.8+/-8.13; P<0.05). The soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (100 microM) reduced the maximum response to diethylamine NONOate to 76.9+/-14.4% in conductance CA (P<0.05), but had no effect on resistance CA (E(MAX) 77.2+/-18.4%). There was no difference between responses to ANP in conductance and resistance CA (EC(50) values 4.25 nM (0.84 - 21.4 nM) and 18.4 nM (2.92 - 116 nM), E(MAX) 53.1+/-14.7% and 48.6+/-11.8% respectively). BNP was a more potent vasodilator of conductance than resistance CA. In conductance CA the mean EC(50) value was 2.4 nM (0.74 - 7.75 nM), E(MAX) 54.5+/-14.9%. Concentration-response curves to BNP were incomplete in resistance CA. Concentration-response curves to CNP were incomplete in both conductance and resistance CA. The greater potency of ET-1 in resistance vessels may exacerbate the effects of increased circulating levels of the peptide in disease. Only NO could fully reverse ET-1 mediated constrictions in conductance CA, and none of the dilators tested could completely counteract constrictions in resistance CA.
 ...
PMID:Physiological antagonism of endothelin-1 in human conductance and resistance coronary artery. 1139 74

Endothelium plays a central role in regulating the vascular tone, blood flow and blood brain barrier (BBB) permeability. The experiments presented here examine the mechanisms by which nitric oxide (NO) and endothelin-1 (ET-1) may be involved in these processes. The findings indicate that ET-1-stimulated [Ca2+]i accumulation occurs through activation of ETA receptor. The capacity of NO to affect this response was indicated by results showing: 1) a two-fold increase in ET-1-stimulated [Ca2+]i by L-NAME, the inhibitor of nitric oxide synthase, and 2) a dose-dependent decrease in [Ca2+]i accumulation by pretreatment with Nor-1 (NO donor). Abrogation of this Nor-1 effect by ODQ (an inhibitor of guanylyl cyclase) or Rp-8-pCPT-cGMPS (an inhibitor of protein kinase G) and inhibition of ET-1 stimulated intracellular Ca2+ accumulation by 8-bromo-cGMP (a permeable, analog of cGMP) substantiate the involvement of interplay between ET-1 and NO in [Ca2+]i accumulation in HBMEC. ET-1 treatment also increased thickness of F-actin cytoskeletal filaments in HBMEC. This effect was attenuated by pretreatment with NO; NO also rarefied F-actin filaments in control cultures. The findings support a linkage between NO and ET-1 in regulating microvascular tone, microcirculation and BBB permeability and indicate a role for cGMP/cGMP protein kinase system and cytoskeletal changes in responses of HBMEC.
 ...
PMID:Endothelin-1 and nitric oxide affect human cerebromicrovascular endothelial responses and signal transduction. 1144 92

The present study aimed to characterize pulmonary vascular reactivity in the chicken embryo from the last stage of prenatal development and throughout the perinatal period. Isolated intrapulmonary arteries from non-internally pipped embryos at 19 days of incubation and from internally and externally pipped embryos at 21 days of incubation were studied. Arterial diameter and contractile responses to KCl, endothelin-1, and U-46619 increased with incubation but were unaffected by external pipping. In contrast, the contractions induced by norepinephrine, phenylephrine, and electric field stimulation decreased with development. No developmental changes were observed in endothelium-dependent [acetylcholine (ACh) and cyclopiazonic acid] or endothelium-independent [sodium nitroprusside (SNP)] relaxation. These relaxations were abolished by the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Endothelium-dependent relaxation was unaffected by blockade of cyclooxygenase or heme oxygenase but was significantly reduced by nitric oxide (NO) synthase inhibitors. Reduction of O2 concentration from 95 to 5% produced a marked reduction in ACh and SNP-induced relaxations. Chicken embryo pulmonary arteries show a marked endothelium-dependent relaxation that is unaffected by transition to ex ovo life. Endothelium-derived NO seems to be the main mediator responsible for this relaxation.
 ...
PMID:Vascular reactivity in intrapulmonary arteries of chicken embryos during transition to ex ovo life. 1183 15

