Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two important mediators of endothelium-dependent regulation of vascular smooth muscle tone and proliferation are nitric oxide (NO) and endothelin (ET-1). An imbalance between NO and ET-1 may contribute to the alterations in vascular tone characteristic of cardiovascular disease. The objective of this study was to determine whether NO regulates ET receptors in cultured rat superior mesenteric artery vascular smooth muscle cells (RVSMC). Chronic treatment of quiescent RVSMC with any one of three chemically dissimilar NO-generating drugs, S-nitroso-N-acetyl penicillamine (SNAP), sodium nitroprusside (SNP), and isosorbide dinitrate (ISDN) produced a significant dose- and time-dependent increase in the number of ET-A receptors, while concomitantly increasing the affinity of ET-1 for this receptor. This effect was mimicked by both 8-bromo-cGMP and 8-bromo-cAMP. The requirement of both protein and RNA synthesis and activation of a cAMP-dependent protein kinase (A-kinase) was demonstrated following inhibition of this regulation by cycloheximide, actinomycin D and KT5720 (a specific A-kinase inhibitor), respectively. In addition, the cytokine interleukin 1 beta (IL-1 beta) which induced NOS activity with subsequent NO synthesis in vascular smooth muscle, also caused a similar upregulation of ET receptors. This effect was attenuated in the presence of the specific NOS inhibitor, L-NAME. To assess the possible functional consequences of this NO-mediated upregulation, the effect of SNAP pretreatment on isolated vessel reactivity was determined. In both superior mesenteric artery and thoracic aorta rings, SNAP pretreatment caused a significant increase in the maximal force of contraction to ET-1. Collectively, these data suggest that NO regulates ET-A receptors in vitro through a cGMP-dependent mechanism via activation of the cAMP-dependent protein kinase. We conclude that a similar interaction between NO and ET-1 may be operational in vivo.
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PMID:Regulation of endothelin receptors by nitric oxide in cultured rat vascular smooth muscle cells. 860 Jan 50

This study was designed to test the hypothesis that active thermoregulatory vasodilation (AVD) is the result of a neurotransmitter-induced adenosine 3',5'-cyclic monophosphate (cAMP) pathway interacting with a nitric oxide-induced guanosine 3',5'-cyclic monophosphate (cGMP) pathway. Rabbits were instrumented for measurement of arterial pressure and ear blood flow (EBF) and the infusion of drugs. In four groups of conscious animals, whole-body heating increased EBF from 0.5 +/- 0.3 to 8.3 +/- 1.3 kHz. In group 1 (n = 6), N(omega)-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor, 10-40 mg) reduced EBF from 7.1 +/- 0.9 to 1.9 +/- 0.5 kHz. Subsequent infusion of 8-bromo-cGMP (a cGMP analog, 5-10 mg) returned EBF to 6.2 +/- 0.7 kHz. In group 2 (n = 3), (R)-p-adenosine 3',5'-cyclic monophosphothioate (a cAMP-dependent protein kinase inhibitor, 10 mg) reduced EBF to 1.6 +/- 0.4 kHz. In group 3 (n = 6), nerve blockade of the ear (procaine, 20 mg/ml, 1.5 ml) reduced EBF from 8.6 +/- 1.3 to 1.6 +/- 0.3 kHz. Subsequent infusion of 8-bromo-cAMP (a cAMP analog, 5-10 mg) returned EBF to 8.3 +/- 2.0 kHz. In group 4 (n = 6), the infusion of L-NAME caused EBF to fall from 9.0 +/- 1.1 to 1.2 +/- 0.3 kHz. Infusion of the cAMP phosphodiesterase inhibitor Ro 20-1724 (0.2-0.5 mg) raised EBF to 5.5 +/- 0.7 kHz. These results suggest that cGMP plays a permissive role in AVD and indicate that the transmitter acts through cAMP.
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PMID:The roles of cGMP and cAMP in active thermoregulatory vasodilation. 908 63

