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)

1. In rat isolated hepatic arteries contracted with phenylephrine, acetylcholine and the calcium ionophore A23187 each elicit endothelium-dependent relaxations, which involve both nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). However, the contribution of prostanoids to these responses, and the potential interaction between EDHF and other endothelium-derived relaxing factors have not been examined. 2. In the presence of the NO synthase inhibitor N(G)-nitro-L-arginine (L-NOARG, 0.3 mM) and a mixture of charybdotoxin (0.3 microM) and apamin (0.3 microM), inhibitors of the target potassium (K) channel(s) for EDHF, acetylcholine and A23187 each induced a concentration-dependent and almost complete relaxation, which was abolished in the additional presence of indomethacin (10 microM). Thus, in addition to EDHF and NO, a relaxing factor(s) generated by cyclo-oxygenase (COX) contributes to endothelium-dependent relaxation in the rat hepatic artery. 3. The resting membrane potentials of endothelium-intact and endothelium-denuded vascular segments were -57 mV and -52 mV, respectively (P>0.05). In intact arteries, the resting membrane potential was not affected by L-NOARG plus indomethacin, but reduced to -47 mV in the presence of charybdotoxin plus apamin. Acetylcholine and A23187 (10 microM each) elicited a hyperpolarization of 13 mV and 15 mV, respectively. The hyperpolarization induced by these agents was not affected by L-NOARG plus indomethacin (12 mV and 14 mV, respectively), but reduced in the presence of charybdotoxin plus apamin (7 mV and 10 mV, respectively), and abolished in the combined presence of charybdotoxin, apamin and indomethacin. 4. The NO donor 3-morpholino-sydnonimine (SIN-1) induced a concentration-dependent relaxation, which was unaffected by charybdotoxin plus apamin, but abolished by the selective soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10 microM). SIN-1 (10 microM) did not alter the resting membrane potential in endothelium-denuded vascular segments. 5. The COX-dependent relaxation induced by acetylcholine was abolished following exposure to 30 mM KCl, but unaffected by glibenclamide (10 microM). The prostacyclin analogue iloprost induced a concentration-dependent relaxation, which was also abolished in 30 mM KCl and unaffected by the combined treatment with glibenclamide, charybdotoxin and apamin. Iloprost (10 microM) induced a glibenclamide-resistant hyperpolarization (8 mV with and 9 mV without glibenclamide) in endothelium-denuded vascular segments. 6. Exposure to SIN-1 or iloprost did not affect the EDHF-mediated relaxation induced by acetylcholine (i.e. in the presence of L-NOARG and indomethacin). Replacement of L-NOARG with the NO scavenger oxyhaemoglobin (10 microM) or the soluble guanylate cyclase inhibitor ODQ (10 microM) or methylene blue (10 microM), which all significantly inhibited responses to endothelium-derived NO, did not affect the acetylcholine-induced relaxation in the presence of indomethacin, indicating that endogenous NO also does not suppress EDHF-mediated responses. 7. These results show that, in addition to EDHF and NO, an endothelium-derived hyperpolarizing factor(s) generated by COX contributes significantly to endothelium-dependent relaxation in the rat heptic artery. Neither this factor nor NO seems to regulate EDHF-mediated responses. Thus, EDHF does not serve simply as a 'back-up' system for NO and prostacyclin in this artery. However, whether EDHF modulates the NO and COX pathways remains to be determined.
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PMID:Interactions between endothelium-derived relaxing factors in the rat hepatic artery: focus on regulation of EDHF. 969 86

