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)

To evaluate the cellular mechanisms involved in hypoxic relaxation of airway smooth muscle, we investigated the effects of hypoxia on the behavior of third- and fourth-order porcine bronchial rings contracted with either carbachol or KCl. In one series of experiments, hypoxia (95% N2-5% CO2) was imposed and rings were then exposed to increasing concentrations of carbachol or KCl. In separate experiments, rings were first contracted with carbachol (10(-6) M) or KCl (40 mM) and were then exposed to solutions bubbled with decreasing concentrations of O2. The CO2 concentration was maintained constant at 5% in all experiments. The initial magnitude of KCl-induced but not carbachol-induced contractions was profoundly reduced by 95% N2-5% CO2. The sensitivity of the airway to carbachol was unchanged. In rings precontracted with either carbachol or KCl, hypoxia caused similar losses of airway smooth muscle tone in a reversible and concentration-dependent manner. The effects of hypoxia were independent of the presence of an intact epithelium and were not inhibited by the cyclooxygenase inhibitor indomethacin (5 microM), the soluble guanylate cyclase inhibitor methylene blue (50 microM), or the beta-adrenoceptor antagonist propranolol (1 microM). The impairment by hypoxia of the initiation phase of KCl-induced contractions and of the maintenance phase of both KCl- and carbachol-induced contractions, but not the initiation phase of carbachol-induced contractions, suggests that changes in O2 tension modulate airway tone by altering the entry of extracellular calcium into the airway smooth muscle.
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PMID:Role of Ca2+ entry in the modulation of airway tone by hypoxia. 846 Jul 17

As in the adult circulation, the endothelium may play an important role in determining fetal vascular tone. The purpose of this study was to determine the influence of the endothelium on norepinephrine- and phenylephrine-induced contraction of pulmonary and carotid arteries from near-term fetal guinea pigs. Isometric contractions of isolated rings to the cumulative addition of norepinephrine (10(-9)-10(-5) M) were measured before and after 1) endothelium removal, 2) NG-monomethyl-L-arginine (L-NMMA; 10(-4) M) to inhibit endothelium-derived relaxing factor (EDRF), 3) methylene blue (10(-5) M) to inhibit guanylate cyclase, 4) oxyhemoglobin (3 x 10(-6) M) to bind EDRF, and 5) indomethacin (10(-5) M) to inhibit cyclooxygenase. All treatment effects were measured in endothelium-intact segments. The maximal norepinephrine contraction of fetal pulmonary (40 +/- 8% KCl, n = 7) and carotid (13 +/- 7% KCl, n = 7) arteries was much less (P < 0.05) than the maximal contraction to 120 mM KCl. Treatments that inhibit the action of EDRF increased contraction of both fetal pulmonary and carotid arteries. L-NMMA also increased contraction to phenylephrine. Indomethacin had no effect on the contractile responses to norepinephrine of either artery. Thus EDRF inhibits alpha-adrenoceptor-stimulated contraction of fetal pulmonary and carotid arteries and may attenuate the constrictor responsiveness of the fetal circulation in vivo.
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PMID:Endothelium-derived relaxing factor inhibits norepinephrine contraction of fetal guinea pig arteries. 847 91

To clarify the interaction between endothelin-1 (ET-1) and atrial natriuretic peptide (ANP), the effects of ET-1 on ANP secretion were investigated in isolated perfused rat hearts and in conscious unrestrained rats. Perfusion with 10(-9) M ET-1 stimulated ANP secretion from the isolated perfused rat heart. However, 10(-10) M ET-1 significantly decreased ANP secretion for the initial 15 min of the perfusion period. The perfusion with 10(-11) M ET-1, which is near the plasma level of ET-1 (2 x 10(-12) M), inhibited ANP secretion throughout the perfusion period. The perfusion of 10(-12) M ET-1 slightly decreased ANP secretion. After the ET-1 perfusion period, ANP secretion increased in proportion to ET-1 dose. The inhibitory action of ET-1 on ANP secretion was almost abolished by simultaneous perfusion of indomethacin, a cyclooxygenase inhibitor, but not by methylene blue, an inhibitor of soluble guanylate cyclase. In conscious unrestrained rats the iv infusion of 1 pmol/kg.min ET-1, which doubled the plasma ET-1 level, slightly but significantly decreased the plasma ANP level 5 and 10 min after the initiation of the infusion. The infusion of 10 and 30 pmol/kg.min ET-1 increased the plasma ANP level. These results demonstrate that low doses of ET-1 exert an inhibitory and short-acting action on ANP secretion from the heart, although high doses of ET-1 exert stimulating and long-lasting action, and suggest that prostanoids are involved in this inhibitory action.
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PMID:Low doses of endothelin-1 inhibit atrial natriuretic peptide secretion. 847 43