The purpose of this study was to investigate the role of endothelial nitric-oxide synthase (eNOS), cAMP, and p38 MAPK in tumor necrosis factor-alpha (TNF-alpha) expression induced by lipopolysaccharide (LPS). LPS dose- and time-dependently induced phosphorylation of p38 MAPK and TNF-alpha expression in neonatal mouse cardiomyocytes. TNF-alpha expression was preceded by p38 MAPK phosphorylation, and selective inhibition of p38 MAPK abrogated LPS-induced TNF-alpha expression. Deficiency in eNOS decreased basal and LPS-stimulated TNF-alpha expression in cardiomyocytes. NOS inhibitor l-NAME attenuated LPS-induced p38 MAPK phosphorylation and TNF-alpha production in wild-type cardiomyocytes, whereas NO donor 2,2'-(hydroxynitrosohydrazono)bis-ethanamine (DETA-NO) (2 microm) or overexpression of eNOS by adenoviral gene transfer restored the response of eNOS(-/-) cardiomyocytes to LPS. These effects of NO were mediated through cAMP-dependent pathway based on the following facts. First, deficiency in eNOS decreased basal levels of intracellular cAMP, and DETA-NO elevated intracellular cAMP levels in eNOS(-/-) cardiomyocytes. Second, a cAMP analogue 8-Br-cAMP mimicked the effect of NO in eNOS(-/-) cardiomyocytes. Third, either inhibition of cAMP or cAMP-dependent protein kinase attenuated LPS-stimulated p38 MAPK phosphorylation and TNF-alpha production in wild-type cardiomyocytes. In conclusion, eNOS enhances LPS-stimulated TNF-alpha expression in cardiomyocytes. Activation of p38 MAPK is essential in LPS-stimulated TNF-alpha expression. Moreover, the effects of NO on LPS-stimulated TNF-alpha expression are mediated through cAMP/cAMP-dependent protein kinase-dependent p38 MAPK pathway in neonatal cardiomyocytes.
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PMID:Endothelial nitric-oxide synthase enhances lipopolysaccharide-stimulated tumor necrosis factor-alpha expression via cAMP-mediated p38 MAPK pathway in cardiomyocytes. 1250 17

Adrenomedullin (AM) is a vasoactive hormone which exerts its action through cyclic adenosine monophosphate(cAMP) /cAMP-dependent protein kinase (PKA) cascade and intracellular Ca2+ mobilization. Recently, evidence has accumulated that AM plays a critical role in the regulation of vascular tone, remodeling and morphogenesis. And although numerous reports have examined the action of AM on cultured vascular cells, the results have not been consistent and have depended on the experimental conditions used. Accordingly, the purpose of this study was to clarify the effect of AM on the proliferation and migration of cultured endothelial cells. Our results revealed that AM promoted the growth and migration of endothelial cells (ECs). AM significantly promoted the proliferation of human umbilical vein endothelial cells (HUVECs) (56.0 +/- 8.7% over the controls at 10(-9) mol/l) and this stimulative effect was inhibited by two AM antagonists, AM(22-52) and calcitonin gene-related peptide (CGRP) (8-37). The number of HUVECs migrated to the lower surface of the transwell apparatus was also increased dose-dependently in the AM group (30.4 +/- 4.2% over the controls at 10(-7) mol/l), and this increase was suppressed by the two AM antagonists and by two PKA antagonists, adenosine 3'5'-cyclic monophosphorothioate Rp-isomer and myristoylated protein kinase A inhibitor amide 14-22. The promoting action of AM on endothelial migration was also suppressed by LY294002, an inhibitor for phosphatidylinositol 3-kinase, but not by N(G)-nitro-L-arginine-methyl ester (L-NAME), an antagonist for nitric oxide synthase (NOS). These results indicate that AM promotes proliferation and migration of ECs via a cAMP/PKA dependent pathway and lend support to the idea that AM exerts beneficial effects on vascular regeneration and might be used as a novel therapeutic strategy for patients with vascular disease.
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PMID:Adrenomedullin promotes proliferation and migration of cultured endothelial cells. 1263 Aug 17