In order to explore the role of nitric oxide (NO) in the control of fetoplacental vascular tone in normal pregnancy we have examined the effects of NO donors on uteroplacental arteries pre-contracted with the vasoconstrictor endothelin-1 (ET-1) or serotonin (5-HT). We have furthermore examined the effects of guanylate cyclase inhibitors on the NO-induced relaxation. Segments of placental arteries (n=102) obtained from 39 placentas immediately after delivery were mounted in organ baths and superfused with Krebs-Ringer solution at 37 degrees C. The vessel segments were exposed to drugs for various intervals and the tension was recorded isometrically and registered on a polygraph. Cyclic guanosine monophosphate (cGMP) analysis was performed after extraction of vessel segments using a specific radioimmunoassay. The placental artery segments responded to ET-1 and 5-HT with a dose-dependent vasoconstriction. After pre-contraction with ET-1 (10(-7) M) or 5-HT (10(-6) M), the vessels relaxed in response to the NO donors glyceryltrinitrate (GTN) (10(-6) M) and S-nitroso-N-acetyl-penicillamine (SNAP) (10(-5) M). In the presence of the non-specific guanylate cyclase inhibitor LY 83583 (10(-6) M), the vessels responded with a small contraction. In the presence of the soluble guanylate cyclase (sGC) inhibitor 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) the non-treated vessels responded with a relaxation. 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one gave no obvious relaxation in pre-contracted vessels. Addition of 8-Br-cGMP, the cell-permeant analogue of cGMP, with or without pre-contraction had no effect on the vessels. Cyclic guanosine monophosphate analysis showed that GTN treatment caused an increase in cGMP after 12 min. Our results indicate that NO acts as a vasodilator in placental vessels. The cGMP-dependent mechanisms may be involved in NO-induced relaxation but cGMP-independent mechanisms appear also to be involved.
 ...
PMID:Effects of nitric oxide donors and inhibitors of nitric oxide signalling on endothelin- and serotonin-induced contractions in human placental arteries. 1190 20

Development and maintenance of penile erection requires the relaxation of the smooth muscle cells in the cavernous bodies and is essentially mediated by nitric oxide (NO). The penile flaccid state is conversely maintained by the alpha adrenergic neuroeffector system and by other vasoconstrictors, such as endothelin-1 (ET-1). In this study we examined the mechanisms involved in yohimbine-induced relaxation in human and rabbit corpora cavernosa (CC). We essentially found that yohimbine not only blocks contractions induced by adrenergic agonists, but also by non-adrenergic substances, such as ET-1. This effect was unrelated to antagonism at the level of ET receptors, because yohimbine did not affect ET-1-induced increase in intracellular calcium in isolated CC cells. Conversely, our data suggest that yohimbine counteracts ET-1-induced contractions by interfering with NO release from the endothelium. In fact, yohimbine-induced CC relaxation was inhibited by the mechanical removing of the endothelium and by blocking NO formation or signalling via guanylate cyclase and cGMP formation. Conversely, yohimbine activity was strongly increased by inhibiting cGMP degradation. In an experimental model of hypogonadism, performed on rabbits by chronic treatment with a long-lasting GnRH agonist, the relaxant yohimbine activity was also decreased, but completely restored by androgen supplementation. This effect was evident only in preparations in which the main source of NO was present (endothelium) or in which NO formation was not impaired by L-NAME. Our data indicate that the relaxant effect of yohimbine is both endothelium and androgen-dependent. This might justify the lack of efficacy of this drug in treatment of some form of organic erectile dysfunction.
 ...
PMID:Endothelium-dependency of yohimbine-induced corpus cavernosum relaxation. 1215 20


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>