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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to investigate whether interleukin (IL)-1 beta would stimulate nitric oxide (NO) production in cultured aortic vascular smooth muscle cells (VSMCs), and to determine the basic effect of the liberated NO on VSMC proliferation. NO production was estimated from nitrite concentration of culture medium in multi-well plates, determined by the Griess method. VSMCs were IL-1 beta-pretreated in insert cups, and co-cultured with untreated VSMC in the wells. 3H-thymidine (3H-Tdr) incorporation into the VSMC in wells was evaluated for VSMC proliferative activity. IL-1 beta stimulated NO production in VSMCs in a concentration-dependent manner. This effect was further enhanced by the addition of a membrane-permeable cyclic adenosine monophosphate derivative, dibutyryl cyclic AMP (db-cAMP), and was significantly reduced by concomitant use of an NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). IL-1 beta-pretreated VSMCs significantly inhibited 3H-Tdr incorporation of the co-cultured VSMC. This inhibitory effect was significantly enhanced by the addition of db-cAMP, while this inhibition was significantly decreased by preincubation with L-NAME, and was abolished in the L-arginine-free medium. These results suggest that, in human VSMC, IL-1 beta stimulates NO production that is enhanced by intracellular cAMP accumulation, and that the liberated NO inhibits further VSMC proliferation in an autocrine fashion.
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PMID:Autocrine growth inhibition of IL-1 beta-treated cultured human aortic smooth muscle cells: possible role of nitric oxide. 912 41

The participation of nitric oxide and vasoactive intestinal peptide (VIP) in the neurogenic regulation of bovine cerebral arteries was investigated. Nitrergic nerve fibers and ganglion-like groups of neurons were revealed by NADPH-diaphorase staining in the adventitial layer of bovine cerebral arteries. NADPH diaphorase also was present in endothelial cells but not in the smooth muscle layer. Double immunolabeling for neuronal nitric oxide synthase and VIP indicated that both molecules co-localized in the same nerve fibers in these vessels. Transmural nerve stimulation (200 mA, 0.2 milliseconds, 1 to 8 Hz) of endothelium-denuded bovine cerebral artery rings precontracted with prostaglandin F2 alpha, produced tetrodotoxin-sensitive relaxations that were completely suppressed by NG-nitro-L-arginine methyl ester (L-NAME) and by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline (ODQ), but were not affected by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22,536), nor by VIP tachyphylaxis induced by pretreatment with 1 mumol/L VIP. Transmural nerve stimulation also elicited increases in intracellular cyclic GMP concentration, which were prevented by L-NAME, and small decreases in intracellular cyclic AMP concentration. Addition of VIP to bovine cerebral artery rings without endothelium produced a concentration-dependent relaxation that was partially inhibited by L-NAME, ODQ, and SQ 22,536. The effects of L-NAME and SQ 22,536 were additive. VIP induced a transient increase in intracellular cyclic GMP concentration, which was maximal 1 minute after VIP addition, when the highest relaxation rate was observed, and which was blocked by L-NAME. It is concluded that nitric oxide produced by perivascular neurons and nerve fibers fully accounts for the experimental neurogenic relaxation of bovine cerebral arteries and that VIP, which also is present in the same perivascular fibers, acts as a neuromodulator by activating neuronal nitric oxide synthase.
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PMID:Neuronal nitric oxide synthase activation by vasoactive intestinal peptide in bovine cerebral arteries. 930 11

Human endothelial cells are injured by the action of leukocytes. We investigated the role of nitric oxide (NO) in the induction of injury to human pulmonary artery endothelial cells. NO has been a putative source of cytotoxic reactive oxygen species in some settings. Incubation of endothelial cells with neutrophils increased the release of lactate dehydrogenase activity and preloaded fura-2 from endothelial cells, indicating that neutrophils induce endothelial cell injury. This effect was augmented by treatment with carboxy-PTIO, which traps NO in the medium, or with L-NAME, an inhibitor of NO synthase. When endothelial cells were incubated with neutrophils stimulated by phorbol myristate acetate, an activator of protein kinase C, endothelial cell damage was further enhanced and the amount of NO in the medium was decreased. Dibutyryl cyclic AMP, a cell-permeable analogue of cyclic AMP, protected against neutrophil-induced endothelial cell injury and increased NO release into the medium. The effects of dibutyryl cyclic AMP were abrogated by treatment with H-89, a potent inhibitor of cyclic AMP-dependent protein kinase. The protective effect on neutrophil-induced endothelial cell injury by dibutyryl cyclic AMP was abolished by addition of carboxy-PTIO or L-NAME. Thus, our studies suggest that NO, presumably released from endothelial cells, protects against endothelial injury by activated neutrophils and the protective effect by cyclic AMP during coculture with activated neutrophils is mediated through the action of NO. However, when monocytes activated by lipopolysaccharide and IFN-gamma were used instead of neutrophils, endothelial cells were likewise injured, but a much higher level of NO was detected and injury was diminished by addition of carboxy-PTIO to the medium. These observations suggest that the high levels of NO released by activated monocytes contribute to endothelial injury, whereas low levels of NO protect endothelial cells against injury by neutrophils.
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PMID:The role of nitric oxide in human pulmonary artery endothelial cell injury mediated by neutrophils. 941 36

