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)

Nitric oxide (NO) is an important signal substance in cell-cell communication and can induce relaxation of blood vessels by activating guanylate cyclase in smooth muscle cells (SMCs). NO is synthesized from L-arginine by the enzyme NO synthase, which is present in endothelial cells. It was recently shown that SMCs may themselves produce NO or an NO-related compound. We have studied NO production and its effects on energy metabolism in cultured rat aortic smooth muscle cells. It was observed that the cytokines, interferon-gamma and tumor necrosis factor-alpha, synergistically induced an arginine-dependent production of NO in these cells. This was associated with an inhibition of complex I (NADH: ubiquinone oxidoreductase) and complex II (succinate: ubiquinone oxidoreductase) activities of the mitochondrial respiratory chain, suggesting that NO blocks mitochondrial respiration in these cells. Lactate accumulated in the media of the cells, implying an increased anaerobic glycolysis, but there was no reduction of viability. An NO-dependent inhibition of mitochondrial respiration and a switch to anaerobic glycolysis would reduce energy production of the SMCs. This would in turn reduce the contractile capacity of the cell and might represent another NO-dependent vasodilatory mechanism. It could be of particular importance in inflammation, since cytokines released by inflammatory cells may induce autocrine NO production in SMCs.
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PMID:Interferon-gamma and tumor necrosis factor synergize to induce nitric oxide production and inhibit mitochondrial respiration in vascular smooth muscle cells. 139 84

Recent evidence has shown that activation of the N-methyl-D-aspartate receptor mediates the thermal hyperalgesia produced in a model of neuropathic pain. As the acute nociceptive effects of N-methyl-D-aspartate have been reported to be mediated through production of nitric oxide and activation of soluble guanylate cyclase, these experiments were designed to determine whether the thermal hyperalgesia produced in a rat model of neuropathic pain is also mediated through the production of nitric oxide and activation of soluble guanylate cyclase. Loose ligation of the sciatic nerve with chromic gut sutures, but not bilateral sham rats, demonstrated evidence of a marked thermal hyperalgesia on day 3 post-surgery. In bilateral sham rats, intrathecal administration of either an alternate substrate for nitric oxide synthase, NW-nitro-L-arginine methyl ester, or the soluble guanylate cyclase inhibitor, Methylene Blue, did not produce any change in thermal nociceptive withdrawal latencies. These same treatments blocked the thermal hyperalgesia in rats with chromic gut ligatures for a period of 2 and 4 h, respectively. These results suggest that a sustained production of nitric oxide and subsequent activation of soluble guanylate cyclase in the lumbar spinal cord mediate the thermal hyperalgesia produced in a model of neuropathic pain in the rat.
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PMID:Nitric oxide mediates the thermal hyperalgesia produced in a model of neuropathic pain in the rat. 140 61

Coculture of endothelial cells with atrial cells (R. A. Lew and A. J. Baertschi. Biochem. Biophys. Res. Commun. 163: 701-709, 1989) increased atrial natriuretic factor (ANF) release to 205 +/- 15% (n = 33 experiments) of basal secretion (2.02 +/- 0.33 ng/ml). Stimulation of ANF release by endothelial cells was significantly reduced (P < 0.05) by addition of the calcium channel antagonist nicardipine (Nic, 100 nM; by 69 +/- 4%), the guanylate cyclase activator sodium nitroprusside (SNP, 1 microM; by 97 +/- 27%), or acetylcholine (ACh, 10 microM; by 55 +/- 13%). Endothelial cell-conditioned medium elicited a 62 +/- 10% (n = 10) increase in ANF release. Rat and porcine endothelin (0.1-100 nM) each elicited a dose-dependent increase in ANF release [up to 84 +/- 14% (n = 18) over baseline]. The activity of conditioned medium was not affected by heat or trypsin treatment, but was significantly reduced by addition of Nic or SNP and was attenuated by ACh. Stimulation of ANF by 1 nM synthetic rat or porcine endothelin was also unaffected by heat or trypsin but was significantly reduced by Nic, SNP, and ACh. Addition of endothelin-specific antiserum abolished the ANF stimulatory activity of endothelial cell-conditioned medium. Neither inhibition of superoxide anion by superoxide dismutase nor inhibition of endothelium-derived nitric oxide production by NG-monomethyl-L-arginine affected the ANF release from coculture. Thus endothelial cells release a heat-stable, diffusible ANF stimulatory factor, which is not endothelium-derived relaxing factor or superoxide anion but is biologically and immunologically similar to endothelin.
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PMID:Endothelium-dependent ANF secretion in vitro. 141 54