This study tested the hypothesis that nitric oxide (NO) production contributes to relaxation induced by 3',5'-cyclic adenylate monophosphate (cAMP)-elevating agents and that high salt diet impairs this mechanism of relaxation. Relaxation response to isoproterenol but not sodium nitroprusside, a NO donor, was reduced in the thoracic aorta from rats that were placed on a high salt diet (8% NaCl; 60+/-4%, P<0.001). 1H-[1,2,4]oxadiazolol [4,3,-alpha]quinoxalin-1-one (ODQ, 10 microM), a soluble guanylate cyclase inhibitor, but not N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM), an inhibitor of NO synthase (NOS), attenuated the relaxation to isoproterenol (59+/-16%, P<0.01). High salt diet also impaired the relaxation responses to forskolin, an activator of adenylate cyclase, or 8-Bromo-cAMP (8-Br-cAMP). (N-[2-((p-bromocinnamyl)aminoethyl]-5-isoquinolinesulfonamide hydrochloride (H-89) (8 microM), an inhibitor of cAMP-dependent protein kinase, did not affect the relaxation produced by isoproterenol. These data suggest that high salt diet impairs relaxation response to isoproterenol by a dual mechanism involving diminished NO/NOS pathway linked to cGMP pathway and diminished cAMP pathway that is independent of protein kinase A.
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PMID:High salt diet modulates cAMP- and nitric oxide-mediated relaxation responses to isoproterenol in the rat aorta. 1292 69

Excessive excitatory action of glutamate and nitric oxide (NO) has been implicated in degeneration of striatal neurons. Evidence had been provided that Na+K+-ATPase might be involved in this process. Here we investigated whether glutamate-regulated messengers, such as NO and cyclic GMP, could modulate the activity of membrane Na+K+-ATPase. Our results demonstrated that NO donors sodium nitroprusside (SNP at 30 and 300 microM) and S-nitroso-N-acetylpenicillamine (SNAP at 200 microM) increased alpha2,3Na+K+-ATPase activity which was blocked by the NO chelator, haemoglobin and was independent of [Na+]. This regulation was associated with cGMP synthesis and mimicked by glutamate (300 microM) and 8-Br-cyclic GMP (4 mM). 8-Br-cGMP-induced stimulation of Na+K+-ATPase activity could be blocked by KT5823 (an inhibitor of cGMP-dependent protein kinase, PKG), but not by KT5720 (an inhibitor of cAMP-dependent protein kinase, PKA). N-Methyl-D-aspartate (NMDA) receptors appeared to be involved in the effect of glutamate, since MK-801 (NMDA receptor antagonist) produced a partial reduction in glutamate-induced activation of the enzyme. MK-801 was not synergistic to L-NAME (NOS inhibitor), suggesting that glutamate stimulates the NMDA-NOS pathway to activate alpha2,3 Na+K+-ATPase in rat striatum. This regulation was associated with cyclic GMP (but not cyclic AMP) synthesis. These data indicate the existence, in vitro, of a regulatory pathway by which glutamate, acting through NO and cGMP, can cause alterations in striatal alpha2,3 Na+K+-ATPase activity.
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PMID:Glutamate modulates sodium-potassium-ATPase through cyclic GMP and cyclic GMP-dependent protein kinase in rat striatum. 1562 18

