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)

Guanosine 3',5'-cyclic monophosphate (cGMP) is an important second messenger in many biological systems including vascular smooth muscle where it mediates relaxation. Cellular levels of cGMP are regulated primarily by three enzymes; nitric oxide (NO) synthase, soluble guanylate cyclase, and cGMP-phosphodiesterase. Basal cGMP levels of isolated endothelium intact porcine pulmonary vein are five fold higher than in pulmonary artery. The objective of this study was to investigate possible reasons for this difference. Therefore, we compared NO synthase activity of pulmonary vein with artery and used pharmacologic approaches to compare soluble guanylate cyclase and phosphodiesterase activities in these vessels. NO synthase activities of pulmonary vein and artery were measured by monitoring the conversion of exogenous L-[14C]arginine to L-[14C]citrulline and by quantifying NO formation from endogenous L-arginine. Rates (pM/min per mg protein) of basal L-citrulline and NO formation from endothelium intact pulmonary vein (29.0 +/- 4.8 and 44 +/- 7.1, respectively) were significantly higher than from artery (8.3 +/- 2.2 and 17.1 +/- 3.3). Western blot analysis indicated higher constitutive NO synthase protein in the vein than in artery. N-nitro-L-arginine (0-100 microM), a potent inhibitor of NO synthase, induced contractions of the pulmonary vein which were significantly higher than those of the artery. N-nitro-L-arginine (5 and 20 microM) in the presence of phosphodiesterase inhibitors, decreased basal cGMP levels of endothelium intact blood vessels. In endothelium denuded pulmonary vein and artery, basal cGMP levels were not different from each other, but increased significantly following stimulation of soluble guanylate cyclase with exogenous NO. In the presence of both non-specific and specific cGMP phosphodiesterase inhibitors, exogenous NO-induced cGMP levels of endothelium denuded tissues were not significantly different from each other. However, in the absence of the phosphodiesterase inhibitors, exogenous NO-induced cGMP was significantly less in the artery than in the vein. These results suggest that (I) the intact porcine pulmonary vein contains higher levels of NO synthase activity than pulmonary artery, and that (II) the soluble guanylate cyclase activities in pulmonary vein and artery are equally responsive to NO, and finally (III) pulmonary artery expresses greater phosphodiesterase activity than vein. Higher NO synthase and lower phosphodiesterase activity may explain the greater accumulation of cGMP in the pulmonary vein compared to the artery.
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PMID:Factors contributing to differences in the regulation of cGMP in isolated porcine pulmonary vessels. 968 10

In recent years, nitric oxide (NO), a single but highly reactive molecule has become known as the central point of many researchs. NO is synthesized by the enzyme nitric oxide synthase (NOS) in mammals from the amino-acid L-arginine. The products of L-arginine oxidation by NOS are L-citrulline and NO. Nitric oxide has a very short half life, is lipid soluble, reacts easily with several enzymatic systems, and is produced by a wide amount of cells. At least, three kinds of enzymes NOS have been described: two of them are calcium-dependent and continuously present in select cells (constitutive NOS, cNOS). One cNOS isoform is present in the cytosol of neuronal cells, while the other isoform is present in membrane-bound form, in endothelial cells. cNOS produces small quantities of NO, following stimulation by specific agonist. NO produced by cNOS frequently mediates cellular communications and cellular signaling. A third isoform is calcium-independent, is not present in unstimulated cells, and produces large quantities of NO following stimulation of the appropriate cell with cytokines or LPS (inducible NOS, iNOS). NO is a mediator of both physiological and pathological process. It acts directly on its targets, one of them, maybe the most important, is the soluble guanylate cyclase, and produces a variety of biological effects, ranged from cytoprotection to cytotoxicity. An analysis of the biochemistry and physiology of NO is the focus of this review, together with its biological action and potential therapeutical implications.
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PMID:[Physiological and physiopathological aspects of nitric acid in mammalian tissues]. 970 23

