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)

The development of vasodilator drugs that open the K+ channels in blood vessels has been of great academic and practical interest. The discoveries of the ATP-sensitive K+ channel and the glibenclamide-sensitive K+ channel have promoted these interests. In relation to this channel, the cardioprotective effectiveness of a K+ channel opener (Aprikalim) in doses that did not change haemodynamics or collateral blood flow were demonstrated in infarct dog heart. The effects were antagonized by glibenclamide. Thus, ATP-sensitive K+ channels seem to play an important role in this effect. Clinical evaluations of the K+ channel openers are reviewed. The hypotensive effects of the drugs are well-recognized. At present, however, the clinical usefulness of K+ channel openers has not been accepted widely, because of their side-effects including reflex tachycardia, edema, flushing and headache. An approach to reduce these side-effects is critical if these K+ channel openers are to be used as good hypotensive drugs. The K+ channel opener nicorandil has been evaluated as a highly effective antianginal drug. It seems likely that the clinical benefits of nicorandil result from both its K+ channel opening properties and its ability to stimulate smooth muscle guanylate cyclase. Clinical data on the pure-selective K+ channel opener cromakalim (lemakalim) as an antianginal drug is limited. However, on the basis of the vasodilator profile of this drug, it is expected to be useful for this purpose. The application of K+ channel openers to treat other disorders such as bladder instability is limited because of its hypotensive action.
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PMID:[The recent development and the present status of K+ channel opener]. 139 33

The effects of methylene blue, an inhibitor of soluble guanylate cyclase, on pulmonary vasodilator responses to efferent vagal stimulation were investigated in the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. In animals pretreated with reserpine or phenoxybenzamine, under elevated tone conditions, efferent vagal stimulation at frequencies of 2-16 Hz caused stimulus-frequency-dependent decreases in lobar arterial pressure and pulmonary lobar vascular resistance. The vasodilator response to vagal stimulation was reproducible, blocked by atropine, and reduced by methylene blue. Intralobar infusion of methylene blue increased lobar arterial pressure without significantly altering systemic arterial or left atrial pressure. Methylene blue had no significant effect on vasodilator responses to isoproterenol, albuterol, atriopeptin III, lemakalim, adenosine, ATP, and pituitary adenylate cyclase-activating polypeptide-27 but significantly decreased vasodilator responses to acetylcholine, nitric oxide (NO), sodium nitroprusside, and the S-nitrosothiol, S-nitroso-N-acetyl-penicillamine. The effects of methylene blue on responses to vagal stimulation were reversible and were similar with the addition of a NO synthase inhibitor. The present data suggest that vasodilator responses to cholinergic nerve stimulation involve an increase in the production of guanosine 3',5'-cyclic monophosphate in the pulmonary vascular bed. These results provide additional evidence to support the hypothesis that neurogenically released acetylcholine induces endothelium-dependent, muscarinic, guanylate cyclase-mediated vasodilation.
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PMID:Methylene blue inhibits neurogenic cholinergic vasodilator responses in the pulmonary vascular bed of the cat. 144 61

The spasmolytic mechanisms of nicorandil, a novel antianginal drug, were investigated using 3,4-diaminopyridine (3,4-DAP)-induced phasic contractions of isolated canine coronary arteries in comparison with those of cromakalim and pinacidil. Nicorandil (10(-4) M), cromakalim (10(-6) M) and pinacidil (10(-5) M) suppressed the phasic contractions. Pretreatment with glibenclamide (10(-6) M), a specific blocking agent of ATP-sensitive K+ channel, eliminated the suppression of phasic contractions by these drugs; glibenclamide completely eliminated the suppression by cromakalim, while the eliminations against nicorandil and pinacidil were incomplete. The recoveries of peak tensions were only 56.8% and 76.1% for nicorandil and pinacidil, respectively. Nicorandil and pinacidil may suppress the phasic contractions via K+ channel opening and additional mechanisms. Methylene blue (10(-7)-10(-5) M) alone, a guanylate cyclase inhibitor, had no effect on the suppression of phasic contractions by nicorandil. In the presence of glibenclamide (10(-6) M), however, the pretreatment with methylene blue significantly augmented the recovery of peak tension for nicorandil. These results indicate that K+ channel openers may suppress the phasic contractions induced by 3,4-DAP via ATP-sensitive K+ channels, and that additionally, nicorandil may suppress the phasic contractility through guanylate cyclase stimulation, as a nitrate.
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PMID:[The vasospasmolytic effects of nicorandil, cromakalim and pinacidil on 3,4-diaminopyridine-induced phasic contractions in canine coronary arteries as an experimental vasospasm model]. 144 82