We studied the mechanisms of retinal and choroidal vasorelaxation elicited by nitric oxide (NO) using piglet eyes. The NO donors sodium nitroprusside (SNP) and diethylamine-NONOate caused comparable concentration-dependent relaxation that was partially (approximately 40%) attenuated by the guanylate cyclase inhibitors methylene blue and LY83583 and reduced to a lesser extent (approximately 25%) by the inhibitor of cGMP-dependent kinase, KT 5823. In contrast, NO-induced dilatation (by NO donors and endogenous NO after stimulation with bradykinin) was substantially (approximately 70%) diminished by the KCa channel blockers tetraethylammonium (TEA), charybdotoxin, and iberiotoxin; by the cyclooxygenase inhibitors indomethacin and ibuprofen; by the prostaglandin I (PGI2) synthase inhibitor trans-2-phenyl cyclopropylamine (TPC); and by the removal of endothelium; whereas relaxation of endothelium-denuded vasculature to SNP was unaltered by indomethacin, TPC, and charybdotoxin but was nearly nullified by methylene blue and the Kv channel blocker 4-aminopyridine. NO donors significantly increased PGI2 synthesis and the putative PGI2 receptor-coupled second messenger cAMP, from ocular vasculature (retinal microvessels and choroidal perfusate), and this increase in PGI2 formation was markedly reduced by TPC, tetraethylammonium, charybdotoxin, and/or the removal of endothelium, but it was only slightly reduced by methylene blue and LY83583. Also, SNP and KCa channel openers NS1619 and NS004 caused an increase in PGI2 synthesis in cultured endothelial cells, which was virtually abolished by KCa blockers. Finally, vasorelaxation to a cGMP analogue, 8-bromo cGMP, and protein kinase G stimulant beta-phenyl-1,N2-etheno-8-bromoguanosine 3':5'-cyclic monophosphate was mostly Kv dependent and, in contrast to NO, largely unrelated to PGI2 formation. In conclusion, data indicate that NO-induced ocular vasorelaxation is partly mediated by cGMP through its action on smooth muscle, and more importantly, by stimulating PGI2 formation of endothelial origin via a mechanism mostly independent of guanylate cyclase, which involves the opening of a KCa channel.
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PMID:A major role for prostacyclin in nitric oxide-induced ocular vasorelaxation in the piglet. 975 42

Non-restrictive, porous, external stents inhibit neointima formation in porcine vein grafts. Since the mechanisms underlying these effects are unknown we investigated the impact of this external stent on factors known to inhibit vascular smooth muscle cell proliferation: prostacyclin (PGI2), nitric oxide (NO), cAMP and cGMP formation in different regions of stented and unstented porcine vein grafts. Paired stented and unstented saphenous vein-carotid artery interposition grafting was carried out in Landrace pigs. One month after surgery, the vessels were excised and the formation of PGI2, cAMP and cGMP determined using radioimmunoassay and nitric oxide synthase (NOS) distribution studied using autoradiography and histochemistry. There were no significant differences between PGI2, cAMP and cGMP (nitroprusside-stimulated) formation in the medial/intimal regions of grafts of stented vein graft and ungrafted saphenous vein whereas all were significantly reduced in unstented vein graft. A23187-stimulated cGMP formation (mediated by NO release) and NOS content was significantly greater in the medial/intimal region of stented and unstented vein graft compared to ungrafted saphenous vein, indicating induction of endothelial NOS (eNOS) in both types of graft. This normalisation of the PGI2-cAMP axis and guanylyl cyclase activity in the medial/intimal region may contribute to the beneficial impact of the external stent on vein graft thickening. The increase in eNOS in both stented and unstented vein grafts mitigates against this isoform as playing a role in mediating the inhibitory effect of the stent on neointima formation. In the adventitia of both stented and unstented grafts there was an increase in PGI2, cAMP and cGMP formation compared to ungrafted saphenous vein, the production being greater in the stented compared to the unstented graft. In the adventitia of stented veini grafts, NOS, detected with NAPDH diaphorase staining, was associated with microvessels as well as with inflammatory cells. Taken together, these data are suggestive of a role for PGI2 and NO in promoting microangiogenesis in the adventitia of stented vein grafts which may in turn minimize graft hypoxia, an established contributory factor to neointima formation.
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PMID:Nitric oxide, prostacyclin and cyclic nucleotide formation in externally stented porcine vein grafts. 986 78

Corticotropin-releasing factor (CRF), a potent vasorelaxant, is increased tremendously during human pregnancy. Placenta is the main source for this increase. CRF is thought to be important in modulating vascular resistance and uteroplacental blood flow during pregnancy. Here we investigated pathways mediating a vasorelaxant effect of CRF in the uterine artery. Two-millimeter segments of uterine artery (o.d. 300-400 microm) from day 18 pregnant rats were mounted in a small vessel myograph and precontracted with norepinephrine, and relaxation responses to CRF were studied. CRF relaxed the uterine artery in a concentration-dependent manner. Relaxation of uterine artery by CRF was abolished completely by alpha-helical CRF 9-41 (CRF antagonist, 1 micromol) and partially by removal of endothelium, Nomega-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor, 0.1 mmol), 6-anilino-5,8-quinolinedione (guanylate cyclase inhibitor, 10 micromol), or thiopental/miconazole (cytochrome P-450 inhibitors, 0.3 mmol/30 micromol), but remained unaffected by indomethacin (cyclo-oxygenase inhibitor, 10 micromol). Relaxation was also inhibited when depolarizing solution (K+, 120 mmol) was used for precontraction. In deendothelized preparations, relaxation was not inhibited by 9-tetrahydro-2-furanyl-9H-purin-6-amine (adenylate cyclase inhibitor, 0.2 mmol), glibenclamide (adenosine triphosphate-dependent K+ channel blocker, 10 micromol), tetrabutyl ammonium (nonspecific K+ channel blocker, 1 mmol), nitrendipine (voltage-gated Ca++ channel blocker, 1 micromol), or when vessels were precontracted with depolarizing solution. CRF causes vasorelaxation by receptor-operated, endothelium-dependent and -independent pathways. The endothelium-dependent relaxation is mediated by nitric oxide-cyclic guanosine monophosphate pathway and endothelium-derived hyperpolarizing factor but not prostacyclin. However, cyclic adenosine monophosphate, K+ channels, or Ca++ channels are not involved in endothelium-independent vasorelaxation by CRF.
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PMID:Endothelium-dependent and -independent mechanisms of vasorelaxation by corticotropin-releasing factor in pregnant rat uterine artery. 991 39

