Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of mesangial cells with recombinant human interleukin 1 beta (IL-1 beta) or recombinant human tumor necrosis factor alpha (TNF alpha) dose-dependently increased cGMP formation. Both IL-1 beta and TNF alpha-stimulated formation of cGMP occurred after a initial lag period of 4 to 8 hours. Treatment of cells with actinomycin D, cycloheximide or dexamethason completely abolished cytokine-induced cGMP formation. Furthermore, the guanylate cyclase inhibitor Methylene blue completely blocked IL-1 beta- and TNF alpha-stimulated cGMP generation. NG-mono-methyl-L-arginine attenuated IL-1 beta- and TNF alpha-induced cGMP production, an effect that was reversed by L-arginine.
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PMID:Interleukin 1 and tumor necrosis factor stimulate cGMP formation in rat renal mesangial cells. 217 27

Endothelium-dependent relaxation mediated by the formation of nitric oxide (NO) from L-arginine, is prevented by the arginine analog NG-monomethyl L-arginine (L-NMMA) (Palmer et al., Biochem. Biophys. Res. Comm. 153:1251-1256 (1988)). In the rat mesenteric arterial bed, incubation with L-NMMA did not prevent acetylcholine-induced relaxation, which, however, was reversed when L-NMMA was added during its maximum effect. A similar profile of action was observed with methylene blue, an inhibitor of guanylate cyclase. Methylene blue, but not L-NMMA, increased basal perfusion pressure. These data indicate that in the mesenteric arterial bed, NO formation via the L-NMMA-sensitive pathway occurs during stimulation with acetylcholine, but not under basal conditions.
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PMID:Influence of NG-monomethyl-L-arginine on endothelium-dependent relaxations in the perfused mesenteric vascular bed of the rat. 236 29

Transmural electrical stimulation was used to elicit frequency-dependent adrenergic neurogenic contractions in isolated carotid arteries from cholesterol-fed and control rabbits. In rings with endothelium, responses to adrenergic nerve stimulation were significantly greater in arteries from cholesterol-fed as compared with those from control rabbits. Responses to adrenergic nerve stimulation of rings without endothelium were not different between the two groups. Methylene blue, a guanylate cyclase inhibitor, increased contractions of rings with endothelium and abolished the difference between the responses of arteries from cholesterol-fed and control rabbits. Methylene blue had no significant effect on arteries without endothelium. The overflow of endogenous norepinephrine (NE) caused by transmural electrical stimulation was not different between segments of arteries from cholesterol-fed and control rabbits. In control rabbits, exogenously applied NE contracted arteries with endothelium less than arteries without endothelium, whereas in cholesterol-fed rabbits the contractions caused by NE were not different between arteries with and without endothelium. Acetylcholine-induced relaxations were not different between rings with endothelium from cholesterol-fed and control rabbits. These results suggest that hypercholesterolemia selectively impairs the inhibitory influence of the endothelium on adrenergic contractions.
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PMID:Augmented adrenergic contractions of carotid arteries from cholesterol-fed rabbits due to endothelial cell dysfunction. 248 75

The present study investigates the mechanism of endothelium-dependent relaxation of vascular smooth muscle. Melittin, a polypeptide found in honeybee venom and a known activator of phospholipase A2, induced transient, endothelium-dependent relaxations of rat thoracic aortae contracted with norepinephrine. Higher concentrations of melittin induced relaxations followed by contractions. Prior incubation of melittin with trypsin abolished the changes in relaxation and contraction due to melittin. Melittin (10 micrograms/ml)-induced relaxations were associated with transiently elevated levels of cyclic GMP with a peak increase of 30-fold, which occurred 30 seconds after melittin exposure. Melittin (10 micrograms/ml) elevated cyclic AMP levels less than twofold and this effect was variable. A lower concentration of melittin (1 microgram/ml) elevated cyclic GMP levels approximately twofold, while exposure to 1 microgram/ml melittin in the presence of the cyclic GMP phosphodiesterase inhibitor, M&B 22948 (1 mM), increased cyclic GMP levels fivefold. Removal of the endothelium prevented the increased levels of cyclic GMP and cyclic AMP due to melittin. Exposure to the guanylate cyclase inhibitor, methylene blue, prevented the increased levels of cyclic GMP. Methylene blue, nordihydroguaiaretic acid, and the phospholipase A2 inhibitor, parabromophenacyl bromide, inhibited melittin-induced relaxations, while the cyclo-oxygenase inhibitor, indomethacin, was without effect. Arachidonic acid increased cyclic AMP levels but had no effect on cyclic GMP levels in the presence or absence of indomethacin. Relaxations to melittin, and to the endothelium-dependent vasodilators acetylcholine, trypsin, histamine, and the Ca2+ ionophore A23187, and/or the associated increased cyclic GMP levels, were reduced following exposure to melittin. Prior exposure to polyarginine (10 micrograms/ml), which induced endothelium-dependent relaxations that were prevented by methylene blue, also inhibited relaxations to the endothelium-dependent vasodilators. In contrast, relaxations to sodium nitroprusside were potentiated in tissues previously exposed to melittin. Removal of the endothelium by rubbing the intimal surface also potentiated relaxations to sodium nitroprusside. Scanning electron micrographs of the intimal surface demonstrated that melittin and polyarginine greatly damaged the endothelial cells. The present results suggest that polycation containing peptides induce endothelium-dependent relaxation through elevation of cyclic GMP levels within the smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of melittin on endothelium-dependent relaxation and cyclic GMP levels in rat aorta. 253 55