1. Vascular endothelium plays a pivotal role in the control of vascular tone through the release of vasoactive factors such as EDRF (NO). 2. The aim of this study was to investigate whether the addition of exogenous L-citrulline, the byproduct of the NO-synthesis, could relax vascular smooth muscle. 3. L-citrulline relaxed both endothelium-denuded and endothelium-intact rabbit aortic rings precontracted with noradrenaline 10(-6) M (maximum relaxations induced by L-citrulline 10(-8) M were 74.1+/-5.2% vs 51.3+/-2.8% in endothelium-denuded and endothelium-intact arteries, respectively). 4. This relaxant effect was enhanced by zaprinast (a phosphodiesterase type 5 inhibitor) and inhibited by HS-142-1 (a particulate guanylate cyclase inhibitor) and by apamin (a K(Ca)-channel blocker). 5. L-citrulline (10(-13)-10(-8) M) increased cGMP levels in aortic rings (maximum value with L-citrulline 10(-8) M was 0.165+/-0.010 pmol cGMP mg(-1) of tissue vs 0.038+/-0.009 pmol mg(-1) of tissue in basal). 6. L-citrulline as well as NO were released from endothelial cells in culture stimulated with ACh. The values were 6.50+/-0.50 microM vs 2.30+/-0.20 microM (stimulated with ACh and basal respectively) for L-citrulline and 4.22+/-0.10 microM vs 0.87+/-0.26 microM (stimulated with ACh and basal respectively) for NO. 7. These results suggest that L-citrulline could be released together with NO from endothelium and may have actions complementary to those of NO in the control of vascular smooth muscle relaxation.
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PMID:Relaxant effects of L-citrulline in rabbit vascular smooth muscle. 977 59

It is believed that nitric oxide (NO) plays a significant role in migraine attacks. This molecule is formed due to the conversion of L-arginine into L-citrulline. The target receptor for NO is ferrum in the heme group of cytoplasmic guanyl cyclase, the enzyme catalyzing cyclic guanosine monophosphate (cGMP) formation. To confirm this hypothesis, cGMP and nitrite level in the blood serum were measured in patients with migraine. The group under study included 37 subjects suffering from migraine with and without aura and 40 normal control subjects. The cGMP was measured during a migraine attack and 60 min following the administration of sumatriptan 6 mg subcutaneously. A statistically significant increase in cGMP level was observed in patients during a migraine attack compared to the controls. This level decreased after the administration of sumatriptan, but it was still higher than in the controls. No correlation was found between the increased cGMP level and pain intensification with clinical symptoms of migraine. The results suggest the participation of biochemical changes in migraine pathogenesis in the L-arginine-NO-cGMP pathway.
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PMID:Level of nitric oxide-dependent cGMP in patients with migraine. 987 87

Endothelium injury plays an important role in atherosclerosis. Damage to the endothelium results in vascular smooth muscle cell proliferation. Natriuretic peptides present a potent antimitogenic action, mediating their biological effects via the binding of guanylate cyclase-linked atrial natriuretic peptide (ANP) receptor and the production of cyclic GMP. In a previous study, we demonstrated that L-citrulline, the by-product of nitric oxide synthesis, could relax rabbit aortic rings by stimulating the guanylate cyclase-linked ANP receptor. In this work, we investigated the effect of L-citrulline on vascular smooth muscle cell proliferation. L-Citrulline (10(-8) M) significantly decreased rat aortic (A10 cell line) vascular smooth muscle proliferation. The percentage of inhibition exerted by L-citrulline on days 3, 5, and 7 of the proliferation curve was 20.0 +/- 0.5%, 37.5 +/- 8.3%, and 28. 5 +/- 7.2%, respectively. In addition, L-citrulline also inhibited serum-induced DNA synthesis, measured as 5-bromo-2'-deoxyuridine incorporation. 5-Bromo-2'-deoxyuridine incorporation into nuclei of vehicle-treated cells was 40.5 +/- 2.4%, whereas in L-citrulline-treated cells the percentage decreased to 36.0 +/- 4.1%, 29.1 +/- 2.0% (P <.01, n = 4), 30.5 +/- 2.4% (P <.05, n = 4), and 23.1 +/- 0.5% (P <.001, n = 4) for 10(-10), 10(-9), 10(-8), and 10(-7) M, respectively. Zaprinast, a phosphodiesterase type V inhibitor, enhanced 5-bromo-2'-deoxyuridine incorporation in serum-stimulated cells. Moreover, L-citrulline inhibition of serum-stimulated DNA synthesis was abolished by HS-142-1 (10(-5) M), an ANP receptor antagonist. In another group of experiments, L-citrulline was shown to increase intracellular cyclic GMP levels from 2.1 +/- 0.2 pmol of cGMP/mg protein to 4.1 +/- 0.1 for L-citrulline (10(-8) M) (P <.001, n = 3). These findings suggest that L-citrulline decreases vascular smooth muscle cell proliferation in the A10 cell line by acting on DNA synthesis by mechanisms that involve the ANP receptor.
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PMID:L-Citrulline, the by-product of nitric oxide synthesis, decreases vascular smooth muscle cell proliferation. 1038 92