1. Linomide (N-phenylmethyl-1,2-dihydro-4-hydroxyl-1-methyl-2-oxoquinoline-3-carb oxa mide) inhibits vascular proliferation and has been proposed as an antiangiogenic drug. We have investigated the vascular effect of linomide in rabbit aortic and saphenous vein ring preparations and in rat cultured vascular smooth muscle cells (VSMCs). 2. Linomide (25-300 micrograms ml-1) did not alter the basal tone of the preparations. The drug induced a concentration-dependent relaxant effect in aortic rings with endothelium, preconstricted by noradrenaline (NA), 5-hydroxytryptamine (5-HT) and by the thromboxane mimetic U46619. 3. The degree of relaxation induced by linomide was significantly reduced by exposure to the cyclooxygenase inhibitors indomethacin (3 microM) and acetylsalicylic acid (500 microM), and was not influenced by pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (100 microM) in aortic rings with endothelium, preconstricted with NA. 4. Endothelium removal significantly reduced the relaxant response to linomide in aortic ring preparations. 5. A concentration-dependent relaxant response was observed also in rabbit saphenous vein preparations deprived of endothelium and preconstricted either by NA or U46619. The degree of relaxation obtained in a high potassium solution was consistently smaller than that observed in NA-pretreated venous preparations. 6. The vasorelaxant effect of linomide was consistently blunted by the adenylate cyclase inhibitor SQ 22536 (50 microM), both in intact aortic rings and in those deprived of endothelium. 7. In rat cultured vascular smooth muscle cells, linomide (100-200 micrograms ml-1) induced a significant increase in cyclic AMP levels, which was blocked by exposure to 50 microM SQ 22536. 8. In endothelium-deprived aortic ring preparations, the linomide-induced relaxant effect was greatly reduced in high potassium medium (KCl = 25 mM). Pretreatment with the ATP potassium channel inhibitor glibenclamide (3 microM) significantly reduced the linomide-induced relaxation. 9. The results show that linomide possesses a vasorelaxant effect which is attributable to both endothelium-dependent and -independent properties. While the former component of the drug's activity is apparently due to the release of a prostanoid from endothelial cells, the endothelium-independent mechanism involved in linomide relaxation is linked to cyclic AMP accumulation and to ATP-sensitive potassium channel activation in VSMCs.
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PMID:Vasorelaxant effects induced by the antiangiogenic drug linomide in aortic and saphenous vein preparations of the rabbit. 942 22

1. Arteriolar diameter and membrane voltage have been measured to investigate the actions of calcitonin gene-related peptide (CGRP) in rat irideal arterioles. 2. Activation of sensory nerves inhibited sympathetic vasoconstriction, reduced the accompanying 40-50 mV depolarization by 90% and caused a 4 mV hyperpolarization. 3. The inhibition of vasoconstriction was prevented by either preincubation in L-NAME (10 microM), to inhibit nitric oxide production, by preincubation in the cell-permeant adenylate cyclase inhibitor dideoxyadenosine (1 mM) or by preincubation in the ATP-sensitive potassium channel blocker glibenclamide (10 microM). The subsequent addition of a nitric oxide donor to the glibenclamide solution inhibited nerve-mediated vasoconstriction, suggesting that the potassium channel involvement preceded the production of nitric oxide. The small hyperpolarization was not affected by L-NAME. 4. Nerve-mediated vasodilatation persisted in the presence of L-NAME (10 microM) but was abolished with the CGRP1 receptor antagonist CGRPS-37. 5. In arterioles preconstricted with the alpha 2-adrenoceptor agonist UK-14304 (100 nM), exogenous CGRP caused a hyperpolarization and a dose-dependent vasodilatation, neither of which was affected by L-NAME (10 microM). 6. In arterioles preconstricted with 30 mM KCl, CGRP (10 nM) caused vasodilatation but not hyperpolarization, suggesting that the hyperpolarization was not causal to the vasodilatation. 7. Forskolin (30 nM), in the presence of L-NAME to present effects due to nitric oxide, caused vasodilatation. 8. These results suggest that CGRP inhibits sympathetic nerve-mediated vasoconstriction through sequential increases in cyclic AMP and nitric oxide, while vasodilatation results from increases in cyclic AMP alone. The production of nitric oxide, but not its mechanism of action, appears to be dependent on the activation of ATP-sensitive potassium channels. The possible sites of action of these two pathways are discussed.
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PMID:Pathway-specific effects of calcitonin gene-related peptide on irideal arterioles of the rat. 945 53