Hydroxyurea is a cell-cycle-specific drug that has been used to treat myeloproliferative diseases and sickle cell anemia. We have recently shown that hydroxyurea, like nitric oxide (NO)-donor compounds, increased cGMP levels in human erythroid cells. We show now that hydroxyurea increases endothelial-cell production of NO; this induction of NO in human umbilical vein endothelial cells (HUVECs) and human bone marrow endothelial cell line (TrHBMEC) is blocked by competitive inhibitors of NO synthase (NOS), such as NG-nitro-L-arginine-methyl ester (L-NAME) and NG-nitro-L-arginine. It is dependent on cAMP-dependent protein kinase (PKA) and protein kinase B (PKB/Akt) activity. We found that hydroxyurea dose- and time-dependently induced rapid and transient phosphorylation of eNOS at Ser1177 in a PKA-dependent manner; inhibitors of PKB/Akt could partially abrogate this effect. In addition, hydroxyurea induced cAMP and cGMP levels in a dose-dependent manner, as well as levels of intracellular calcium in HUVECs. These studies established an additional mechanism by which rapid and sustained effects of hydroxyurea may affect cellular NO levels and perhaps enhance the effect of NO in myeloproliferative diseases.
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PMID:Hydroxyurea induces the eNOS-cGMP pathway in endothelial cells. 1652 93

Nitric oxide (NO) generated by neuronal NO synthase (nNOS) initiates penile erection, but has not been thought to participate in the sustained erection required for normal sexual performance. We now show that cAMP-dependent phosphorylation of nNOS mediates erectile physiology, including sustained erection. nNOS is phosphorylated by cAMP-dependent protein kinase (PKA) at serine(S)1412. Electrical stimulation of the penile innervation increases S1412 phosphorylation that is blocked by PKA inhibitors but not by PI3-kinase/Akt inhibitors. Stimulation of cAMP formation by forskolin also activates nNOS phosphorylation. Sustained penile erection elicited by either intracavernous forskolin injection, or augmented by forskolin during cavernous nerve electrical stimulation, is prevented by the NOS inhibitor L-NAME or in nNOS-deleted mice. Thus, nNOS mediates both initiation and maintenance of penile erection, implying unique approaches for treating erectile dysfunction.
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PMID:Cyclic AMP-dependent phosphorylation of neuronal nitric oxide synthase mediates penile erection. 2301 72

Neurological symptoms and cerebral abnormalities are commonly observed in patients with 3-hydroxy-3-methylglutaryl-CoA lyase (HMG lyase) deficiency, which is biochemically characterized by predominant tissue accumulation of 3-hydroxy-3-methylglutaric (HMG), 3-methylglutaric (MGA), and 3-methylglutaconic (MGT) acids. Since the pathogenesis of this disease is poorly known, the present study evaluated the effects of these compounds on the cytoskeleton phosphorylating system in rat brain. HMG, MGA, and MGT caused hypophosphorylation of glial fibrillary acidic protein (GFAP) and of the neurofilament subunits NFL, NFM, and NFH. HMG-induced hypophosphorylation was mediated by inhibiting the cAMP-dependent protein kinase (PKA) on Ser55 residue of NFL and c-Jun kinase (JNK) by acting on KSP repeats of NFM and NFH subunits. We also evidenced that the subunit NR2B of NMDA receptor and Ca(2+) was involved in HMG-elicited hypophosphorylation of cytoskeletal proteins. Furthermore, the antioxidants L-NAME and TROLOX fully prevented both the hypophosphorylation and the inhibition of PKA and JNK caused by HMG, suggesting that oxidative damage may underlie these effects. These findings indicate that the main metabolites accumulating in HMG lyase deficiency provoke hypophosphorylation of cytoskeleton neural proteins with the involvement of NMDA receptors, Ca(2+), and reactive species. It is presumed that these alterations may contribute to the neuropathology of this disease.
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PMID:NMDA Receptors and Oxidative Stress Induced by the Major Metabolites Accumulating in HMG Lyase Deficiency Mediate Hypophosphorylation of Cytoskeletal Proteins in Brain From Adolescent Rats: Potential Mechanisms Contributing to the Neuropathology of This Disease. 2617 40