During fetal life and the transition to extra-uterine air breathing, pulmonary vascular tone is regulated by a complex, interactive group of mechanisms. Arachidonic acid metabolites play an important role in this regulation. Although prostaglandins may not be central to regulation of the resting fetal pulmonary circulation, PGI2 acts to modulate tone and thereby maintain pulmonary vascular resistance relatively constant. PGI2 also may play an important role as one of the components involved in the major changes that occur with the onset of air breathing. Leukotrienes, also metabolites of arachidonic acid and potent smooth muscle constrictors, may play an active role in maintaining the normally high fetal pulmonary vascular resistance, because leukotriene receptor blockade or synthesis inhibition increases pulmonary blood flow about eight-fold; the presence of leukotrienes in fetal tracheal fluid further supports this. In addition to PGI2, vascular endothelial cells produce other vasoactive factors. These include potent vasodilators, such as endothelium-derived relaxing factor (EDRF). EDRF, known to be nitric oxide (NO) and often called endothelium-derived nitric oxide (EDNO), is produced by endothelial cells in response to varied stimuli, generally involving specific receptors and the activation of endothelial NO synthetase (eNOS); subsequent smooth muscle relaxation is produced by a NO/guanylyl cyclase/cGMP-mediated mechanism. NO clearly is involved in regulation of vascular tone in the fetal pulmonary circulation, although it plays a far more important role in the postnatal transition to air breathing. Superfused fetal sheep pulmonary arteries release NO when stimulated with bradykinin. In fetal lambs the vasodilating effects of bradykinin are attenuated by methylene blue and resting tone falls with N(omega)-nitro-L-arginine, an inhibitor of NO synthesis, suggesting that a NO/cGMP-dependent mechanism continuously modulates or offsets the increased tone of the resting fetal pulmonary circulation. Inhibition of NO synthesis blocks the pulmonary vasodilation with oxygenation of fetal lungs in utero. Shear stress-induced NO production as well as the relationship of oxygenation to NO production further support the important function of NO in the transition. Although endothelin-1 (ET-1) has potent vasoactivity as well as ontogenetic differences in effect on pulmonary vascular resistance, its exact physiological role has not been defined. Adrenomedullin and calcitonin gene-related peptide (CGRP), two additional vasoactive substances, have profound, and prolonged, vasodilating effects in the fetal pulmonary circulation. Their physiological roles have not yet been established.
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PMID:Control of the pulmonary circulation in the fetus and during the transitional period to air breathing. 1042 35

1. Acetycholine-mediated relaxations in phenylephrine-contracted aortas, femoral and mesenteric resistance arteries were studied in vessels from endothelial nitric oxide synthase knock-out (eNOS -/-) and the corresponding wild-type strain (eNOS +/+) C57BL6/SV19 mice. 2. Aortas from eNOS (+/+) mice relaxed to acetylcholine in an endothelium-dependent NG-nitro-L-arginine (L-NOARG) sensitive manner. Aortas from eNOS (-/-) mice did not relax to acetylcholine but demonstrated enhanced sensitivity to both authentic NO and sodium nitroprusside. 3. Relaxation to acetylcholine in femoral arteries was partially inhibited by L-NOARG in vessels from eNOS (+/+) mice, but relaxation in eNOS (-/-) mice was insensitive to a combination of L-NOARG and indomethacin and the guanylyl cyclase inhibitor 1H-[1,2, 4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). The L-NOARG/ODQ/indomethacin-insensitive relaxation to acetylcholine in femoral arteries was inhibited in the presence of elevated (30 mM) extracellular KCl. 4. In mesenteric resistance vessels from eNOS (+/+) mice, the acetylcholine-mediated relaxation response was completely inhibited by a combination of indomethacin and L-NOARG or by 30 mM KCl alone. In contrast, in mesenteric arteries from eNOS (-/-) mice, the acetylcholine-relaxation response was insensitive to a combination of L-NOARG and indomethacin, but was inhibited in the presence of 30 mM KCl. 5. These data indicate arteries from eNOS (-/-) mice demonstrate a supersensitivity to exogenous NO, and that acetylcholine-induced vasorelaxation of femoral and mesenteric vessels from eNOS (-/-) mice is mediated by an endothelium-derived factor that has properties of an EDHF but is neither NO nor prostacyclin. Furthermore, in mesenteric vessels, there is an upregulation of the role of EDHF in the absence of NO.
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PMID:Acetylcholine-induced relaxation of peripheral arteries isolated from mice lacking endothelial nitric oxide synthase. 1051 45

