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)

Pharmacological probes were used to assess the possible roles of guanosine 3',5'-cyclic monophosphate (cGMP)-associated endothelium-derived relaxing factor (EDRF) in mediating microvascular responses to endogenous and exogenous agents in vivo. Pentobarbital-anesthetized rats (Wistar, 6 wk old) were prepared for in vivo microscopic observation and quantification of changes in diameter of third-order arterioles (15-25 microns) in the cremaster muscle to topical application of all agents. In indomethacin-pretreated preparations, cremasteric arteriolar dilator responses to acetylcholine, bradykinin, or ATP, but not to adenosine, histamine, or prostaglandin E2, were inhibited by hydroquinone (50 microM). Vasodilation to acetylcholine was also inhibited by methylene blue (5 microM), a blocker of guanylate cyclase activation. Constrictor responses to norepinephrine were not affected by hydroquinone or methylene blue. The inhibition of acetylcholine-induced vasodilation by hydroquinone and methylene blue was reversed by superoxide dismutase, suggesting that superoxide anion antagonized the response. On the other hand, basal arteriolar diameters or responses to acetylcholine were not affected by oxygen metabolite scavengers. Unlike in isolated arteries, vasodilator responses to the calcium ionophore A23187 or arachidonic acid were completely antagonized by cyclooxygenase inhibition. These data suggest that EDRF could be involved in the control of microvascular tone; however, significant differences exist in the stimuli that elicit dilation through this mediator in small and large blood vessels.
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PMID:Endothelium-associated vasodilators in rat skeletal muscle microcirculation. 249 47

Endothelium-dependent relaxation of blood vessels is produced by a large number of agents (e.g., acetylcholine, ATP and ADP, substance P, bradykinin, histamine, thrombin, serotonin). With some agents, relaxation may be limited to certain species and/or blood vessels. Relaxation results from release of a very labile non-prostanoid endothelium-derived relaxing factor (EDRF) or factors. EDRF stimulates guanylate cyclase of the vascular smooth muscle, with the resulting increase in cyclic GMP activating relaxation. EDRF is rapidly inactivated by hemoglobin and superoxide. There is strong evidence that EDRF from many blood vessels and from cultured endothelial cells is nitric oxide (NO) and that its precursor is L-arginine. There is evidence for other relaxing factors, including an endothelium-derived hyperpolarizing factor in some vessels. Flow-induced shear stress also stimulates EDRF release. Endothelium-dependent relaxation occurs in resistance vessels as well as in larger arteries, and is generally more pronounced in arteries than veins. EDRF also inhibits platelet aggregation and adhesion to the blood vessel wall. Endothelium-derived contracting factors appear to be responsible for endothelium-dependent contractions produced by arachidonic acid and hypoxia in isolated systemic vessels and by certain agents and by rapid stretch in isolated cerebral vessels. In all such experiments, the endothelium-derived contracting factor appears to be some product or by-product of cyclooxygenase activity. Recently, endothelial cells in culture have been found to synthesize a peptide, endothelin, which is an extremely potent vasoconstrictor. The possible physiological roles and pathophysiological significance of endothelium-derived relaxing and contracting factors are briefly discussed.
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PMID:Endothelium-derived relaxing and contracting factors. 254 95

It is hoped that his review enables the reader to appreciate the complexities implicit in the interactions among Ca2+, cyclic nucleotides, and phospholipid-metabolizing pathways in cell signal transduction. The interactions are varied and intricate, often involving several levels of cell amplification mechanisms. Upsetting the balance of fatty acids in membrane phospholipids can have detrimental effects on adenylate cyclase. Thus, n - 3 fatty acid enrichment of phospholipids suppresses adenylate cyclase activity. The effects of significant alterations in dietary fatty acids, such as might occur with the current vogue for n - 3 eicosapentaenoic acid and docosahexaenoic acid (fish oil) dietary enrichment regimens, will need to be assessed more fully with regard to stimulus-induced changes in cyclic nucleotide production in various tissues. Since the n - 3 fatty acids have not been demonstrated to affect guanylate cyclase activity, dietary changes in certain of these fatty acids would not be expected to contribute to changes in cGMP generation as much as in cAMP production. Moreover, the ingestion of large quantities of these n - 3 fatty acids can alter the profile of cyclooxygenase and lipoxygenase products produced in cells. According to the paradigm developed in this article, changes in the metabolism of fatty acids are amplified by alterations in cyclic nucleotide production and phospholipase activities, with the eventual physiological impact predicated on the tissue type and the specific stimulus response. There appears to be a rather clear distinction between the regulatory properties of eicosanoids regarding adenylate and guanylate cyclase activities. Whereas prostaglandins often stimulate adenylate cyclase activity, they have little effect on guanylate cyclase activity. On the other hand, the HETE compounds seem to play an important role in guanylate cyclase regulation in certain cells. Moreover, arachidonic acid affects adenylate cyclase activity without prior peroxidation, whereas endoperoxides and hydroperoxides are more effective than arachidonic acid with regard to guanylate cyclase stimulation. However, in the intact cell there is a strong implication that the dual stimulation of guanylate cyclase by Ca2+ and fatty acid evokes optimal enzyme activity. An advantage of multidimensional response mechanisms in cells includes the ability to recognize different stimuli and to respond with specific, coordinated responses modulated in their intensity and/or duration by messenger interaction. Few cell types respond to receptor stimulation in an all-or-none fashion, and the "milieu interior" depends on specific, graded responses to the autonomic nervous system and endocrine stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Coordinate interactions of cyclic nucleotide and phospholipid metabolizing pathways in calcium-dependent cellular processes. 255 30