This experiment was designed to investigate whether chronic hypoxia affect rat pulmonary artery (PA) endothelium-dependent relaxation and the content of cGMP in PA. Both ACh and ATP could induce endothelium-dependent relaxation of PA, not prevented by indomethacin, but completely abolished by methylene blue. These results indicated that vasodilatation of PA induced by both ACh and ATP is mediated by EDRF (endothelium-derived relaxing factor). Chronic hypoxia significantly depressed PA endothelium-dependent relaxation. The percent relaxation of IPPA and EPPA by 10(-6) mol/L ACh was 61.3% and 59.2% of those in control, and the percent relaxation of IPPA and EPPA by 1.8 x 10(-5) mol/L ATP was 64.9% and 55.3% respectively of the control. Chronic hypoxia also depressed SNP-induced endothelium-independent relaxation. Chronic hypoxia significantly decreased the content of cGMP in PA. The basic level of cGMP was 51.9 +/- 5.7 (n = 14) in hypoxia group and 84.9 +/- 9.7 (n = 14) pmol/g wet wt. in control group (P less than 0.01). After treatment of PA with ACh (10(-7) mol/L), the content of cGMP was 91.4 +/- 7.3 (n = 5) pmol/g wet wt. in hypoxic group and 240.8 +/- 30.6 (n = 5) pmol/g wet wt. in control group (P less than 0.01). Our data suggest that chronic hypoxia might depress rat pulmonary artery endothelium-dependent relaxation through the inhibition of soluble guanylate cyclase in vascular smooth muscle cells.
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PMID:[Effect of chronic hypoxia on endothelium-dependent relaxation and the content of cGMP in rat pulmonary artery]. 164 78

The cell membrane of vascular smooth muscle is lined with many receptor sensitive to signals emitted by the vessel wall or transported in the blood stream. Recent data on the mechanisms by which these receptors regulate vascular tone enable them to be classified into two main groups. The first group includes the receptors carried by the membrane proteins which are under their direct control; ATP-P2x receptors on Na+ and Ca2+ channels, pharmacological receptors (dihydropyridines, diltiazem, phenylalkylamines) situated on a voltage operated channel, receptors to cromakaline-like substances associated with a potassium channel, receptors to atriopeptines (ANF-B) with guanylate cyclase activity. The second group of receptors act through the intermediary of the G protein (which has a high affinity for guanylic nucleotides); it regulates the activity of an effector which may be an enzyme or an ionic channel. The receptors of this type which have been identified in vascular smooth muscle are: --positively (beta-adrenergic, DA1-dopaminergic, P1 purinergic or H2-histaminic) or negatively coupled (alpha 2-adrenergic) to adrenylate cyclase; --positively coupled to C phospholipase (angiotensin II, vasopressin V1, 5-H-T2, alpha 1-adrenergic, M1-cholinergic, H1-histaminic). In addition, the same receptor may act by different mechanisms (V1-vasopressin, alpha 2-adrenergic, for example). Whatever the initial mechanism of action, all these receptors influence the contraction by changing ionic permeability or by producing secondary relaxing (cyclic AMP, cyclic GMP) or contractility messengers (inositol phosphates, diacylglycerol).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Current data of the membrane receptors of the vascular smooth muscle fibers]. 164 53

The effects of cyclic GMP on the release of calcium from intracellular stores, induced in murine peritoneal macrophages by either ATP or platelet-activating factor, were studied by microfluorimetry with fura-2. When macrophages were incubated for 10-20 min with 10 microM LY83583, an inhibitor of guanylate cyclase, the rise in intracellular calcium induced by agonist application was strongly depressed. This inhibition of the response to platelet-activating factor could be reversed by the addition of 0.1 mM cyclic 8-bromo-GMP. In the presence of cyclic 8-bromo-GMP, the decay of the calcium transient was speeded. Furthermore, when two calcium transients were evoked within 1 min by stimulating the cells with 10 microM ATP, the second calcium transient was more depressed than the first one in the presence of LY83583. These findings are compatible with the hypothesis that cyclic GMP is necessary for the activation of the calcium pump of the intracellular stores.
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PMID:Cyclic-GMP-dependent refilling of calcium stores in macrophages. 164 19

Atrial natriuretic factor (ANF-R1) receptor is a 130-kDa protein that contains a cytoplasmic guanylate cyclase domain. We report that ATP interacts in an allosteric manner with the ANF-R1 receptor, resulting in reduced ANF binding and enhanced ANF-stimulated guanylate cyclase activity. The modulatory properties of various nucleotides indicate a preference for the adenine family with a rank order of potency of ATP greater than App(NH)p greater than or equal to ADP greater than or equal to AMP while cyclic and guanine nucleotides except GTP are inactive. The negative modulation by ATP of ANF binding is specific for the ANF-R1 receptor subtype since the amount of ANF bound by the guanylate cyclase uncoupled ANF-R2 subtype is increased in the presence of ATP. Furthermore, the effects of ATP on ANF-R1 receptor binding function are still observed with the affinity-purified ANF-R1 receptor, suggesting an allosteric binding site for ATP on the ANF-R1 receptor. In intact membranes, limited proteolysis of the ANF-R1 receptor with trypsin dose-dependently prevents the ATP-induced decrease in ANF binding concomitantly with the formation of a membrane-associated ANF-binding fragment of 70 kDa. These results confirm the direct modulatory role of ATP on hormone binding activity of ANF-R1 receptor and suggest that the nucleotide regulatory binding site is located in the intracellular domain vicinal to the protease-sensitive region.
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PMID:Allosteric modulation by ATP of the bovine adrenal natriuretic factor R1 receptor functions. 165 83