Nitric oxide (NO) is thought to play an important role in the regulation of neonatal pulmonary vasculature. It has been suggested that neonates with pulmonary hypertension have a defective NO pathway. Therefore, we measured in 1-day-old piglets exposed to hypoxia (fraction of inspired O(2) = 0.10) for 3 or 14 days to induce pulmonary hypertension 1) the activity of NO synthase (NOS) via conversion of L-arginine to L-citrulline and the concentration of the NO precursor L-arginine in isolated pulmonary vessels, 2) the vasodilator response to the NO donor 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1) and the cGMP analog 8-bromo-cGMP in isolated perfused lungs, and 3) the production of cGMP in response to SIN-1 in isolated perfused lungs. After 3 days of exposure to hypoxia, endothelial NOS (eNOS) activity was unaffected, whereas, after 14 days of hypoxia, eNOS activity was decreased in the cytosolic fraction of pulmonary artery (P < 0.05) but not of pulmonary vein homogenates. Inducible NOS activity was decreased in the cytosolic fraction of pulmonary artery homogenates after both 3 (P < 0.05) and 14 (P < 0.05) days of hypoxia but was unchanged in pulmonary veins. Pulmonary artery levels of L-arginine were unaffected by hypoxic exposure. After 3 days of exposure to hypoxia, the reduction in the dilator response to SIN-1 (P < 0.05) coincided with a decrease in cGMP production (P < 0.005), suggesting that soluble guanylate cyclase activity may be altered. When the exposure was prolonged to 14 days, dilation to SIN-1 remained decreased (P < 0.05) and, although cGMP production normalized, the dilator response to 8-bromo-cGMP decreased (P < 0.05), suggesting that, after prolonged exposure to hypoxia, cGMP-dependent mechanisms may also be impaired. In conclusion, neonatal hypoxia-induced pulmonary hypertension is associated with multiple disruptions in the NO pathway.
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PMID:Decreased synthesis and vasodilation to nitric oxide in piglets with hypoxia-induced pulmonary hypertension. 1066 11

Nitric oxide synthase (NOS) catalysis results in formation of NO or superoxide (O(2)(-.)) depending on the presence or absence of the cofactor tetrahydrobiopterin (BH4). In the absence of O(2)(-.) scavengers, net NO formation cannot be detected even at saturating BH4 concentrations, which is thought to be due to O(2)(-.) production by BH4 autoxidation. Because the N-5-methylated analogue of BH4 (5-Me-BH4) sustains NOS catalysis and is autoxidation-resistant, net NO formation by the neuronal isoform of NOS (nNOS) can be observed at saturating 5-Me-BH4 concentrations. Here we compare the effects of 5-Me-BH4 on L-citrulline formation, NADPH oxidation, H(2)O(2) production and soluble guanylate cyclase (sGC) stimulation. All activities were stimulated biphasically (EC(50) approx. 0.2 microM and more than 1 mM), with an intermediate inhibitory phase at the same pterin concentration as that required for net NO generation and sGC stimulation (4 microM). Concomitantly with inhibition, the NADP(+)/L-citrulline stoichiometry decreased from 2.0 to 1.6. Inhibition occurred only at high enzyme concentrations (IC(50) approx. 10 nM nNOS) and was antagonized by oxyhaemoglobin and by BH4. We ascribe the first stimulatory phase to high-affinity binding of 5-Me-BH4. The inhibitory phase is due to low-affinity binding, resulting in fully coupled catalysis, complete inhibition of O(2)(-.) production and net NO formation. At high enzyme concentrations and thus high NO levels, this causes autoinhibition. NO scavenging by 5-Me-BH4 at concentrations above 1 mM, resulting in the antagonization of inhibition of NOS, explains the second stimulatory phase. In agreement with these assignments 5-Me-BH4 was found to stimulate formation of a haem-NO complex during NOS catalysis. The observation of inhibition with 5-Me-BH4 but not with BH4 implies that, unless O(2)(-.) scavengers are present, a physiological role for NO-induced autoinhibition is unlikely.
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PMID:Nitric oxide-induced autoinhibition of neuronal nitric oxide synthase in the presence of the autoxidation-resistant pteridine 5-methyltetrahydrobiopterin. 1074 77