Current dogma associates reperfusion injury with the introduction of reactive oxygen species (ROS) into the ischemic tissue. The sources of ROS under discussion are xanthine oxidase in the endothelium of small vessels and/or invaded polymorphonuclear leukocytes (PMN). The beneficial effects of both superoxide dismutase and catalase suggest an involvement of superoxide anions and hydrogen peroxide in this pathophysiological process, without describing the targets of their action. In our work we demonstrate that these two ROS effectively interact with two enzymes. Superoxide anions inhibit soluble guanylate cyclase. Its product, cGMP, is considered to antagonize platelet activation and to cause smooth muscle relaxation. Thus O2- can intensify platelet aggregability and small vessel occlusion. Similar effects are elicited by H2O2, which shifts the dose response curve of several agonists towards smaller concentrations by activating cyclooxygenase. This enzyme provides the substrate for thromboxane synthase which generates TxA2, the most potent physiologically occurring platelet aggregating and smooth muscle contacting agonist. These results lead us to the suggestion that the influence of the oxidative burst of PMN in the phenomenon of reperfusion injury should be reconsidered.
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PMID:Physiological targets of superoxide anion and hydrogen peroxide in reperfusion injury. 257 64

The experiments on anesthetized dogs demonstrated that reaction of the femoral vessels reactive hyperemia essentially decreased after chemical inhibition of endothelium by saponin, inhibition of lipoxygenase by quercetin and guanylate cyclase by methylene blue. Reaction was increased after cyclooxygenase inhibition by indomethacin. We concluded that the endothelium plays an important role in reaction of reactive hyperemia by endothelium-derived relaxing factor release.
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PMID:[Role of the endothelium in the development of reactive hyperemia]. 257

This study was designed to investigate whether the respiratory epithelium can modulate the tone of the underlying smooth muscle in response to decreases in partial pressure of O2 (PO2). Canine bronchial segments with or without epithelium (diameter, 4-6 mm; length, 50-60 mm) were mounted in organ chambers and perfused intraluminally with modified Krebs-Ringer bicarbonate solution [temperature, 37 degrees C; PO2 varying from 600 (control) to 40 mmHg; PCO2, 36 mmHg]. Isometric tension was recorded by means of stirrups passed through the wall of the central part of the bronchial segment. During contractions to carbachol, the tissues with epithelium showed epithelium-dependent relaxations when the PO2 was decreased. The level of relaxation was dependent on the PO2. The epithelium-dependent relaxation could not be blocked by the following agents: indomethacin, methylene blue, propranolol, or tetrodotoxin (antagonists or blockers of cyclooxygenase, guanylate cyclase, beta-adrenoceptors, and sodium channels, respectively). The epithelium-dependent relaxation was not accompanied by the release of an assayable relaxing factor in the bronchial lumen. The experiments suggest that 1) lowering the PO2 induces the epithelium to release a relaxing factor(s), which is neither a product of cyclooxygenase nor endothelium-derived relaxing factor; 2) a local reflex mechanism is not involved in the phenomenon; and 3) the relaxing factor(s) either is not released into the bronchial lumen or, if it is, is catalyzed rapidly in the lumen on release.
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PMID:Lowering Po2 induces epithelium-dependent relaxation in isolated canine bronchi. 259 82