It has been shown that endothelium-derived relaxing factor (EDRF) may inhibit platelet aggregation in vitro through activation of platelet-soluble guanylate cyclase. To assess whether EDRF may also affect platelet function in vivo, intravascular platelet aggregation was initiated by placing an external constrictor around endothelially injured rabbit carotid arteries. Carotid blood flow velocity was measured continuously by a Doppler flow probe placed proximal to the constrictor. After placement of the constrictor, cyclic flow reductions (CFRs), due to recurrent platelet aggregation, developed at the site of the stenosis. After CFRs were observed for 30 minutes, a solution of authentic nitric oxide (NO, n = 10) was infused into the carotid artery via a small catheter placed proximally to the stenosis. Before infusion of NO, CFR frequency averaged 18.3 +/- 2.9 cycles per hour, and CFR severity (lowest carotid blood flow as percentage of baseline values) was 6 +/- 1%. NO completely inhibited CFRs in all animals, as shown by the normal and constant pattern of carotid blood flow (CFR frequency, 0 cycles per hour, p < 0.001; carotid blood flow, 92 +/- 5%, p = NS versus baseline). These effects were transient; CFRs were restored spontaneously within 10 minutes after cessation of NO infusion. After CFRs returned, S-nitroso-cysteine (S-NO-cys), a proposed form of EDRF, was infused into the carotid artery. S-NO-cys also abolished CFRs in all animals but at a significantly lower dose than NO (0.3 +/- 0.1 versus 12 +/- 4 nmol/min). The role of endogenously released EDRF in modulating in vivo platelet function was then tested in additional experiments. In 10 animals, endogenous release of EDRF was stimulated by infusing acetylcholine into the aortic root during CFRs. Infusion of acetylcholine was also associated with a complete inhibition of CFRs, similar to that observed during exogenous infusion of NO or S-NO-cys. These antithrombotic effects of acetylcholine were completely lost when EDRF synthesis was prevented by administration of the L-arginine analogue NG-monomethyl L-arginine (L-NMMA). Furthermore, in six additional rabbits the basal release of EDRF was blocked by L-NMMA after CFRs had been previously abolished with aspirin or the combination of aspirin and ketanserin, a serotonin S2 receptor antagonist. L-NMMA caused restoration of CFRs in all animals, indicating that even the basal release of EDRF is important in modulating platelet reactivity in vivo. Taken together, the data of the present study demonstrate that endogenous EDRF might importantly contribute to the modulation of platelet function in vivo.
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PMID:Endothelium-derived relaxing factor modulates platelet aggregation in an in vivo model of recurrent platelet activation. 142 38

The endothelium-derived relaxing factor, probably NO, is a potent vasodilator that mediates the vasodilating action of acetylcholine (ACh). We studied whether NO participates in the cholinergic cerebrovasodilation elicited by stimulation of the cerebellar fastigial nucleus (FN). Rats were anesthetized with halothane and ventilated. FN or pontine reticular formation (PRF) were stimulated through microelectrodes. Hypertension was prevented by spinal cord transection with arterial pressure maintained by intravenous phenylephrine. Cerebral blood flow (CBF) was continuously monitored through a cranial window over the sensory cortex by a laser-Doppler probe. The window was superfused with Ringer solution (pH 7.3-7.4; 37 degrees C). During Ringer superfusion FN stimulation (100 microA; 50 Hz) increased CBF by 90 +/- 7% (n = 27; P < 0.001, analysis of variance and Tukey's test) and PRF stimulation (100 microA; 100 Hz) by 128 +/- 18% (P < 0.001; n = 9). Superfusion with the guanylyl cyclase inhibitor methylene blue (MB) (1 mM) attenuated the CBF increase elicited by FN stimulation by 77 +/- 3% (n = 22; P < 0.001). MB did not affect the CBF increase elicited by PRF stimulation (+98 +/- 18%; n = 9; P > 0.05). Similarly, superfusion with the NO-synthase inhibitor nitro-L-arginine (L-NA) attenuated the CBF increase elicited by FN stimulation (-67 +/- 3%; n = 14; P < 0.001 from Ringer) but not PRF stimulation (P > 0.05; n = 9). The CBF increases elicited by FN stimulation were not affected by the inactive isomer of nitroarginine, D-NA (P > 0.05; n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide participates in the cerebrovasodilation elicited from cerebellar fastigial nucleus. 144 34