The objective of this study was to characterize the role of membrane potential and cyclic nucleotides in endothelium-dependent dilation of cerebral arteries. Middle cerebral arteries isolated from cats were depolarized and constricted in response to serotonin or when subjected to transmural pressures greater than 50 mm Hg. Acetylcholine (ACh) and ADP caused vasodilation and a sustained, dose-dependent hyperpolarization of up to 20 mV in this artery. The membrane potential change preceded the vasodilation by approximately 6 s. Hyperpolarizations and dilations to ACh and ADP did not occur in preparations without endothelium. The hyperpolarizations were abolished by ouabain (10(-5) M), which also blocked the dilator response to ACh. However, dilations to ADP were unaffected by ouabain. Methylene blue (5 x 10(-5) M), a guanylate cyclase inhibitor, had no effect on the responses to ACh or ADP in the presence or absence of ouabain. Cyclic guanosine monophosphate (cGMP) levels were not altered in cerebral arteries exposed to ACh or ADP. However, ADP did increase cyclic adenosine monophosphate levels in these blood vessels. We conclude that although membrane hyperpolarizations may be adequate to cause vasodilation, at least one other pathway of endothelium-dependent vasodilation also is present in feline cerebral arteries. Cyclic GMP does not appear to be involved in this alternate pathway of dilation.
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PMID:Endothelium-dependent dilation of feline cerebral arteries: role of membrane potential and cyclic nucleotides. 254 Nov 45

Glucose transport in isolated rat cardiomyocytes is stimulated by insulin, catecholamines, and anoxia approximately 2- to 3-fold over basal rates. The molecular mechanisms controlling these responses are unknown. In our search for possible cellular mediators of glucose transport stimulation, we examined the effects of a number of nucleotides on 3-O-methylglucose transport in heart cells. The nucleotides and/or permeable analogs (monosuccinyl, 8-bromo, and dibutyryl derivatives) included cUMP, cIMP, cCMP, cAMP, and cGMP at concentrations ranging from 10 nM to 1 mM. Of all the nucleotides tested only cGMP analogs induced a significant stimulation of transport at concentrations as low as 100 nM. This effect was observed in both the 8-bromo- and dibutyryl derivatives and with 1 mM cGMP itself. The effect was concentration dependent for both analogs and produced a maximal response equivalent to that of 100 nM insulin. This insulinomimetic effect of cGMP was examined in more detail in order to evaluate its role as a potential mediator of this response. Agents that are known to stimulate guanylate cyclase in the heart produced a clear stimulation of transport when added to cardiomyocytes. These include insulin, aminophylline, histamine, beta-estradiol, and biotin-nitrophenyl ester. Methylene blue, an inhibitor of guanylate cyclase, blocked the insulin response when added to cells before insulin, but was ineffective when added after insulin. In addition, agents that raise intracellular cGMP levels by inhibiting cyclic nucleotide phosphodiesterases were also examined for effects on glucose transport. Out of several phosphodiesterase inhibitors tested, only Zaprinast (which selectively increases cGMP in heart) stimulated transport in a concentration-dependent manner to within 80% of the maximal insulin effect. These results are consistent with the notion that cGMP may be involved in glucose transport stimulation.
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PMID:Stimulation of glucose transport in rat cardiac myocytes by guanosine 3',5'-monophosphate. 254 35

1. Field electrical stimulation of perfused segments (15 mm long) of the goat saphenous artery caused frequency-dependent increases in perfusion pressure which were blocked by tetrodotoxin, phentolamine or prazosin. 2. Mechanical removal of the endothelium augmented both resting perfusion pressure and responses to electrical stimulation. 3. Methylene blue enhanced responses with intact endothelium only. It is likely that the endothelium exerts part of its inhibitory influence through the activation of guanylate cyclase.
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PMID:Endothelium attenuates contractile responses of goat saphenous arteries to adrenergic nerve stimulation. 257 79

A bolus injection of methylene blue (1 mg), a guanylate cyclase inhibitor, or aspirin (3 mg) in the isolated rat lung preparation had little or no effect on resting perfusion pressure under normoxic condition. In contrast, methylene blue markedly potentiated hypoxic vasopressor response (4-fold) when injected before or during the alveolar hypoxic stimulation. Hemoglobin also potentiated the hypoxic pressor response. Similarly, methylene blue or aspirin augmented the pressor responses to angiotensin II (0.1-1 microgram). The increased hypoxic response induced by methylene blue was immediate and sustained. Methylene blue, when added during hypoxia in the presence of aspirin, further augmented the response to hypoxia compared with the enhanced hypoxic response observed with aspirin alone. Our results suggest that, in addition to the role of cyclooxygenase products, the pulmonary vascular bed may be regulated by endothelium-dependent factors that can be antagonized directly or indirectly by methylene blue.
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PMID:Methylene blue potentiates vascular reactivity in isolated rat lungs. 270 29

