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

---

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 examine the relationship between responses of bovine intrapulmonary artery and vein to arachidonic acid and cyclic nucleotide levels in order to better understand the mechanism of relaxation elicited by arachidonic acid and acetylcholine. Arachidonic acid relaxed phenylephrine-precontracted arterial rings and elevated both cyclic GMP and cyclic AMP levels in arteries with intact endothelium. In contrast, endothelium-damaged arterial rings contracted to arachidonic acid without demonstrating significant changes in cyclic nucleotide levels. Indomethacin partially inhibited endothelium-dependent relaxation and abolished cyclic AMP accumulation whereas methylene blue, a guanylate cyclase inhibitor, partially inhibited relaxation and abolished cyclic GMP accumulation in response to arachidonic acid. All vessel responses were blocked by a combination of the two inhibitors. Prostaglandin (PG) I2 relaxed arterial rings and elevated cyclic AMP levels whereas PGE2 and PGF2 alpha caused contraction, suggesting that the indomethacin-sensitive component of arachidonic acid-elicited relaxation is due to PGI2 formation and cyclic AMP accumulation. The methylene blue-sensitive component is attributed to an endothelium-dependent but cyclooxygenase-independent generation of a substance causing cyclic GMP accumulation. Intrapulmonary veins contracted to arachidonic acid with no changes in cyclic nucleotide levels and PGI2 was without effect. Homogenates of intrapulmonary artery and vein formed 6-keto-PGF1 alpha, PGF2 alpha and PGE2 from [14C]arachidonic acid, which was inhibited by indomethacin. Thus, bovine intrapulmonary vein may not possess receptors for PGI2. The failure of endothelium-intact vein to relax to acetylcholine may be related to the lack of a relaxant effect by arachidonic acid, perhaps attributed to the absence of generation of an endothelium-derived relaxing factor.
...
PMID:Differences in responsiveness of intrapulmonary artery and vein to arachidonic acid: mechanism of arterial relaxation involves cyclic guanosine 3':5'-monophosphate and cyclic adenosine 3':5'-monophosphate. 298 87

Flow-dependent dilation of the canine femoral artery is endothelial cell dependent and is not mediated by prostaglandins, adrenergic or cholinergic receptors, an ascending message from the microcirculation, or by myogenic mechanisms. We investigated the mechanism of flow dilation in 38 pentobarbital anesthetized dogs. A femoral artery-jugular vein shunt was constructed, and femoral artery diameter was continuously measured (sonomicrometer crystals) during control and maximum flow (1 l/min). Inhibition of prostaglandin formation by indomethacin did not alter the dilation response to increased flow, but the lipoxygenase-cyclooxygenase inhibitor 5, 8, 11, 14 eicosatetraynoic acid (ETYA) irreversibly inhibited the dilation response to increased flow. The guanylate cyclase inhibitor, methylene blue, caused a dose-dependent decrease in the dilation response to increased flow. Pretreatment with the H1 receptor antagonist tripelennamine sensitized the vessel to the inhibitory effects of methylene blue. Both methylene blue and ETYA shifted the ED50 for acetylcholine relaxation two orders of magnitude to the right, but did not alter the ability of the vessel to dilate or constrict to other stimuli. These data suggest that both cyclic GMP and a non-prostaglandin metabolite of arachidonic acid are involved in flow dilation. We propose that endothelial cells release a metabolite of arachidonic acid that stimulates vascular smooth muscle guanylate cyclase leading to relaxation. The role of histamine in this system is unknown.
...
PMID:Methylene blue and ETYA block flow-dependent dilation in canine femoral artery. 301 27

