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)

12-Hydroperoxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) as well as several other fatty acid hydroperoxides are potent inhibitors of platelet activation. 12-HPETE but not 12-hydroxy-5,8,10,14-eicosatetraenoic acid blocks the U46619- and the thrombin-triggered aggregation of aspirin-treated platelets, dose dependently. 12-HPETE suppresses thromboxane production by inhibiting platelet cyclooxygenase and stimulates its own production by increasing lipoxygenase activity, although this effect does not explain the inhibitory activity of 12-HPETE during the initial phase of cell activation. The inhibitory effect is related to altered calcium homeostasis during platelet activation. 12-HPETE inhibits calcium release from intracellular stores and modifies the influx of extracellular calcium. The inhibitory effect on calcium mobilization is explained by activation of soluble guanylate cyclase. These inhibitory properties are shared by sodium nitroprusside, a compound known to activate soluble guanylate cyclase. Fatty acid hydroperoxides, especially 12-HPETE, produce a rapid and dose-dependent activation of soluble guanylate cyclase, using intact human platelets as a detection system. Activation of the enzyme shows a position isomer specificity, with 12-HPETE being the most potent activator. The generation of the labile lipoxygenase product 12-HPETE during platelet activation may modulate platelet reactivity by increasing cyclic GMP. This pathway may contribute to a physiological feedback mechanism to limit the size of a growing platelet plug.
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PMID:12-hydroperoxyeicosatetraenoic acid inhibits main platelet functions by activation of soluble guanylate cyclase. 167 88

Pretreatment of phenylephrine (0.5 microM)-preconstricted, isolated perfused kidneys of the male rat with indomethacin (2.8 microM) or BM 13.177 (20 microM) abolished the vasoconstrictor response to arachidonic acid (AA), uncovering a vasodilator response. BW 755C (25 microM), a dual cyclooxygenase/lipoxygenase inhibitor, did not modify the vasodilator effect of AA, whereas 5,8,11,14-eicosatetraynoic acid (10 microM), which blocks all pathways of AA metabolism, abolished AA-induced vasodilation, thus suggesting the involvement of nonlipoxygenase AA metabolites. Clotrimazole (0.7 microM) and 7-ethoxyresorufin (1 microM), both considered to be specific inhibitors of the cytochrome P-450 monooxygenase enzymes, inhibited the vasodilator effect, suggesting that AA-induced renal vasodilation is mediated by one or more cytochrome P-450-derived AA metabolites. None of these interventions affected the vasodilator responses to acetylcholine (100 ng) and nitroprusside (1 microgram). Denudation of the endothelium with CHAPS (10 mg/l) reduced the vasodilator responses to AA, suggesting a requirement of an intact endothelium, whereas inhibition of guanylate cyclase with methylene blue (10(-4) M) was without effect, suggesting that cGMP was not involved in the vasodilator response to AA. The AA-induced renal vasodilation was accompanied by the generation of biologically active material or materials released into the renal effluent, which relaxed endothelium-intact and endothelium-denuded rings of isolated aorta and mesenteric and celiac arteries of the rabbit. These results suggest that in the rat kidney, AA is metabolized by endothelial cytochrome P-450-dependent enzymes to vasodilator metabolites.
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PMID:Cytochrome P-450-dependent vasodilator responses to arachidonic acid in the isolated, perfused kidney of the rat. 190 Dec 56