1. The ability of guinea-pig trachea to release an epithelium-derived relaxant factor (EpDRF) was assessed in a co-axial bioassay system. 2. Histamine (100 microM) and methacholine (25 microM) caused endothelium-dependent relaxation of rat isolated aorta, presumably via the release of endothelium-derived relaxant factor (EDRF). In contrast, endothelium-denuded rat aorta did not relax in response to these agents. 3. EDRF release was detected in response to methacholine in a co-axial bioassay system, consisting of intact rabbit aorta tube (EDRF donor) and endothelium-denuded rat aorta strip (assay preparation). These results indicated the transfer of EDRF from a donor to an assay preparation, thereby validating the co-axial bioassay method. 4. Substitution of endothelium-intact rabbit aorta tube by epithelium-intact guinea-pig tracheal tube tissue in co-axial assemblies, still allowed the assay preparation to relax in response to histamine or methacholine. Removal of the intact tracheal tube from the system, or removal of the epithelium from the donor tracheal tube in co-axial preparations, abolished such relaxant responses. These observations are consistent with histamine- or methacholine-induced release of an epithelium-derived relaxant factor (EpDRF) from the trachea. 5. In the co-axial assembly comprising intact guinea-pig trachea and endothelium-denuded rat aorta, histamine and methacholine produced concentration-dependent, EpDRF-induced aortic relaxation. Mean concentrations of histamine and methacholine producing 50% of the maximum relaxation (EC50) were 39.8 microM and 2.7 microM respectively. Histamine-induced relaxation was inhibited in the presence of mepyramine (2 microM) and responses to methacholine were inhibited by atropine (0.1 microM). 6. Methylene blue (50 microM) had no effect on such relaxant responses, indicating that EpDRF does not activate guanylate cyclase. Furthermore, the cyclo-oxygenase inhibitor indomethacin (5 microM), the cyclo-oxygenase/lipoxygenase inhibitor BW 755C (150 microM) and the leukotriene receptor antagonist FPL 55712 (10 microM) each failed significantly to alter EpDRF-mediated relaxation of vascular smooth muscle suggesting that EpDRF is not a prostanoid. Platelet activating factor (Pat) failed to cause relaxation of endothelium-denuded rat aorta, indicating that this mediator was also not EpDRF. 7. EpDRF was also released from human bronchial segments. 8. This study provides direct evidence for the release of an EpDRF from non-diseased airway tissue and further suggests that healthy airway reactivity to spasmogens is modulated by the release of an endogenous protective, spasmolytic substance. The bronchial hyperreactivity of asthma may be partly caused by attenuated production of such an inhibitory signal.
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PMID:Co-axial bioassay of a smooth muscle relaxant factor released from guinea-pig tracheal epithelium. 278 36

The contractile and intracellular responses to acetylcholine (ACh) were measured in isolated segments of the guinea pig circumflex coronary artery. ACh (10(-5) M) led to hyperpolarization of the membrane in the presence or absence of the H1-receptor agonist 2-(2-aminoethyl)pyridine (AEP). This hyperpolarization was associated with relaxation of vessels precontracted with AEP. Hyperpolarization and relaxation were abolished after complete removal of the endothelium. Less endothelial coverage was required to obtain a relaxation with ACh (10(-5) M) than with bradykinin (BK, 10(-7) M). BK did not initiate hyperpolarization. A23187 (10(-8) to (10(-5) M) did not relax vessels precontracted with AEP. Three muscarinic antagonists were compared and the following order of potency was obtained: atropine greater than pirenzapine greater than AFDX116. Although atropine (10(-7) M) reduced the ACh (10(-5) M)-induced hyperpolarization by 83%, this same concentration of pirenzapine had no effect on hyperpolarization. Oxyhemoglobin (10(-5) M) significantly reduced relaxation to nitroglycerine but not ACh. Methylene blue (10(-5) or 5 x 10(-5) M) inhibited relaxation to submaximal but not maximal concentrations of ACh. In vessels precontracted with elevated potassium, ACh (10(-5) M) caused contraction rather than relaxation. The onset and time to peak hyperpolarization with carbachol was more rapid with luminal as opposed to adventitial application of drug. It is concluded that relaxation and hyperpolarization with ACh in the coronary artery are mediated via the endothelium. The results are compatible with the hypothesis that relaxation is initiated by both endothelial-derived relating factor stimulation of guanylate cyclase activity and hyperpolarization of the smooth muscle.
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PMID:Effect of ACh on electrical and mechanical activity in guinea pig coronary arteries. 280 72


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