Experiments were performed to elucidate the role of cyclic guanosine monophosphate (cGMP) on platelet activation induced by protein kinase C (PKC) activators and calcium ionophore. Human platelets were pretreated with acetylsalicylic acid and with hirudin and apyrase. Aggregation and ATP secretion in response to the PKC activators 4 beta-phorbol 12-myristate 13-acetate (PMA) and 1-oleoyl 2-acetylglycerol (OAG) were inhibited by the nitrovasodilator sodium nitroprusside (SNP), an activator of guanylate cyclase, and by 8-bromo-cyclic GMP (8-Br-cGMP). The experiments were performed in the presence of M&B 22948, an inhibitor of cGMP phosphodiesterase. SNP and 8-Br-cGMP also inhibited platelet aggregation and secretion evoked by the ionophore ionomycin. In fura-2 loaded platelets SNP did not affect basal cytosolic Ca2+ level nor the rise induced by low concentrations of ionomycin, both in the presence and absence of extracellular Ca2+. The phosphorylation of the 47 and 20 kDa protein induced by ionomycin or PMA were not significantly decreased by SNP or 8-Br-cGMP. The present results suggest that cGMP is able to inhibit both the PKC and the Ca(2+)-dependent pathways leading to platelet activation by interfering, similarly to cAMP, with processes following protein phosphorylation, close to the effector systems.
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PMID:Platelet activation by diacylglycerol or ionomycin is inhibited by nitroprusside. 165 43

In vitro evidence suggests that resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation are mediated by changes in vascular smooth muscle concentrations of guanosine 3',5'-cyclic monophosphate (cGMP). We investigated this hypothesis in vivo in 19 mechanically ventilated intact lambs by determining the hemodynamic effects of methylene blue (a guanylate cyclase inhibitor) and then by comparing the hemodynamic response to five vasodilators during pulmonary hypertension induced by the infusion of U-46619 (a thromboxane A2 mimic) or methylene blue. Methylene blue caused a significant time-dependent increase in pulmonary arterial pressure. During U-46619 infusions, acetylcholine, ATP-MgCl2, sodium nitroprusside, isoproterenol, and 8-bromo-cGMP decreased pulmonary arterial pressure. During methylene blue infusions, the decreases in pulmonary arterial pressure caused by acetylcholine and ATP-MgCl2 (endothelium-dependent vasodilators) and sodium nitroprusside (an endothelium-independent guanylate cyclase-dependent vasodilator) were attenuated by greater than 50%. The decreases in pulmonary arterial pressure caused by isoproterenol and 8-bromo-cGMP (endothelium-independent vasodilators) were unchanged. This study in intact lambs supports the in vitro evidence that changes in vascular smooth muscle cell concentrations of cGMP in part mediate resting pulmonary vascular tone and endothelium-dependent pulmonary vasodilation.
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PMID:In vivo attenuation of endothelium-dependent pulmonary vasodilation by methylene blue. 165 62

The Na-H antiporter of renal-brush border membranes is inhibited by cyclic AMP and stimulated by protein kinase C. The proximal tubule contains guanylate cyclase and is capable of cyclic GMP production. The effect of cGMP on renal Na-H antiporter activity was analyzed in phosphorylated brush border membranes by 22Na uptake in the presence or absence of 1 mM amiloride. 8-Bromo cyclic GMP (1 microM) increased the amiloride-sensitive 22Na uptake in control from 1.26 +/- 0.13 to 1.54 +/- 0.12 nmol/mg/protein/10 sec, P less than 0.01, without altering the amiloride-insensitive component. In the absence of exogenous ATP, cGMP also stimulated the amiloride-sensitive 22Na uptake, which can be explained by the presence of endogenous ATP in concentrations of up to 50 microM in the membranes. In ATP-depleted membrane vesicles, however, cGMP inhibited the amiloride-sensitive 22Na uptake. These data indicate that cGMP acts on the Na-H antiporter by at least two different mechanisms, one of which is ATP dependent. It is likely that cGMP-dependent protein kinase mediates the stimulatory effects seen in the presence of ATP, and the inhibition seen in ATP-depleted membranes results from cGMP direct action on the Na-H antiporter.
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PMID:Dual effect of cyclic GMP on renal brush border Na-H antiporter. 165 8


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