A role for altered endothelial cell function is emerging in the pathogenesis of disease. We have previously demonstrated that Dirofilaria immitis, the canine heartworm, depresses endothelium-dependent responses and alters the mechanism of relaxation in the in vivo femoral artery of infected dogs. Exposure of rat aorta to the parasite or parasite-conditioned medium selectively depresses endothelium-dependent relaxation. D. immitis is closely related to the major human filarial pathogens. This study was designed to examine the effect of chronic infection with the filarial nematode Brugia pahangi on endothelium-mediated responses of the rat aorta in vitro. We tested the hypothesis that endothelium-dependent responses are depressed in the aorta from rats infected with B. pahangi. Rings of thoracic and abdominal aorta were suspended in muscle baths for measurement of isometric tension. Dose-response relations to norepinephrine, endothelium-dependent dilators (acetylcholine, histamine, and A23187), and nitroglycerin were done. In some experiments, inhibitors of cyclooxygenase (indomethacin and aspirin), guanylate cyclase (methylene blue), and nitric oxide formation (N-nitro-L-arginine methyl ester; L-NOARG) were used. No differences in vascular reactivity were detected in the thoracic aorta. In contrast, endothelium-dependent responses in abdominal aorta of Brugia-infected rats were significantly depressed when compared with control aorta from noninfected rats. Acetylcholine relaxation was further depressed by indomethacin and aspirin. After L-NOARG, acetylcholine relaxation in control abdominal aorta was completely abolished; however, in abdominal aorta of Brugia-infected rats, acetylcholine still caused relaxation. Methylene blue inhibited acetylcholine relaxation in both control and Brugia-infected abdominal aorta; however, relaxation in Brugia-infected aorta was significantly greater than control. This study demonstrates that endothelium-dependent relaxation can be altered by chronic experimental filarial infection in the absence of direct contact between the blood vessel and the parasite. The mechanism of relaxation in the Brugia-infected abdominal aorta appears to be altered when compared with control, suggesting that parasites are capable of modulating vascular reactivity by inducing changes in endothelial cell behavior. The mechanism may involve parasite-induced local inflammation or alterations in endothelial cell metabolism. Understanding how chronic experimental filarial infection alters vascular reactivity may enhance our understanding of the pathogenesis of human filariasis.
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PMID:Depression of endothelium-dependent relaxation in aorta from rats with Brugia pahangi lymphatic filariasis. 190 79

The role of the endothelium as a participant in the responses to vasoactive agents was evaluated in isolated canine hepatic artery (HA) and portal vein (PV) rings. Endothelial and smooth muscle integrity was determined by pharmacologic responses as well as by histologic examination. Smooth muscle relaxation was expressed as the percent of decrease of norepinephrine-induced isometric contraction. Acetylcholine (ACh)-induced relaxation of the HA was abolished by removing the endothelium or by the addition of either hemoglobin, methylene blue (MB) or Ng-mono-methyl-L-arginine. In addition, relaxation induced by nitroglycerin, but not that induced by prostaglandin E1, was attenuated by MB. These data suggest endothelium-dependency of the relaxation to ACh and mediation of the response by endothelium-derived relaxing factor through activation of guanylate cyclase. In contrast, ACh produced contraction of the PV which was unaffected by removing the endothelium. The calcium ionophore, A23187, on the other hand, produced relaxation of the PV, which was significantly decreased by removing the endothelium. Relaxation of both HA and PV, produced by 2-chloroadenosine (2-C-Ado) was partially attenuated by removing the endothelium. With the endothelium intact, neither hemoglobin, MB, Ng-monomethyl-L-arginine nor indomethacin affected the responses to 2-C-Ado in the HA and PV, suggesting that the responses were not mediated by endothelium-derived relaxing factor or products of guanylate cyclase or cyclooxygenase activity. Nitroglycerin relaxed both vessels in the presence or absence of endothelium, indicating that removal of the endothelium had not affected smooth muscle function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of endothelium in responses of isolated hepatic vessels to vasoactive agents. 192 Jan 37