1. The role of the endothelium as an effector of the neurogenic cholinergic vasodilatation in submucosal arterioles of the guinea-pig ileum was investigated by measuring changes in arteriolar diameter in response to exogenous application of muscarine or electrical stimulation of the submucosal ganglia. 2. NG-Monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, competitively inhibited the vasodilatation produced by muscarine in arterioles which had been preconstricted with the prostaglandin analogue U46619. L-Arginine (10 mM), but not D-arginine (10 mM), prevented the inhibition by L-NMMA. 3. Neither tetrodotoxin (TTX, 1 microM), nor the cyclo-oxygenase inhibitor, indomethacin (10 microM), altered the muscarinic vasodilatation or the inhibitory effect of L-NMMA. 4. Sodium nitroprusside (SNP), an activator of the soluble guanylate cyclase, dilated the arterioles in a concentration-dependent manner. This vasodilatation was unaffected by L-NMMA but was abolished by the guanylate cyclase inhibitor, methylene blue (10 microM). In addition, methylene blue antagonized the muscarinic vasodilatation to a similar degree as did L-NMMA. 5. The vasodilatation produced by ganglionic stimulation (10 Hz, 10 s) was blocked by TTX and the muscarinic receptor antagonist, 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP, 1 microM). The neurally evoked vasodilatation was inhibited by 70% in the presence of L-NMMA; this inhibition was prevented by L-arginine. Methylene blue inhibited the neurogenic vasodilatation to the same extent as did L-NMMA. 6. These results show that arteriolar vasodilatation by muscarine is mediated mainly through the release of NO formed from L-arginine; the origin of the L-arginine appears to be the endothelium. These results also demonstrate that acetylcholine released from submucosal nerves onto submucosal blood vessels reaches the endothelium to cause the release of NO formed from L-arginine; the endothelial-derived NO dilates the arteriole.
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PMID:Acetylcholine released from guinea-pig submucosal neurones dilates arterioles by releasing nitric oxide from endothelium. 146 42

1. The effects of NG-nitro-L-arginine (L-NNA), NG-nitro-L-arginine methyl ester (L-NAME), haemoglobin and methylene blue have been examined on vascular reactivity in the rat isolated caudal artery. The effects of L-NNA and sodium nitroprusside were also investigated on the stimulation-induced (S-I) efflux of noradrenaline in the rat caudal artery. 2. L-NNA (10 microM) and L-NAME (10 microM) significantly attenuated the vasodilator responses to acetylcholine (1 nM-1 microM), but had no effect on vasodilator responses to papaverine (1-100 microM). 3. Vasoconstrictor responses to sympathetic nerve stimulation (3 Hz, 10 s), noradrenaline (0.01-1 microM), methoxamine (1-10 microM), 5-hydroxytryptamine (0.01-0.3 microM), phenylephrine (0.1-10 microM), endothelin-1 (10 nM) and KCl (40 mM) were significantly enhanced by 10 microM L-NNA. L-NAME (10 microM) caused a significant enhancement of vasoconstrictor responses to noradrenaline and sympathetic nerve stimulation in endothelium-intact, but not in endothelium-denuded tissues. 4. Haemoglobin and methylene blue (both 10 microM) enhanced the vasoconstrictor responses to sympathetic nerve stimulation and noradrenaline. The enhancements were absent in endothelium-denuded arterial segments. 5. In endothelium-denuded arterial segments precontracted with phenylephrine, the vasodilator responses to the nitric oxide donor, sodium nitroprusside (0.1-300 nM) were decreased by increasing the level of precontraction. 6. L-NNA (10 microM) had no effect on the S-I efflux of radioactivity from arteries in which transmitter stores had been labelled with [3H]-noradrenaline. 7. These results suggest that endothelial nitric oxide attenuates vasoconstrictor responses in the rat caudal artery through activation of soluble guanylate cyclase to decrease smooth muscle contractility. Therefore, the findings provide evidence that nitric oxide acts as a functional antagonist to oppose vasoconstriction.
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PMID:Attenuation of vasoconstriction by endogenous nitric oxide in rat caudal artery. 146 34