1 5-Hydroxytryptamine (5-HT; 1 nM - 100 microM) concentration-dependently inhibited the amplitude and frequency of spontaneous contractions in longitudinal and circular muscles of the porcine myometrium. The circular muscle (EC50; 68-84 nM) was more sensitive than the longitudinal muscle (EC50; 1.3-1.44 microM) to 5-HT. To characterize the 5-HT receptor subtype responsible for inhibition of myometrial contractility, the effects of 5-HT receptor agonists on spontaneous contractions and of 5-HT receptor antagonists on inhibition by 5-HT were examined in circular muscle preparations. 2 Pretreatment with tetrodotoxin (1 microM), propranolol (1 microM), atropine (1 microM), guanethidine (10 microM) or L-NAME (100 microM) failed to change the inhibition by 5-HT, indicating that the inhibition was due to a direct action of 5-HT on the smooth muscle cells. 3 5-CT, 5-MeOT and 8-OH-DPAT mimicked the inhibitory response of 5-HT, and the rank order of the potency was 5-CT>5-HT>5-MeOT>8-OH-DPAT. On the other hand, oxymethazoline, alpha-methyl-5-HT, 2-methyl-5-HT, cisapride, BIMU-1, BIMU-8, ergotamine and dihydroergotamine had almost no effect on spontaneous contractions, even at 10-100 microM. 4 Inhibition by 5-HT was not decreased by either pindolol (1 microM), ketanserin (1 microM), tropisetron (10 microM), MDL72222 (1 microM) or GR113808 (10 microM), but was antagonized by the following compounds in a competitive manner (with pA2 values in parentheses): methiothepin (8.05), methysergide (7.92), metergoline (7.4), mianserin (7.08), clozapine (7.06) and spiperone (6.86). 5 Ro 20-1724 (20 microM) and rolipram (10 microM) significantly enhanced the inhibitory response of 5-HT, but neither zaprinast (10 microM) nor dipyridamole (10 microM) altered the response of 5-HT. 6 5-HT (1 nM - 1 microM) caused a concentration-dependent accumulation of intracellular cyclic AMP in the circular muscle. 7 From the present results, the 5-HT receptor, which is functionally correlated with the 5-HT7 receptor, mediates the inhibitory effect of 5-HT on porcine myometrial contractility. This inhibitory response is probably due to an increase in intracellular cyclic AMP through the activation of adenylate cyclase that is positively coupled to 5-HT7 receptors.
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PMID:Involvement of 5-hydroxytryptamine7 receptors in inhibition of porcine myometrial contractility by 5-hydroxytryptamine. 948 4

