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)

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

We studied the effects of organic nitrates and human atrial natriuretic polypeptide (hANP) on relaxation and tissue cyclic guanosine monophosphate (cGMP) levels using isolated canine coronary arteries with and without endothelial injury. Glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), pentaerythritol tetranitrate (PETN), and hANP relaxed both the injured and control coronary arteries, and they increased tissue cGMP levels in a dose-dependent fashion without changing tissue adenosine 3':5'-cyclic phosphate (cAMP) levels. The extent of relaxation was larger and the increase in cGMP was greater in the injured coronary artery than in the control artery. Methylene blue inhibited relaxation induced by GTN and hANP, and decreased tissue cGMP levels in both the injured and control groups. M&B 22,948 enhanced relaxation induced by GTN and hANP and increased tissue cGMP levels in both groups. The results suggest that organic nitrates and hANP relax the coronary artery by directly activating the guanylate cyclase in coronary smooth muscle and that such activation is independent of the endothelium-dependent vasodilator system.
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PMID:Effects of atrial natriuretic polypeptide and organic nitrates on levels of relaxation and cyclic nucleotide of canine coronary artery with and without endothelial injury. 284 5

The effects of nitrates on a Ca+2 increase and the content of cyclic nucleotides in human platelets were studied. Nitroglycerin (GTN), isosorbide dinitrate (ISDN) and sodium nitroprusside (NP) were found to inhibit dose-dependently the intracellular Ca+2 increase induced by the platelet activating factor (PAF). The inhibiting effect of NP was at lower concentrations than those of GTN and ISDN. GTN calcium blocking action did not change significantly regardless of vasopressin, serotonin or PAF used as inducers of the intracellular Ca+2 increase. GTN suppressed the PAF provoked Mn+2 entering into the cells. NP and GTN induced increase of the cGMP content correlated with their calcium blocking activity. They did not augment the level of cAMP. Methylene blue (MB), a guanylate cyclase and glutathione reductase inhibitor, decreased the calcium blocking effect of GTN and its influence on the cGMP content but failed to suppress the inhibitory effect of NP. Ascorbic acid increased the calcium blocking effect of NP but did not influence the inhibitory effect of GTN. An increase in Ca+2 content induced by PAF in platelets from patients with chronic congestive heart failure was significantly higher in the group with dilatation cardiomyopathy. The effect of 10 mg of ISDN sublingually on forearm venous tone was higher in patients with initially elevated venous tone. There was a direct statistical correlation between the IC50 of GTN calcium blocking effects in platelets and the elevation of a forearm venous tone reaction from a statistic mean reaction to ISDN.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[New approaches to the study of the mechanism of action of nitrates]. 285 8

The dependence of relaxation of rabbit aortic strips by carbachol and by the inhibitory factor from the bovine retractor penis (BRP) on the presence of endothelium has been compared. Carbachol-induced relaxation is abolished by removing the endothelium, inhibitory factor-induced relaxation is unimpaired. The inhibitory factor, therefore, does not act by releasing an endothelium-derived relaxing factor (EDRF). The effect of inhibitors of eicosanoid metabolism on relaxation was examined. Quinacrine and nordihydroguaiaretic acid abolished the relaxant effect of carbachol and flurbiprofen had no effect. The relaxation produced by the inhibitory factor was unaffected by quinacrine and flurbiprofen while nordihydroguaiaretic acid potentiated the response. No eicosanoid appears, therefore, to be involved in the relaxant effect of the inhibitory factor from the BRP. Methylene blue, a drug reported to inhibit guanylate cyclase, in a concentration of 10 microM selectively abolished the relaxation produced by carbachol. However, at the higher concentration of 30 microM it abolished almost completely the response to inhibitory factor from the BRP and reduced inhibition by sodium nitroprusside. It is not possible from these results to exclude the possibility that the EDRF and the inhibitory factor from the BRP are chemically related.
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PMID:A comparison of the action of the endothelium-derived relaxant factor and the inhibitory factor from the bovine retractor penis on rabbit aortic smooth muscle. 286 8

The objective of this study was to ascertain whether "endothelium-derived relaxing factor" (EDRF) released from bovine intrapulmonary artery and vein is capable of directly activating soluble guanylate cyclase, thereby accounting for elevated vascular levels of cyclic GMP during EDRF release. Isolated arterial and venous rings, after equilibration and depolarization in bath chambers, were transferred to reaction tubes and incubated with soluble guanylate cyclase that had been purified to homogeneity from bovine lung. Addition of test agents to either bath chambers or enzyme reaction mixtures enabled the determination of their sites of action. Arterial and venous rings caused an endothelium-dependent 2- to 3-fold enzyme activation that was inhibited by methylene blue. Endothelium-dependent enzyme activation in artery but not vein was enhanced several-fold by acetylcholine in an atropine-sensitive manner. Bradykinin, which relaxes both artery and vein when endothelium is intact, activated guanylate cyclase upon addition of endothelium-intact rings to enzyme reaction mixtures. Vasoactive intestinal peptide, which causes endothelium-dependent relaxation of artery but not vein, also activated guanylate cyclase in the presence of endothelium-intact artery but not vein. Arachidonic acid activated the enzyme directly as well as through EDRF release from artery but not vein. Atrial peptides, prostacyclin, isoproterenol and nitroglycerin were inactive. Methylene blue was a powerful inhibitor of EDRF-elicited activation of guanylate cyclase but was without effect when rings were merely pretreated with methylene blue in bath chambers with no further addition to enzyme reaction mixtures. Thus, methylene blue did not interfere with the formation, release or chemical stability of EDRF, but rather inhibited its influence on guanylate cyclase. No agent was found to inhibit EDRF generation or release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of purified soluble guanylate cyclase by endothelium-derived relaxing factor from intrapulmonary artery and vein: stimulation by acetylcholine, bradykinin and arachidonic acid. 287 27


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