The study was prompted by the report of Ruiz E. & Tejerina T., 1998 describing endothelium-independent relaxation by L-citrulline via activation of particulate guanylate cyclase. We compared the effects of L-citrulline and L-arginine in isolated aortic rings of rats and in isolated aortic, carotid and femoral artery rings of rabbits. No significant relaxation to either L-citrulline or L-arginine was found in the concentration range of 10(-12) to 10(-3) M, while 3-morpholinosydnonimine hydrochloride (SIN-1, 10(-6) M) relaxed vascular tissues. This study does not support the conclusion that L-citrulline has direct vasorelaxing action on vascular smooth muscle.
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PMID:Citrulline does not relax isolated rat and rabbit vessels. 1086 75

The relaxing effect of extracellular ATP on renal glomeruli has been investigated by applying ATP and its analogues to suspensions of angiotensin II-precontracted rat renal glomeruli. Based on changes of glomerular [3H]inulin space (GIS) the relaxation of glomeruli was analysed in the presence of agonists: ATP, ADP, AMP, UTP, 2-methylthio-ATP (P2Y agonist), beta,gamma-methylene-ATP (P2X agonist) and adenosine. ATP, 2-methylthio-ATP, ADP and UTP induced concentration-dependent relaxation whereas AMP, beta,gamma-methylene-ATP and adenosine had no effect. The rank order of relaxation potency was 2-methylthio-ATP > ATP > ADP > UTP. An inhibitor of constitutive nitric oxide synthase (NOS), Nomega-nitro-L-arginine (NNA) prevented the ATP-induced increased accumulation of L-citrulline and the relaxation effect of ATP. An inhibitor of the neuronal isoform of NOS, 7-nitroindazole, had no effect on the relaxation effect of ATP. The relaxing effect of ATP was prevented in the presence of inhibitors of cyclic guanylyl cyclase: methylene blue (MB) and the more specific inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ). ATP stimulated an accumulation of cGMP that was diminished in the presence of MB. We indicated that extracellular ATP may relax the glomeruli via activation of P2Y receptors with the subsequent activation of the endothelial isoform of nitric oxide synthase and soluble guanylyl cyclase. We suggest that, based on the described mechanism, extracellular ATP may increase the filtration surface which, in turn, may influence the glomerular filtration rate.
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PMID:Cyclic GMP-dependent relaxation of isolated rat renal glomeruli induced by extracellular ATP. 1113 64

It was hypothesized that hypoxia may inhibit nitric oxide (NO) production by reducing the availability of endothelial NO synthase (NOS III) substrate. To evaluate the effect of L-arginine on the NO release in high altitude, 11 subjects were infused with L-arginine (0.5 g x kg(-1)) during 30 min in normoxia and after 36 h at 4,350 m (hypoxia). The L-citrulline and cyclic guanosine monophosphate (cGMP) concentrations were measured to investigate NO synthesis and guanylyl cyclase activity respectively. L-citrulline concentration, arterial oxygen saturation (Sa,O2), systemic blood pressure, heart rate and acute mountain sickness (AMS) score were measured at rest and 15, 30 and 45 min after starting infusion. The results showed that baseline L-citrulline was lower in hypoxia (p<0.05). L-arginine infusion increased L-citrulline concentration in both conditions. However, in hypoxia L-citrulline concentration remained lower than in normoxia (p<0.05). The concentration of cGMP was lower in hypoxia (p<0.05). In hypoxia, Sa,O2 increased from 15 min after the start of the infusion to 45 min (p<0.05). Blood pressure and heart rate were not affected by L-arginine infusion. Subjects who experienced symptoms of AMS showed a slight decrease in AMS score with L-arginine. The decreased L-citrulline suggests a hypoxia-induced impairment of nitric oxide synthase III or a decrease in L-arginine availability. The improvement of arterial oxygen saturation by pretreatment with L-arginine could be ascribed to an enhancement of the ventilation/perfusion ratio. Collectively, these results are consistent with a decrease in nitric oxide production in hypoxia that could be antagonized by supplying nitric oxide synthase cosubstrate.
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PMID:Response of nitric oxide pathway to L-arginine infusion at the altitude of 4,350 m. 1152 86


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