We tested the hypothesis that tumor necrosis factor-alpha (TNF-alpha) increases pulmonary vasoconstriction by decreases in nitric oxide- (NO) dependent vasodilation. Lungs were isolated from guinea pigs 18 h after intraperitoneal injection of either TNF-alpha (1.60 x 10(5) U/kg) or control. U-46619 (365 mM/min) caused increases in pulmonary arterial and capillary pressures, pulmonary arterial and venous resistances, and lung weight. TNF-alpha augmented the U-46619-induced increases in pulmonary arterial and capillary pressures, pulmonary arterial and venous resistances, and lung weight. Methylene blue (1 microM), which inhibits the activation of soluble guanylate cyclase by NO, had an effect similar to TNF-alpha on the pulmonary response to U-46619 alone but was not additive to the effect of TNF-alpha. NG-monomethyl-L-arginine (270 microM), an inhibitor of NO generation, also enhanced the response to U-46619. Lung effluent levels of nitrite, the oxidation product of NO, were reduced after treatment with either TNF-alpha or NG-monomethyl-L-arginine compared with U-46619 alone. In addition, lungs isolated after TNF-alpha treatment showed decreased vasodilation in response to acetylcholine (10(-8)-10(-5) M) compared with control; however, vasodilation in response to L-arginine (10 mM) and nitroprusside (10(-6.3) and 10(-6) M), agents that promote NO release, was not decreased in TNF-alpha-treated lungs. The data indicate that TNF-alpha induces an increase in vascular constriction in response to U-46619 and a decrease in vasodilation in response to acetylcholine. The mechanism for the TNF-alpha-induced alteration in pulmonary vascular reactivity may be decreased generation of NO.
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PMID:TNF-alpha augments pulmonary vasoconstriction via the inhibition of nitrovasodilator activity. 149 Sep 62

We examined the effect of methylene blue (MB), a putative inhibitor of guanylate cyclase (GC) activation by endothelium-derived relaxing factor (EDRF) and nitrovasodilator compounds, on vascular tone and reactivity to vasoactive substances in the isolated, blood-perfused canine lower left lung lobe. Lobar vascular resistance was partitioned into arterial and venous segments by venous outflow occlusion. Because MB did not alter vasoconstriction to either serotonin or acetylcholine (P greater than 0.05) except after cyclooxygenase inhibition (COI), we determined the effectiveness of MB as an inhibitor of GC activation by nitrovasodilators. Lobes were given graded bolus doses of nitroglycerin (GTN), sodium nitroprusside (SNP), and bradykinin (BK) at baseline vascular tone, after COI, and after vascular tone was raised by either U-46619, a thromboxane analogue, or MB infusion. GTN and BK but not SNP induced dose-dependent vasodilation when vascular tone was raised by U-46619. However, when vascular tone was increased to a similar level by 30 mg MB and 0.5 mg/min infusion, vasodilation to GTN, SNP, and BK was enhanced from U-46619 infusion. In contrast to MB, NG-nitro-L-arginine, a putative inhibitor of EDRF synthesis, diminished vasodilation to BK in cyclooxygenase-inhibited lobes with elevated vascular tone. Because MB potentiated vasodilation to GTN, SNP, and BK, it is questionable whether MB is an effective inhibitor of vasodilation to nitrovasodilators or BK in the isolated, blood-perfused canine lung.
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PMID:Effect of methylene blue on vasoreactivity in dog lung. 151 Jan 56

The endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) or a closely related nitrosothiol derivative. It is formed from the amino acid, L-arginine. NO is rapidly inactivated locally and is instantly destroyed by haemoglobin when released into the blood stream. EDRF-NO as well as NO generated from vasodilator nitrates act by activation of soluble guanylate cyclase, elevating cellular cyclic GMP levels, causing vasodilatation and inhibition of platelet aggregation. Endothelium-dependent vasodilatation is attenuated in hypertension, atherosclerosis and diabetes. This is due to either loss of endothelium or deficient formation of EDRF-NO. In these conditions, therapy with exogenous nitrates may substitute for a failing endogenous mechanism.
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PMID:Endogenous and exogenous nitrates. 155 42


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