Participation of calcium-induced vasodilation (due to an increase in synthesized nitric oxide (NO) content in endothelial cells) in the arterio-venous circulation, including the vascular bed was investigated by the vessel perfusion method in the isolated rabbit ear preparation. The perfusion medium used was a tris-buffered solution. When CaCl2 (6.25, 12.5 and 25 mg) was injected in the perfused vessel of the rabbit ear preparation, dose-dependent vasocontraction was observed when vascular tone was kept at a normal level. However, CaCl2 dose-dependently induced vasodilation of the vessel when it was continuously contracted by norepinephrine (1.2 x 10(-7) M). This calcium-induced vasodilation was inhibited in the presence of NG-nitro-L-arginine (5 x 10(-5) M), a selective inhibitor of NO synthesis, and methylene blue, a guanylate cyclase inhibitor, although it was rarely affected by indomethacin (10(-5) M), a cyclooxygenase inhibitor. Calcium-induced vasodilation was also obtained in the in situ circulation containing vascular bed, and this suggests that the vasodilation was due to a Ca(2+)-induced increase in the synthesis of NO derived from endothelial cells.
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PMID:Calcium-induced vasodilation due to increase in nitric oxide formation in the vascular bed of rabbit ear preparation. 848 94

We examined the effects of acetylcholine (ACh) on coronary perfusion pressure (CPP) and force of cardiac contraction (FCC) in isolated rat hearts. Perfusion of hearts with ACh increased both CPP and the FCC, whereas cardiac contraction rate fell. These effects of ACh were abolished by atropine but were not affected by the beta 1-adrenergic antagonist metoprolol. The nonselective beta-adrenergic antagonist propranolol decreased ACh-mediated increase in FCC but did not affect the rise in CPP. Pretreatment of hearts with cyclooxygenase inhibitor indomethacin or thromboxane (Tx) A2-endoperoxide receptor antagonist SQ 29,548 decreased ACh-mediated increase in CPP and FCC, suggesting release of TxA2 in the microvasculature, which may partially account for the increase in CPP and FCC with ACh infusion. In contrast to the effect of indomethacin and SQ 29,548, pretreatment of hearts with endothelium-derived relaxing factor (EDRF) synthetase inhibitor NG-monomethyl-L-arginine (L-NMMA) or guanylate cyclase inhibitor methylene blue potentiated ACh-mediated increase in CPP and attenuated the increase in FCC, suggesting that ACh-mediated increase in CPP is modified by basal EDRF release. Thus the cardiac effects of ACh are related to muscarinic receptor activation, and the release of prostaglandins and EDRF modulates the effects of ACh in isolated rat heart.
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PMID:Cardiac effects of acetylcholine in rat hearts: role of endothelium-derived relaxing factor and prostaglandins. 849 52

The diffusible second messenger, nitric oxide, is synthesised in central neurons in response to activation of glutamate receptors or other stimuli that increase cytosolic Ca2+ concentrations. Among the many roles suggested for nitric oxide in the central nervous system is that of mediating synaptic plasticity. For example, long-term potentiation in the CA1 region of the rat hippocampus was reported to be blocked by inhibitors of nitric oxide synthase and exogenous nitric oxide has been claimed to induce an enduring enhancement of synaptic strength under certain conditions. These findings, however, are controversial and even when a participation of nitric oxide is evident, the transduction mechanism is unclear. A well-known action of nitric oxide is to stimulate the soluble form of guanylyl cyclase, thereby evoking an accumulation of cyclic GMP in target cells but several other mechanisms have been proposed, including stimulation of ADP ribosyltransferase or cyclooxygenase, and nitrosylation of protein thiol residues. The identification of a selective inhibitor of soluble guanylyl cyclase, the oxadiazoloquinoxaline derivative, ODQ, provides, for the first time, the means to investigate the importance of the cyclic GMP pathway in nitric oxide signal transduction. We find that ODQ and the nitric oxide synthase inhibitor, nitroarginine, reduce hippocampal long-term potentiation in an equal and mutually exclusive manner, suggesting that the actions of nitric oxide in this phenomenon are entirely mediated through cyclic GMP. The experiments also show that there is a component of long-term potentiation that involves neither nitric oxide nor cyclic GMP.
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PMID:Nitric oxide-dependent long-term potentiation is blocked by a specific inhibitor of soluble guanylyl cyclase. 859 40

Hepatic nitric oxide (NO) biosynthesis is induced by local or systemic inflammation. The highly reactive NO radical binds to prosthetic iron groups such as heme or iron-sulfur clusters leading to either activation or inhibition of enzymes such as guanylate cyclase, cyclooxygenase and aconitase. It has been known for years that NO also binds to the heme moiety of cytochrome P450s (CYP) with high affinity. However, it was demonstrated recently that binding of NO to CYPs also inhibits their enzymatic activity. This is true for exogenously applied as well as for endogenously synthesized NO. Suppression of CYP-dependent metabolism, which is a major problem of inflammatory liver diseases, can be significantly reversed by inhibition of NO synthesis in vivo under experimental conditions. We investigated whether these findings are applicable as a novel therapeutic principle in severe inflammatory liver dysfunction.
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PMID:Inhibition of biotransformation by nitric oxide (NO) overproduction and toxic consequences. 859 55