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

Carbon monoxide (CO) inhibits human platelet aggregation triggered with threshold levels of agonists like arachidonate, ADP, collagen, thrombin, or the prostaglandin endoperoxide analogue U46619. This inhibition is counteracted by illumination with light above 400 nm indicating the involvement of a ferrous hemoprotein. An earlier suggestion that the mechanism of CO inhibition involves the cytochrome P450 protein thromboxane A2 synthase was ruled out as well as the involvement of the iron containing enzymes like cyclooxygenase or 12-lipoxygenase. In the presence of CO, no arachidonate was released from phospholipids, no increase of intracellular calcium levels was observed, and phospholipase C was not activated suggesting that the transducing mechanisms from the receptors to phospholipase C was effected in the presence of CO. cAMP levels were also unchanged but cGMP levels showed an increase of about 30%. By comparison with the guanylate cyclase stimulator nitroprusside, it was shown that such levels could block aggregation. In a 10,000 X g supernatant, CO enhanced guanylate cyclase activity 4-fold, supporting the view that CO acts by increasing platelet cGMP levels. With respect to the mechanism of guanylate cyclase action, the binding of CO to the regulatory subunit of guanylate cyclase must be responsible for the observed activation. It is concluded that cGMP is an important feedback regulator of the Pl response and that already a 25% increase in its steady state levels can cause inhibition of platelet aggregation.
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PMID:Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase. 289 93

The aggregation of gel-filtered rabbit platelets by 50 microM ADP was inhibited by a labile factor produced by suspensions of cultured bovine pulmonary artery endothelial cells. Inhibition of aggregation occurred when indomethacin-treated endothelial cells (6.10(5) per ml) and rabbit platelets (3.2.10(8) per ml) were incubated together. This anti-aggregatory activity was characterized as similar to endothelium-derived relaxing factor (EDRF) in that it was unstable at neutral pH and by its inhibition by hemoglobin. The activity was unaffected by treatment of the platelets and endothelial cells with the cyclooxygenase inhibitor, indomethacin, and by the lipoxygenase inhibitor, BW755c. In association with the anti-aggregatory activity, the levels of cyclic GMP were elevated 4-fold. The effect of the EDRF-like product on the levels of cyclic nucleotides was mimicked by treatment of platelets with sodium nitroprusside, an activator of soluble guanylate cyclase; sodium nitroprusside had no measurable effect on the levels of cyclic nucleotides of endothelial cells. We conclude that a factor with the properties of EDRF inhibits platelet aggregation, and that this is associated with an activation of guanylate cyclase as in smooth muscle. Thus, EDRF may exert an inhibitory effect on platelets in a manner analogous to its actions on vascular smooth muscle.
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PMID:Activation of guanylate cyclase and inhibition of platelet aggregation by endothelium-derived relaxing factor released from cultured cells. 289 9

A large number and variety of compounds (acetylcholine, adenosine diphosphate, adenosine triphosphate, arachidonic acid, bradykinin, Ca2+ ionophores, calcitonin gene-related peptide, histamine, hydralazine, substance P, thrombin, and vasoactive intestinal polypeptide) have been shown to relax arterial smooth muscle indirectly. The endothelium in muscular arteries from several species appears to have receptors for these vasodilators. Binding of one of these compounds to its endothelial receptors results in the release (and presumably synthesis) of substance(s) that act on arterial smooth muscle to cause relaxation. The name endothelium-derived relaxing factor (EDRF) has been proposed for the substance or substances responsible for inhibition of contraction. Studies to determine additivity of endothelium-dependent relaxing agents and sensitivity of EDRF-mediated responses to a variety of inhibitors suggest that a single factor or a single common mechanism induces relaxation of vascular smooth muscle. Pharmacological studies have been equivocal with regard to the postulated involvement of phospholipases or arachidonic acid and to the suggestion that EDRF is an oxidative, non-cyclooxygenase product of arachidonate. Experiments on transfer of EDRF and reversal of endothelium-dependent relaxation consistently indicate that EDRF is quite labile. There is convincing evidence that EDRF activates smooth muscle guanylate cyclase, which results in an increase in intracellular cyclic guanosine 3',5'-monophosphate levels. The stimulation of guanylate cyclase by EDRF provides a valuable and sensitive parameter for studies with arteries as well as cells in culture. At present, the identity of EDRF and its role in cardiovascular homeostasis are unknown.
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PMID:Endothelium-derived vascular relaxing factor. 298 29


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