1) Eicosanoids are a family of polyunsaturated 20-carbon fatty acids and their metabolites. The metabolites are produced by three enzymatic pathways: the cyclooxygenase pathway, giving prostaglandins (PGs), the lipoxygenases and the epoxygenases pathways. Arachidonic acid (C20:4) is the most common fatty acid precursor in mammalian cells, where it is incorporated, as an ester, into the membrane lipid complex. 2) The eicosanoids have a variety of effects on several cell activities, including secretion, muscle contraction, cell growth and differentiation. The type of effect--stimulation or inhibition--depends on the metabolite, its concentration, the metabolic activity of the cell and the involvement of other humoral factors. 3) The message may be transmitted via a specific membrane receptor to a specific transduction system: the adenyl or guanyl cyclase system and mobilization of free cytosolic Ca2+, or via the participation of membrane ion channels. Depending on which is involved, the eicosanoid message applies to the cell in which it was synthesized or to neighboring cells (autocrine or paracrine action). 4) The eicosanoids, especially the PGs, take part in many reproductive processes; in the hypothalamic-pituitary axis, particularly through the synaptic modulation by PGE2 (stimulation of LHRH secretion and inhibition of noradrenaline secretion); in the ovary: follicle maturation and luteolysis; in the oviducts: gamete migration; in the uterus: ovum implantation and parturition. 5) PGs seem to have a variety of species-dependent effects on the normal onset of labor. In sheep there is an increase in fetal cortisol, a drop in the progesterone/estradiol ratio and increased PG synthesis. In women, there is an increase of phospholipase A2 activity in amnios and uterus with an increase of PGE2 in the first tissue and of PGF2 alpha in the second one. 6) The PGs from the seminal fluid have several actions. They effect fertility by acting on the female genital tract or on the spermatozoa. PGE1 and PGE2 influence the fertilization capacity. PGs also effect the process of ejaculation (inhibition of the stimulatory effect of noradrenaline). Finally, they effect the immune responses: PGEs and 19 hydroxy PGEs immuno-suppressive characteristics.
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PMID:[Prostaglandins and reproduction. I. Physiological aspects]. 201 23

The great discovery by Furchgott of the relaxing factor released from the endothelium (EDRF) awakened us to the necessity to reevaluate the functional importance of endothelial cells that have been chemically or physically stimulated. EDRF was first demonstrated to be released by acetylcholine, substance P, bradykinin and calcium ionophore A23187; thereafter, many substances have been found to release EDRF. This factor is quite unstable, is not produced by cyclooxygenase, and is an activator of soluble guanylate cyclase that synthesizes cyclic GMP; its action is suppressed by antioxidants via the superoxide anions produced, potentiated by superoxide dismutase and abolished by methylene blue and oxyhemoglobin. Recently, the role of lipoxygenase products in the production of EDRF was evaluated with new 5-lipoxygenase inhibitors without antioxidant activity. During the last couple of years, the actions and chemical properties of EDRF were verified to be quite similar to those of nitric oxide (NO); therefore, the hypothesis of "EDRF = NO" is widely being accepted. NO is produced from L-arginine via catalysis by an enzyme that is activated by Ca2+. The enzyme activity is inhibited by L-monomethyl arginine and other L-arginine analogs. Chemical and physical stimulations increase intracellular Ca2+ in endothelial cells that seems to be associated with K(+)-channel opening and hyperpolarization. Current interests are directed to the possible roles of NO in the regulation of nerve function. There are evidences suggesting that NO modulates adrenergic nerve function in blood vessels and some brain cell functions regulated by cellular cyclic GMP. Particularly, NO may be a transmitter substance in non-adrenergic, non-cholinergic vasodilator nerves innervating the cerebral arteries. Future investigations will determine the physiological roles of EDRF or NO and its relationships to pathophysiology of vascular dysfunctions, such as vasospasm and those related to hypertension, diabetes, aging, etc., and the extended roles of NO in nerve function, inflammation, immune reactions, etc. would be clarified more extensively by accelerated progress in this field of research.
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PMID:[Endothelium-derived relaxing factor (EDRF)]. 216 93

Epidermal growth factor (EGF) is released from platelets during aggregation. Because we thought that EGF played a role in vascular tone, we investigated its vascular reactivity using isolated rat aortic strips with and without the endothelium. In the presence of endothelium, EGF relaxed vascular smooth muscle precontracted with 40 mM K+, 10(-5) M prostaglandin F2 alpha or 10(-6) M norepinephrine. The relaxation induced by EGF was more prominent on the prostaglandin F2 alpha- and norepinephrine-induced contractions than on the K(+)-induced contraction. Atropine (10(-5) M) and aspirin (10(-5) M) had no effect on the EGF-induced relaxation, but methylene blue (10(-5) M) partly abolished the relaxation evoked by EGF. These results suggest that EGF relaxes vascular smooth muscle in the presence of the endothelium. They also suggest that EGF has an effect on the endothelium to produce relaxing factor independent of cyclooxygenase; the releasing factor activates soluble guanylate cyclase, resulting in relaxation of vascular smooth muscle through the production of cyclic GMP.
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PMID:Vascular smooth muscle relaxation induced by epidermal growth factor is endothelium-dependent. 236 6