The sesquiterpene polygodial produces graded relaxation in rings of rabbit pulmonary artery or thoracic aorta and guinea-pig pulmonary artery with endothelium. In rings with rubbed endothelium its vasorelaxant action was largely reduced. The N(omega)-nitro-L-arginine (L-NOARG), N(G)-nitro-L-arginine methyl ester (L-NAME), 6-anilino-5,8-quinolinedione (LY 83583) and 1H-[1,2, 4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), inhibited the endothelium-dependent vasorelaxant action of polygodial. In contrast, N(omega)-nitro-D-arginine (D-NOARG), indomethacin, N(2)-[(4R)-4-hydroxy-1-(1methyl-1H-indol-3yl)carbonyl-L-prol yl]-N-met hyl-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide (FK 888), (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3, 4-dichlorophenyl)butyl]benzamide (SR 48968), (8R,9S, 11S)-(-)-9-hydroxy-9-n-hexyloxy-carbonyl-8-methyl-2,3,9, 20-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triaqzadibenzo[a, g]cycloocta[c,d,e]-trinden-1-one (KT 5720), calcitocin gene-related peptide receptor antagonist (CGRP-(8-37), apamin, charybdotoxin and 4-aminopyridine had no effect on polygodial action. However, glibenclamide inhibited partially, but significantly, its relaxant responses. These results demonstrate that the vasorelaxation of polygodial is partly dependent on the release of nitric oxide (NO )or an NO-derived substance from the vascular endothelium through an activation of a guanylyl cyclase-dependent mechanism. Finally, results demonstrate that the polygodial vasorelaxant action is not related with the opening of potassium (K(+)) channels, release of prostacyclin, substance P, or with the activation of adenylyl cyclase-dependent mechanisms.
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PMID:Mechanisms underlying the relaxation caused by the sesquiterpene polygodial in vessels from rabbit and guinea-pig. 1061 63

A number of studies have demonstrated that prostacyclin and nitric oxide (NO) regulate blood pressure, blood flow and platelet aggregation. In this paper, we have examined the possible relationship between NO and prostaglandin endoperoxide H synthase (PGHS)-1 and -2 activities in cultured bovine aortic endothelial cells. In the non-activated condition endothelial cells expressed PGHS-1 activity alone. When these cells were pretreated with aspirin to inactivate their PGHS-1 and then activated by serum and phorbol ester (TPA) for 6 h, the cells expressed PGHS-2 activity alone. The PGHS activity was assessed by the generation of 6-ketoprostaglandin F1alpha (6-ketoPGF1alpha), a stable metabolite of prostacyclin, after the treatment of these cells with arachidonic acid. The simultaneous addition of NOC-7, a NO donor, with arachidonic acid did not affect the production of 6-ketoPGF1alpha in PGHS-1 expressed cells, but attenuated it in PGHS-2-expressed cells. The inhibitory effect of NOC-7 on PGHS-2 activity was dose dependent, and the different effects of NOC-7 on the activities of PGHS isozymes were also observed in other NO donors. To confirm the different effect of NO on PGHS isozymes demonstrated in the cultured endothelial cells, we carried out an ex vivo perfusion assay in aorta isolated from normal and lipopolysaccharide (LPS)-treated rats. In the aortae isolated from normal rats, where dominant expression of PGHS-1 was expected, the NO donor did not affect the PGHS activity, while in aortae isolated from LPS-treated rats, where PGHS-2 was dominantly expressed, the NO donor dramatically inhibited the PGHS activity, suggesting that NO suppressed PGHS-2 activity alone. The inhibitory effect of NO on PGHS-2 activity was not mediated by cyclic GMP (cGMP), since (a) methylene blue, an inhibitor of soluble guanylate cyclase did not abolish the inhibitory effect of the NO donor on PGHS-2 activity, and (b) 8-Br-cGMP, a permeable cGMP analogue, failed to mimic the effect of NO donors. These data suggest that the effect of NO on prostacyclin production in endothelial cells was dependent on the expression rate of PGHS-1 and PGHS-2 in the cells.
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PMID:Differential effects of nitric oxide on the activity of prostaglandin endoperoxide H synthase-1 and -2 in vascular endothelial cells. 1084 Oct 38

