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)

Vascular endothelial growth factor-A (VEGF), which binds to both VEGF receptor-1 (Flt1) and VEGFR-2 (KDR/Flk-1), requires nitric oxide (NO) to induce angiogenesis in a cGMP-dependent manner. Here we show that VEGF-E, a VEGFR-2-selective ligand stimulates NO release and tube formation in human umbilical vein endothelial cells (HUVEC). Inhibition of phospholipase Cgamma (PLCgamma) with U73122 abrogated VEGF-E induced endothelial cell migration, tube formation and NO release. Inhibition of endothelial nitric oxide synthase (eNOS) using l-NNA blocked VEGF-E-induced NO release and angiogenesis. Pre-incubation of HUVEC with the soluble guanylate cyclase inhibitor, ODQ, or the protein kinase G (PKG) inhibitor, KT-5823, had no effect on angiogenesis suggesting that the action of VEGF-E is cGMP-independent. Our data provide the first demonstration that VEGFR-2-mediated NO signaling and subsequent angiogenesis is through a mechanism that is dependent on PLCgamma but independent of cGMP and PKG.
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PMID:VEGF-E activates endothelial nitric oxide synthase to induce angiogenesis via cGMP and PKG-independent pathways. 1672 9

This study was conducted to evaluate the expression of endothelial nitric oxide synthase (eNOS) in ovarian follicles and corpora lutea (CL) throughout the estrous cycle in sheep. Three experiments were conducted to (1) immunolocalize eNOS protein, (2) determine expression of mRNA for eNOS and its receptor guanylate cyclase 1 soluble beta3 (GUCY1B3), and (3) co-localize eNOS and vascular endothelial growth factor (VEGF) proteins in the follicles and/or CL throughout the estrous cycle. In experiment 1, ovaries were collected from ewes treated with FSH, to induce follicular growth or atresia. In experiment 2, ovaries were collected from ewes treated with FSH and hCG to induce follicular growth and ovulation. In experiment 3, ovaries were collected from superovulated ewes to generate multiple CL on days 2, 4, 10, and 15 of the estrous cycle. In experiments 1 and 2, the expression of eNOS protein was detected in the blood vessels of the theca externa and interna of healthy ovarian follicles. However, in early and advanced atretic follicles, eNOS protein expression was absent or reduced. During the immediate postovulatory period, eNOS protein expression was detected in thecal-derived cells that appeared to be invading the granulosa layer. Expression of eNOS mRNA tended to increase in granulosa cells at 12 and 24 h, and in theca cells 48 h after hCG injection. In experiment 3, eNOS protein was located in the blood vessels of the CL during the estrous cycle. Dual localization of eNOS and VEGF proteins in the CL demonstrated that both were found in the blood vessels.
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PMID:Expression of endothelial nitric oxide synthase in the ovine ovary throughout the estrous cycle. 1700 69

Vasoactive intestinal peptide (VIP) relaxes smooth muscle by interacting with receptors coupled to cAMP- or cGMP-signalling pathways. Their relative contribution to human gastric relaxation is unknown. This study aimed at investigating, in terms of biological activity, receptor expression and related signalling pathways, the action of VIP separately on the human fundus and the antrum. VIP caused greater relaxation of smooth muscle cells (SMC) and strips of the antrum presenting on the former a higher efficacy and potency (ED(50): 0.53 +/- 0.17 nmol L(-1)) than on the fundus (ED(50): 3.4 +/- 1.4 nmol L(-1)). On both fundus and antrum strips, its effect was tetrodotoxin insentitive. Reverse transcriptase-polymerase chain reaction analysis showed the sole expression of VPAC2 and natriuretic peptide clearance receptors, with VPAC2 being more abundant in the antrum. Functional regional differences in receptor-related signalling pathways were found. Activation of the cAMP-pathway by forskolin or its inhibition by adenylate cyclase (2'5'-dideoxyadenosine) or kinase (Rp-cAMPs) inhibitors had more pronounced effects on antrum SMC. Activation of the cGMP-pathway by sodium nitroprusside or its inhibition by guanylate cyclase (LY83583) or kinase (KT5823) inhibitors had more effects on fundus SMC, on which a higher expression of endothelial nitric oxide synthase was found. In conclusion, regional differences in VIP action on human stomach are related to distinct myogenic properties of SMC of the antrum and the fundus.
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PMID:Vasoactive intestinal peptide receptor subtypes and signalling pathways involved in relaxation of human stomach. 1704 Apr 12