1 Characteristics of cyclic GMP- and cyclic AMP-mediated relaxation in aortic segments of rats with chronic heart failure (CHF) and the effects of chronic treatment with an angiotensin I converting enzyme (ACE) inhibitor, trandolapril, were examined 8 weeks after coronary artery ligation. 2 Cardiac output indices of coronary artery-ligated and sham-operated rats were 125+/-8 and 189+/-10 ml min(-1) kg(-1), respectively (P<0.05), indicating the development of CHF at this period. 3 The maximal relaxant response of aortic segments to 10 microM acetylcholine in rats with CHF and sham-operated rats was 64.0+/-5.7 and 86.9+/-1.9%, respectively (P<0.05), whereas the relaxant response to sodium nitroprusside (SNP) remained unchanged. Tissue cyclic GMP content in rats with CHF was lower than that of sham-operated rats. 4 In endothelium-intact segments of rats with CHF, the maximal relaxant response to 10 microM isoprenaline (44.5+/-6.7%) was lower that sham-operated rats (81.3+/-2.5%, P<0.05) and the concentration-response curve for NKH477, a water-soluble forskolin, was shifted to the right without a reduction in the maximal response. Isoprenaline-induced relaxation of aortic segments was attenuated by NG-nitro-L-arginine methyl ester (L-NAME) in sham-operated rats, but not in rats with CHF. Relaxation to 30 microM dibutyryl cyclic AMP in rats with CHF (26.8+/-2.7%) was lower than that in sham-operated rats (63.4+/-11.8%, P<0.05). 5 Trandolapril (3 mg kg(-1) day(-1)) was orally administered from the 2nd to 8th week after the operation. Aortic blood flow of rats with CHF (38.5+/-3.6 ml min(-1)) was lower than that of sham-operated rats (55.0+/-3.0 ml min(-1)), and this reduction was reversed (54.1+/-3.4 ml min(-1)) by treatment with trandolapril. The diminished responsiveness described above was normalized in the trandolapril-treated rat with CHF (i.e., the maximal relaxation to acetylcholine, 94.7+/-1.0%; that to isoprenaline, 80.5+/-2.8%; that to dibutyryl cyclic AMP, 54.7+/-6.2%). However, aortic segments of trandolapril-treated rats with CHF, L-NAME did not attenuate isoprenaline-induced relaxation and the tissue cyclic GMP level was not fully restored, suggesting that the ability of the endothelium to produce NO was still partially damaged. 6 The results suggest that vasorelaxation in CHF, diminished mainly due to dysfunction in endothelial nitric oxide (NO) production and cyclic AMP-mediated signal transduction, was partially restored by long-term treatment with trandolapril. The mechanism underlying the restoration may be attributed in part to prevention of CHF-induced endothelial dysfunction.
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PMID:The effect of chronic treatment with trandolapril on cyclic AMP-and cyclic GMP-dependent relaxations in aortic segments of rats with chronic heart failure. 948 24

1. We recently demonstrated that intrathecal administration of prostaglandin E2 (PGE2) and PGF2alpha induced allodynia through a pathway that includes the glutamate receptor and nitric oxide (NO)-generating systems from pharmacological studies. In order to clarify the involvement of NO in prostaglandin-induced allodynia, we measured NO released from rat spinal cord slices by a chemiluminescence method. 2. PGE2 stimulated NO release from both dorsal and ventral regions all along the spinal cord. PGE2 stimulated the release within 10 min and increased it in a time-dependent manner. 3. The PGE2-induced NO release was observed at 100 nM-10 microM. PGF2alpha stimulated the release at concentrations higher than 1 microM, but PGD2 (up to 10 microM) did not enhance it. 4. 17-Phenyl-omega-trinor PGE2 (EP1 > EP3) and sulprostone (EP1 < EP3) were as potent as PGE2, but PGE1 was less potent, in stimulating NO release. While M&B 28767 (EP3) did not enhance the release, butaprost (EP2) stimulated it at 1 microM. The PGE2-evoked release was blocked by ONO-NT-012, a bifunctional EP1 antagonist/EP3 agonist. 5. The PGE2-evoked release was Ca2+-dependent and blocked by MK-801 (NMDA receptor antagonist) and L-NAME (NO synthase inhibitor). The release was also inhibited by PGD2 and dibutyryl-cyclic AMP. 6. The present study demonstrated that PGE2 stimulates NO release in the rat spinal cord by activation of NMDA receptors through the EP1 receptor, and supports our previous findings that the NO-generating system is involved in the PGE2-induced allodynia.
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PMID:Stimulation of nitric oxide release from rat spinal cord by prostaglandin E2. 953 17