To evaluate the effect of exogenous nitric oxide (NO) and endogenous NO on the production of prostacyclin (PGI(2)) by cultured human pulmonary artery smooth muscle cells (HPASMC) treated with lipopolysaccharide (LPS), interleukin-1(beta)(IL-1(beta)), tumor necrosis factor alpha (TNF(alpha)) or interferon gamma (IFN(gamma)), HPASMC were treated with LPS and cytokines together with or without sodium nitroprusside (SNP), NO donor, N(G)-monomethyl-L-arginine (L-NMMA), NO synthetase inhibitor, and methylene blue (MeB), an inhibitor of the soluble guanylate cyclase. After incubation for 24 h, the postculture media were collected for the assay of nitrite by chemiluminescence method and the assay of PGI(2)by radioimmunoassay. The incubation of HPASMC with various concentrations of LPS, IL-1(beta)or TNF(alpha)for 24 h caused a significant increase in nitrite release and PGI(2)production. However, IFN(gamma)slightly increased the release of nitrite and had little effect on PGI(2)production. Although the incubation of these cells for 24 h with SNP did not cause a significant increase in PGI(2)production, the incubation of HPASMC with SNP and 10 microg/ml LPS, or with SNP and 100 U/ml IL-1(beta)further increase PGI(2)production and this enhancement was closely related to the concentration of SNP. However, stimulatory effect of SNP on PGI(2)production was not found in TNF(alpha)- and IFN(gamma)- treated HPASMC. Addition of L-NMMA to a medium containing LPS or IL-1(beta)reduced nitrite release and attenuated the stimulatory effect of those agents on PGI(2)production. MeB significantly suppressed the production of PGI(2)by HPASMC treated with or without LPS or IL-1(beta). The addition of SNP partly reversed the inhibitory effect of MeB on PGI(2)production by HPASMC. These experimental results suggest that NO might stimulate PGI(2)production by HPASMC. Exogenous NO together with endogenous NO induced by LPS or cytokines from smooth muscle cells might synergetically enhance PGI(2)production by these cells, possibly in clinical disorders such as sepsis and acute respiratory distress syndrome.
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PMID:Nitric oxide enhances PGI(2)production by human pulmonary artery smooth muscle cells. 1091 30

Oxygen-derived free radicals have been implicated in the pathogenesis of myocardial injury. We therefore investigated the pathophysiology of myocardial injury induced in isolated rat hearts by perfusion with superoxide radical generated by reacting 2.5 mmol/l purine, 0.03 U/ml xanthine oxidase and 300 U/ml catalase. Perfusion with superoxide significantly (P<0.05) increased left ventricular end-diastolic pressure within 15 to 20 min. During the same time period, heart rate and left-ventricular developed pressure significantly declined to 44.6+/-8.2% and 31.0+/-4.9% of control, respectively. Superoxide perfusion also significantly increased production of prostaglandins, nitric oxide (detected as nitrites) and peroxynitrite (detected immunohistochemically as nitrotyrosine). N(G)-nitro-l-arginine (100 micromol/l), a nitric oxide synthase inhibitor, attenuated superoxide-induced generation of peroxynitrite, increased synthesis of prostacyclin, and partially blocked myocardial dysfunction, as did 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (30 micromol/l), a selective inhibitor of soluble guanylate cyclase, and ONO-3708 (10 micromol/l), a selective thromboxane A(2)receptor antagonist. In contrast, nitroglycerin (4 micromol/l) and sodium nitroprusside (1 micromol/l) each exacerbated the superoxide-induced myocardial dysfunction. These results suggest that nitric oxide and related reactive species contribute to myocardial injury induced by superoxide. Moreover, they suggest that oxidative stress can be delayed or inhibited by reducing levels of nitric oxide, by inhibiting soluble guanylate cyclase, and by blocking thromboxane/prostaglandin receptors.
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PMID:Prostaglandins and nitric oxide mediate superoxide-induced myocardial contractile dysfunction in isolated rat hearts. 1144 16


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