Adrenomedullin-2 (ADM2), a novel calcitonin/calcitonin-gene-related peptide family peptide, is reported to reduce blood pressure in both normal and hypertensive rats. This study demonstrates gestational regulation of circulatory ADM2 in rat plasma. ADM2 dose-dependently reduces the mean arterial pressure in rats, whereas the hypotensive effect of ADM2 is significantly higher during pregnancy. In addition, immunoreactive ADM2 protein is distributed in perivascular fibers of rat mesenteric artery, and levels of pre-pro-ADM2 are significantly (P<0.05) elevated in pregnant compared with nonpregnant rat mesenteric artery. Furthermore, incubation of endothelium intact arterial tissue from pregnant rats with ADM217-47, an ADM2 antagonist, shifted the dose-dependent relaxation curve to the right in wire myography. Inhibition of soluble guanylate cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 microM) or endothelial nitric oxide synthase with N-nitro-L-arginine methyl ester (100 microM) reduced the relaxation of mesenteric artery induced by ADM2. Inhibition of adenylate cyclase with SQ22536 (10 microM) or protein kinase A with the Rp diastereomer of cyclic adenosine 3',5'-phosphorothioate (10 microM) also reduced the maximal relaxation responses induced by ADM2. Blockade of calcium-activated potassium channels with tetraethylammonium chloride (1 mM) inhibited the ADM2-induced relaxation, whereas blockade of ATP-sensitive potassium channels with glybenclamide (10 microM) did not affect the relaxation response. Hence the mechanism of ADM2-induced vasorelaxation is nitric oxide and receptor mediated and cGMP and cAMP dependent and occurs through activation of calcium-activated potassium channels. In conclusion, rat pregnancy is associated with increased levels of circulatory and vascular tissue ADM2 with concomitant increase in the in vivo hypotensive effect of ADM2 and vascular reactivity of mesenteric artery to ADM2, thus suggesting involvement of ADM2 in vascular adaptations during pregnancy.
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PMID:Adrenomedullin-2, a novel calcitonin/calcitonin-gene-related peptide family peptide, relaxes rat mesenteric artery: influence of pregnancy. 1721 18

Our previous studies demonstrated that light-induced vascular relaxation (photorelaxation) was mediated by a tissue source of nitric oxide that was independent of endothelial nitric oxide synthase (eNOS), but sensitive to inhibitors of soluble guanylate cyclase, extracellular nitric oxide scavengers and possessed the properties of a nitrosothiol. In the present study we describe High Performance Liquid Chromatography and spectrofluorometric techniques that allowed us to measure tissue levels of the nitrosothiol, S-nitrosoglutathione and its modulation in mouse aortic tissues, smooth muscle cells and human umbilical vein endothelial cells (HUVECs) following exposure to exogenous S-nitrosoglutathione, light and chemical stimuli. Basal levels of S-nitrosoglutathione were similar in control mouse aortae and HUVECs and the store size could be enhanced by exposure of tissues/cells to nitric oxide solution. No basal S-nitrosoglutathione was detected in tissue from diabetic db/db mice; however, ultraviolet light was still able to elicit relaxation of aortic tissues. Ultraviolet light induced the release of nitric oxide from the S-nitrosoglutathione store with an associated increase in the concentration of nitrite. The release of nitric oxide from the store in HUVECs was modulated by extracellular oxidative stress induced by xanthine/xanthine oxidase and also, in an atropine-sensitive process, by acetylcholine, as well as by the calcium ionophore, ionomycin. These interventions resulted in a reduced S-nitrosoglutathione store and elevated levels of nitrite. These data suggest that endothelial and vascular smooth muscle cells possess stores of nitric oxide that, in part, exist in the form of S-nitrosoglutathione. Furthermore, these stores, albeit small, may provide an additional mechanism for the regulation of vascular tone, especially under conditions, such as diabetes, in which nitric oxide generation or bioavailability is compromised; however, additional studies are required to determine not only whether there are additional chemical storage forms of nitric oxide, but also the location of such stores.
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PMID:Nitrosothiol stores in vascular tissue: modulation by ultraviolet light, acetylcholine and ionomycin. 1729 50