Removal of the epithelium increases the sensitivity of mammalian airway smooth muscle to several bronchoactive agents. An epithelium derived relaxing factor (EpDRF) of unknown identity has been postulated to modulate smooth muscle tone in the airways. Rings or segments of porcine third order bronchi, from some of which the epithelium had been removed mechanically, were mounted in organ baths for isometric tension recording. Removal of the epithelium affected bronchial reactivity. Metacholine produced concentration-dependent contractions of porcine bronchi. In the absence of epithelium the concentration response curve was shifted to the left (p less than 0.01). The effect of epithelium removal was not inhibited by diclofenac (100 microM), propranolol (5 microM), the inhibitor of endothelium-derived relaxing factor gossypol (10 microM). These observations suggest that the epithelium of porcine bronchi relaxes the tone of the subjacent smooth muscle. The EpDRF probably responsible for this effect is neither a cyclooxygenase product nor a stimulator of soluble guanylate cyclase.
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PMID:[The effect of bronchial epithelium on bronchial contractility]. 236 20

Substance P is a vasoactive peptide. Nerve fibers containing substance P are present in the media of pulmonary arteries but the physiologic function of substance P in the pulmonary vasculature is unknown. Several doses of substance P were infused intravenously in the anesthetized dog to ascertain its effects on the pulmonary vasculature, both during normoxia and following preconstriction with hypoxia (F1O2 0.1) or prostaglandin F2 alpha (PGF2 alpha 5 mug/kg/min). Substance P resulted in systemic vasodilation during normoxia but had minimal effect on the pulmonary vasculature. During hypoxia and PGF2 alpha-induced pulmonary vasoconstriction, substance P significantly lowered pulmonary artery pressure, pulmonary vascular resistance, mean aortic pressure, and total systemic resistance. It had no effect on cardiac output, wedge pressure, and arterial blood gases. To investigate possible mechanisms for substance P-induced vasodilation, substance P was studied following pretreatment with N-acetylcysteine (a radical scavenging agent), methylene blue (an inhibitor of guanylate cyclase), meclofenamate (a cyclooxygenase inhibitor), and atropine (a muscarinic receptor antagonist). None of these agents impaired substance P-induced vasodilation. Substance P given intravenously is a nonselective vasodilator in the dog but the mechanism of its action remains uncertain.
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PMID:The effects of substance P on the preconstricted pulmonary vasculature of the anesthetized dog. 242 48

Nicorandil, a compound having structural similarities to some of the organic nitrates, was studied for its mechanism of vasodilation. Nicorandil is thought to be a K+ channel opening agent. However, little is known about its receptor activation profile, its endothelial dependence, and its effects in atherosclerotic vessels. Nicorandil, at 0.2 to 5 x 10(-6) M, relaxed norepinephrine precontracted rabbit aortic rings in a concentration-dependent manner. Moreover, nicorandil relaxed aortic rings to the same extent in the presence and absence of an intact endothelium. However, nicorandil's effect was diminished in aortic rings from atherosclerotic rabbits. The vasorelaxation action of nicorandil was unaffected by the cyclooxygenase inhibitor ibuprofen or the lipoxygenase inhibitor propyl gallate, suggesting that nicorandil does not act via the release of a vasodilator eicosanoid. Although the nicorandil effect was not influenced by atropine, a muscarinic receptor antagonist, it was significantly attenuated by methylene blue, a guanyl cyclase inhibitor. Thus, nicorandil has some properties in common with organic nitrates and with K+ channel activators but appears to be a unique type of vasodilator.
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PMID:Studies on the mechanism of the vasodilator action of nicorandil. 245 46


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