Interleukin 1 and nitric oxide (NO) from infiltrating macrophages and activated mesangial cells may act in concert to sustain and promote glomerular damage. To evaluate if such synergy occurs, we evaluated the effect if IL-1 beta and NO on the formation of prostaglandin (PG)E2 and cyclooxygenase (COX) expression. The NO donors, sodium nitroprusside and S-nitroso-N-acetylpenicillamine, alone did not increase basal PGE2 formation. However, these compounds amplified IL-1 beta-induced PGE2 production. Similarly, sodium nitroprusside and S-nitroso-N-acetylpenicillamine by themselves did not induce mRNA and protein for COX-2, the inducible isoform of COX; however, they both potentiated IL-1 beta-induced mRNA and protein expression of COX-2. The stimulatory effect of NO is likely to be mediated by cGMP since (a) an inhibitor of the soluble guanylate cyclase, methylene blue, reversed the stimulatory effect of NO donors on COX-2 mRNA expression; (b) the membrane-permeable cGMP analogue, 8-Br-cGMP, mimicked the stimulatory effect of NO donors on COX-2-mRNA expression; and (c) atrial natriuretic peptide, which increases cellular cGMP by activating the membrane-bound guanylate cyclase, also amplified IL-1 beta-induced COX-2 mRNA expression. These data indicate a novel interaction between NO and COX pathways.
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PMID:Nitric oxide amplifies interleukin 1-induced cyclooxygenase-2 expression in rat mesangial cells. 862 94

During human pregnancy, ACTH is produced by both the placenta and fetal pituitary. ACTH has been shown to cause vasodilatation in the adrenal cortex in vitro. In this context we have investigated the vasoactive effects of ACTH in the human fetal-placental circulation. Single lobules of term human placentas were bilaterally perfused in vitro with Krebs solution (maternal and fetal, 5 mL/min; 95% O2-5% CO2; 37 C; pH 7.3), and changes in fetal placental arterial perfusion pressure (FAP) were measured. ACTH (40-4000 pmol/L; n = 5) caused a dose-dependent reduction of both KC1 and PGF2alpha-induced increases in FAP in the fetal placental circulation. The reductions were of a similar magnitude in the presence of either constrictor agent. ACTH was 187.4 (95% confidence limits, 162.7-215.9) times more potent than prostacyclin (PGI2; 1.2-1180 nmol/L; n = 6), which is a known vasodilator of the fetal-placental circulation. The threshold concentrations for ACTH and PGI2 were 40 pmol/L and 1.2 nmol/L, respectively. ACTH-induced reductions in PGF2alpha-induced increases in FAP in the fetal placental circulation were not inhibited by the nitric oxide synthase inhibitor, N omega-nitro-L-arginine (100 micromol/L; n = 5), the cyclooxygenase inhibitor indomethacin (3 micromol/L; n = 5), or a guanylate cyclase inhibitor LY83583(1 micromol/L; n = 5). The inhibitory effect of ACTH was attenuated by the antagonist, ACTH-(7-38) (240 pmol/L; n = 4), and a polyclonal ACTH antiserum (1:1000 dilution; n = 4). We have demonstrated that ACTH causes a reduction in fetal placental vascular resistance in the human fetal-placental circulation in vitro. The mechanism by which it exerts these effects has not been defined, but neither nitric oxide nor PG-mediated pathways appear to be involved.
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PMID:Adrenocorticotropin causes vasodilatation in the human fetal-placental circulation. 863 42

Methylene blue (MB) is a widely used putative inhibitor of nitric oxide (NO)-dependent responses, particularly in cell culture and vascular ring studies. MB is postulated to diminish vasodilation to NO either by preventing activation of guanylate cyclase by NO or by oxidizing NO formed by NO synthase. In the present study we examined whether MB inhibited vasodilation to bradykinin (BK) in the cyclooxygenase-inhibited, isolated canine lung lobe perfused with blood at constant flow. One group of lobes (n = 5) was challenged with BK at baseline vascular tone, after tone was doubled by infusion of serotonin (5-HT), and again after MB treatment. Bradykinin challenge failed to evoke a depressor response at baseline vascular tone but induced marked vasodilation after vascular tone was increased by 5-HT. Subsequent treatment with MB, however, failed to significantly diminish vasodilation to BK (p > 0.05). A second group of lobes (n = 4) was challenged with BK after cyclooxygenase inhibition and the doubling of vascular tone with serotonin infusion. The dose-dependent vasodilation to BK was diminished (p < 0.01) after treatment with 1.8 mM N omega-nitro-L-arginine (L-NA), a potent inhibitor of nitric oxide synthase. However, subsequent treatment with MB restored the vasodilator response to bradykinin to pre-L-NA values (p < 0.01). While our results suggest that vasodilation to bradykinin is mediated in part by NO formation, MB treatment does not appear to alter BK-induced vasodilation, and even enhanced vasodilation to bradykinin after L-NA. MB appears to have some nonspecific effects on vascular tone and reactivity that are unrelated to NO formation.
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PMID:Methylene blue restores vasodilation to bradykinin after inhibition of nitric oxide production in the isolated dog lung. 869 58


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