The ability of agmatine, formed from L-arginine by the enzyme arginine decarboxylase (ADC), to modulate vasomotor function in rat aorta was investigated in the present study. Agmatine-mediated modulation of vasomotor tone was studied in organ chambers, protein expression quantified by Western blot analysis and cyclic guanosine 5'-monophosphate (cGMP) levels measured by radioimmunoassay. Agmatine (10(-10) to 10(-3) M) produced concentration-dependent relaxations (82+/-5%) in phenylephrine-contracted endothelium intact rat aorta. Relaxations to agmatine were diminished on denudation of endothelium and nitric oxide synthase (NOS) inhibition by L-Nomega-nitro arginine or soluble guanylate cyclase inhibition by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (P<0.001) abolished agmatine-mediated relaxations, while relaxations were insensitive to inducible NOS inhibition by 1400W. Agmatine-treated aorta demonstrated increased protein expression of phosphorylated S473-Akt and phosphorylated S1177-endothelial nitric oxide synthase (eNOS), and elevated the levels of cyclic GMP (P<0.01). Agmatine-mediated potentiation of relaxations and elevation of cGMP levels was sensitive to phosphatidylinositol 3'-kinase inhibitor, wortmannin. Relaxations to agmatine were also affected by pre-treatment with tetraethylammonium (P<0.01) or apamin (P<0.05), and were not affected by charybdotoxin. Relaxations to agmatine were partially affected by pre-treatment of aortic rings with barium chloride (P<0.05), and glybenclamide (P<0.05). Results obtained suggest that agmatine activates protein kinase B/Akt to phosphorylate eNOS and elevate cyclic GMP levels to produce vasodilatation of aorta. Agmatine-mediated relaxations in rat aorta seems to be mediated mainly by endothelial NO-mediated activation of small conductance Ca2+-activated K+ channels, and partly by ATP-sensitive and inward rectifying K+ channels.
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PMID:Activation of protein kinase B/Akt and endothelial nitric oxide synthase mediates agmatine-induced endothelium-dependent relaxation. 1764 Jun 32

We hypothesized that angiotensin subtype-2 receptor (AT(2)R) inhibits renal renin biosynthesis in young rats via nitric oxide (NO). We monitored changes in renal NO, cGMP, renal renin content (RRC), and ANG II in 4-wk-old rats in response to low sodium (LNa(+)) intake alone and combined with 8-h direct renal cortical administration of AT(1) receptor blocker valsartan (VAL), AT(2)R blocker PD123319 (PD), NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME), NO donor S-nitroso-N-acetyl penicillamine (SNAP), or guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,2-alpha] quinoxaline-1-one (ODQ). In addition, we monitored renal endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) in response to VAL or PD. LNa(+), VAL, PD, l-NAME, and ODQ increased RRC, ANG II, and renin mRNA. PD and l-NAME decreased NO and cGMP, while SNAP reduced RRC, ANG II, renin mRNA, and reversed the effects of PD. PD also reduced eNOS and nNOS protein and mRNA. Combined treatment with PD, l-NAME, or ODQ and VAL reversed the effects of VAL and caused further increase in RRC, ANG II, renin mRNA, and protein. ODQ reversed the effects of SNAP. These data demonstrate that the renal AT(2) receptor decreases renal renin biosynthesis and ANG II production in young rats. Reversal of the PD effects by SNAP and SNAP effects by ODQ confirms that NO and cGMP mediate the AT(2) receptor inhibition of renal renin production.
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PMID:NO and cGMP mediate angiotensin AT2 receptor-induced renal renin inhibition in young rats. 1767 Aug 63