The arterial wall is structurally and functionally compartmentalized. Each compartment is characterized by a specific cell type and by specific interactions. The endothelial compartment interacts with circulating blood, and the adventitial compartment with the surrounding tissue. The media, which contains the effector smooth muscle cells, perceives centrifugal messages from the endothelium and centripetal messages from metabolically active tissues, from adventitial nerve endings, and from peptides produced in the interstitium. The degree of contraction or relaxation of the vascular smooth muscle cells characterizes the general vasomotor tone, which governs the local blood pressure level and distributes the flow according to metabolic needs. The main physiologic vasoactive agent is nitric oxide (NO) and is produced by the endothelium. In disease states, other agents can become predominant in centrifugal parietal messages. NO is produced by type 3 NO synthase, an enzyme that is constitutively expressed by endothelial cells. The activity of this enzyme on its substrate, arginine, is regulated by the concentration of free calcium and by intracellular phosphorylations. Several peptides, including receptors, are coupled to the phospholipase C pathway in the endothelial cell; endothelial growth factors such as FGF and VEGF, enhance the activity of endothelial NO synthase. However, the main physiologic factor responsible for endothelial NO synthase activation is the shearing stress produced by friction of the flowing blood against the immobile vessel wall. This shearing stress constantly adjusts the diameter of conductance vessels to peripheral metabolic needs. Expression of endothelial NO synthase is modulated by the chronic effects of the same agents. NO has a vasodilating effect that is mediated by the generation of cyclic GMP. Cyclic GMP and cyclic AMP are the main second messengers in smooth muscle cell relaxation. NO binds to a heme-protein, soluble guanylate cyclase, that converts GMP to cyclic GMP. Kinase-G is the main target for cyclic GMP in the smooth muscle cell. Kinase-G phosphorylates phospholambans and releases the repumping activity of calcium ATPase. More importantly, kinase-G phosphorylates the protein G that links seven-domain membrane-spanning receptors to phospholipases, thus inhibiting coupling between the ligand-receptors interaction and the intracellular signaling process that leads to contraction. NO can relax the smooth muscle cell only in the presence of a preexisting contractile tone. Conversely, absence of NO enhances the preexisting contractile tone. All these notions can be analyzed via the experimental model of L-NAME-induced chronic NO synthase blockade in rats. The decrease in parietal cyclic GMP seen in this model is associated with an increase in contractile tone that translates into systemic arterial hypertension. The increase in contractile tone can be blocked by renin-angiotensin system inhibitors. Chronic blockade of NO production rapidly induces vascular wall phenotype changes that lead to renal failure, ischemic stroke, and fibrosis of target organs. These phenotype changes may be related to the increase in the oxidative potential of the various types of parietal cells, as suggested by the abnormal presence of inflammatory cells and by the increased expression of inflammation mediators including cyclooxygenase II, inducible NO synthase, and adhesion molecules such as ICAM and VCAM. This model therefore holds promise for elucidating interactions between NO and arteriosclerosis. NO system dysfunction is also seen in other cardiovascular disorders, including congestive heart failure.
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PMID:[Role of endothelial nitric oxide in the regulation of the vasomotor system]. 976 14

We investigated the relation between cyclic AMP (cAMP) and nitric oxide (NO) production, as well as the effect of NO on Na , K+-ATPase activity in the human neuroblastoma cell line SH-SY5Y. Two cAMP agonists, dibutyryl cAMP (DBC) and beraprost sodium (BPS), increased cAMP accumulation and NO production in a time and dose dependent manner at 50 mmol/l glucose. On the other hand, cellular sorbitol and myo-inositol contents and protein kinase C activity were not altered by DBC or BPS. A specific protein kinase A inhibitor, H-89, suppressed increases in nitrite/nitrate and cyclic GMP (cGMP) and protein kinase A activity stimulated by DBC or BPS. This finding suggests that cAMP stimulates NO production by activating protein kinase A via a pathway different from the sorbitol-myo-inositol-protein kinase C pathway. We observed that an NO donor, sodium nitroprusside, and an NO agonist, L-arginine, enhanced ouabain sensitive Na+, K+-ATPase activity at 50 mmol/l glucose. We also found that a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited Na+, K+-ATPase activity at 5 mmol/l glucose, and partially suppressed the enzyme activity stimulated by DBC or BPS. The results of this study suggest that cAMP regulates protein kinase A activity, NO production and ouabain sensitive Na+, K+-ATPase activity in a cascade fashion. The results also suggest that protein kinase A at least partially regulates Na+, K+-ATPase activity without mediation by NO in SH-SY5Y cells. We speculate that cAMP and NO are two important regulatory factors in the pathogenesis of diabetic neuropathy.
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PMID:cAMP regulates nitric oxide production and ouabain sensitive Na+, K+-ATPase activity in SH-SY5Y human neuroblastoma cells. 986 12


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