To evaluate the estrogenic potential of the phytoestrogen secoisolariciresinol diglycoside (SDG) found in linseed meal (LSM) on jejunal mass, cellular proliferation, vascularity, and expression of angiogenic factors and their receptors, 48 ovariectomized ewes (54.6 +/- 1.1 kg) were fed a diet containing 12.5% LSM for 0, 1, 7, or 14 d and implanted with estradiol-17beta (E(2)) for 0, 6, or 24 h before tissue collection. Angiogenic factors and receptors measured included vascular endothelial growth factor (VEGF), VEGF receptor-1 (FLT), VEGF receptor-2 (KDR), fibroblast growth factor (FGF), FGF receptor 2 IIIc (FGFR), angiopoietin (ANG)-1, ANG-2, ANG receptor (Tie-2), endothelial nitric oxide synthase (eNOS), and soluble guanylate cyclase (sGC). There was a LSM x E(2) interaction (P = 0.003) on the jejunal cellular proliferation index. Jejunal cellular proliferation increased (P < 0.002) in ewes not fed LSM and implanted with E(2) for 6 or 24 h compared with ewes implanted for 0 h but did not increase when LSM was fed for 1, 7, or 14 d. Neither feeding LSM nor implanting ewes with E(2) altered vascular area density (P > 0.75) or vascular surface area (P > 0.29) of the jejunal villi. Expression of mRNA for the angiogenic factors VEGF, FGF, FGFR, ANG-1, ANG-2, and Tie-2 were not altered (P > 0.33) by feeding LSM or implanting ewes with E(2). Implanting ewes with E(2) for 6 h increased (P = 0.04) eNOS expression compared with ewes implanted for 0 h. Feeding LSM and implanting ewes with E(2) interacted to alter mRNA expression of FLT (P = 0.04), KDR (P < 0.001), and sGC (P = 0.04). When LSM was fed for 1, but not 0, 7, or 14 d, expression of FLT mRNA decreased (P < 0.03) when ewes were implanted with E(2) for 24 h compared with ewes implanted for 0 or 6 h. Expression of KDR mRNA was suppressed in ewes fed LSM for 1 (P = 0.03) or 7 d (P = 0.0007) and implanted with E(2) for 24 h compared with ewes implanted for 0 h. When LSM was fed for 14 d, implanting ewes for 6 h increased (P = 0.04) KDR expression compared with ewes implanted for 0 h. Ewes fed LSM for 0 and 1 d experienced an increase in sGC mRNA expression when implanted for 6 h (P = 0.001) compared with ewes implanted for 0 h. When implanted for 24 h, levels were similar (P = 0.80) to those observed when ewes were implanted for 0 h. Expression of sGC was not altered by E(2) when LSM was fed for 1, 7, or 14 d (P > 0.11). The impacts of E(2) and LSM on nutrient uptake and growth during physiologically important time points are unknown.
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PMID:Impacts of linseed meal and estradiol-17beta on mass, cellularity, angiogenic factors, and vascularity of the jejunum. 1856 19

In endothelial cells, the AMP-activated protein kinase (AMPK) is stimulated by sheer stress or growth factors that stimulate release of nitric oxide (NO). We hypothesized that NO might act as an endogenous activator of AMPK in endothelial cells. Exposure of human umbilical vein endothelial cells (HUVECs) to NO donors caused an increase in phosphorylation of both Thr-172 of AMPK and Ser-1177 of endothelial nitric oxide synthase, a downstream enzyme of AMPK. NO-induced activation of AMPK was not affected by inhibition of LKB1, an AMPK kinase. In contrast, inhibition of calcium calmodulin-dependent protein kinase kinase abolished the effect of NO in HUVECs. NO-induced AMPK activation in HeLa S3 cells was abolished by either 1H-(1,2,4)-oxadiazole[4,3-a]quinoxalon-1-one, a potent inhibitor for guanylyl cyclase, or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM), an intracellular Ca(2+) chelator, indicating that NO-induced AMPK activation is guanylyl cyclase-mediated and calcium-dependent. Exposure of HUVECs or isolated mice aortas to either calcium ionophore A23187 or bradykinin significantly increased AMPK Thr-172 phosphorylation, which was abolished by N-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. Finally, A23187- or bradykinin-enhanced AMPK activation was significantly greater in aortas from wild type mice than those in the aortas of endothelial nitric oxide synthase knock-out mice. Taken together, we conclude that NO might act as an endogenous AMPK activator.
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PMID:Identification of nitric oxide as an endogenous activator of the AMP-activated protein kinase in vascular endothelial cells. 3192 76

The present study aimed to examine whether there is an altered regulation of local hormonal systems in the kidney following the treatment of glycyrrhizic acid (GA), the active ingredient in licorice. Male Sprague-Dawley rats were treated with GA for 3 weeks. The expression of mineralocorticoid receptor (MR) was determined in the kidney by immunoblotting and real-time polymerase chain reaction (PCR). The protein expression of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) was determined. The expression of atrial natriuretic peptide (ANP), natriuretic peptide receptor (NPR)-A and NPR-C was determined by real-time PCR. The activity of guanylyl cyclase was determined by the amount of cGMP generated in responses to sodium nitroprusside (SNP) or ANP. Following the GA treatment, systolic blood pressure was increased. The mRNA and protein expressions of MR were increased in the kidney. The protein expression of eNOS and iNOS was also increased. The expression of ANP mRNA was increased although that of NPR-A and NPR-C mRNA was not changed. The cGMP production provoked by either SNP or ANP was not changed. The increased expression of MR may contribute to GA-induced hypertension. The enhanced expression of NOS and ANP may play a compensatory role in GA-induced hypertension.
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PMID:Increased renal expression of nitric oxide synthase and atrial natriuretic peptide in rats with glycyrrhizic-acid-induced hypertension. 1869 94


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