Inhibitors of arachidonate metabolism and perturbants of the oxidation-reduction state of the cell were employed to develop a pharmacologic profile for muscarinic receptor-mediated cyclic GMP formation in murine neuroblastoma cells (clone N1E-115). Several lipoxygenase inhibitors [eicosatetraynoic acid (ETYA), nordihydroguaiaretic acid (NDGA), FPL 57231, FPL 55712, BW755c, propylgallate, and AA861] blocked the elevation of [3H]cyclic GMP induced by muscarinic receptor activation. The cyclooxygenase inhibitors indomethacin and ibuprofen were two orders of magnitude less potent in blocking the muscarinic receptor-mediated [3H]cyclic GMP response than in blocking cyclooxygenase in other systems. ETYA and NDGA did not affect the muscarinic inhibition of the prostaglandin E1-mediated increases in [3H]cyclic AMP levels in N1E-115 cells. ETYA did not have a reproducible effect on the muscarinic receptor-induced release of inositol phosphates. Thus, these lipoxygenase inhibitors appeared to be selective for the effector system coupled to the low-affinity muscarinic agonist-receptor conformation, i.e. that which induces cyclic GMP formation. Other effective inhibitors of the cyclic GMP response were methylene blue, catalase, bromphenacyl bromide, retinal, dithiothreitol, quinacrine, and oxidized glutathione. The antioxidant alpha-tocopherol in the concentration range of 100 microM to 1 mM potentiated the receptor response. Arachidonic acid itself was an inhibitor of the muscarinic receptor-mediated cyclic GMP response (IC50 = 45 microM). Linoleic acid and oleic acid were less potent (IC50 = 130 and 190 microM, respectively), and stearic acid was ineffective. When arachidonic acid was air-oxidized, its inhibitory potency was increased 10-fold. Most but not all of the spontaneously-produced oxidative metabolites, separable by reverse-phase high pressure liquid chromatography, were inhibitory to the receptor response. Enzymatically synthesized 12-hydroxyeicosatetraenoic acid and 15-hydroxyeicosatetraenoic acid inhibited the muscarinic receptor [3H]cyclic GMP response, with IC50 values of 17 and 8 microM respectively. Catalase was effective in blocking the muscarinic cyclic GMP response (IC50 = 5 microM) while having no effect on either the muscarinic receptor-induced inositol phosphate release or the reduction of cyclic AMP levels. Thus, the effector system for increasing cyclic GMP in these cells displays may of the expected characteristics for the involvement of a lipoxygenase or a related enzyme that oxidatively metabolizes arachidonate in order to activate the guanylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:Blockade of N1E-115 murine neuroblastoma muscarinic receptor function by agents that affect the metabolism of arachidonic acid. 301 48

Dietary intake of unsaturated fatty acid of eicosapentaenoic acid (EPA) is thought to reduce the size and incidence of myocardial infarction. These beneficial effects are postulated to be due to chronic antithrombotic properties of EPA itself. We studied the possible direct effects of EPA on vascular smooth muscle as well as the ability of EPA to modify the vasoactivity of constrictor mediators in rabbit and cat aortic rings and isolated cat coronary arteries. EPA concentration-dependently (30 to 300 microM) relaxed rabbit and cat aortic rings having an intact endothelium, while EPA did not show any significant vasodilator effects on rings without an endothelium. This EPA-induced vasorelaxation was not altered by the cyclooxygenase inhibitor ibuprofen, but was totally abolished by the guanylate cyclase inhibitor methylene blue, indicating an endothelium-dependent smooth muscle relaxation mechanism. In isolated perfused cat coronary arteries, EPA (3 to 300 microM) exerted a dilator effect which was endothelium-independent and not affected by ibuprofen. The response was attenuated by propyl gallate, a lipoxygenase inhibitor. EPA also inhibited leukotriene (LT) C4, (50 nM) and LTD4 (50 nM)-induced vasoconstriction of isolated cat coronary arteries ranging from a blockade of 10% to 15% (P less than 0.05) at 3 microM of EPA to a blockade of 89% to 93% (P less than 0.01) at 300 microM. In contrast, the thromboxane analog, CTA2, induced coronary constriction was not significantly altered by EPA. Thus, EPA produces endothelium-dependent relaxation in rabbit and cat aorta and endothelium-independent vasodilation in cat coronary arteries (i.e., intact vessels or helical strips). Moreover, EPA exerts acute anti-leukotriene actions in coronary arteries. In the case of long-term dietary intake of EPA, these actions may contribute to the protective action of EPA in myocardial ischemia.
...
PMID:Vasoactive effects of eicosapentaenoic acid on isolated vascular smooth muscle. 303 70

The effect of the acidic phospholipase A2 (PLA2) from Vipera russelli venom on the rat aortic ring was studied and compared with that of acetylcholine (ACh). PLA2 induced relaxation of the aortic ring precontracted with noradrenaline (NA) in a dose-dependent manner. Removal of the endothelium did not reduce the relaxant effect of PLA2. Replacement of Ca2+ by Sr2+ in the medium to inhibit the PLA2 enzyme activity reduced the relaxant effect. Atropine, a muscarinic receptor antagonist, did not affect the relaxant response. The cyclooxygenase inhibitor indomethacin, when equilibrated for 50 min, potentiated the relaxation. The lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) partially reduced the relaxation. This relaxation was also partially reduced by the guanylate cyclase inhibitor methylene blue. In contrast, the relaxation elicited by ACh was abolished by de-endothelialization, atropine, NDGA or methylene blue. 6-keto-PGF1 alpha (degradation product of prostacyclin) and PGE2 produced by aortic rings were measured by radioimmunoassay. PLA2 (3 X 10(-6) g/ml) increased the output of 6-keto-PGF1 alpha about 10-fold. The production of PGE2 was also increased but to a lesser extent. ACh also increased the output of 6-keto-PGF1 alpha and PGE2. However, prostacyclin released by PLA2 and ACh appears not to contribute to the relaxant effect, since prostacyclin does not relax the rat aorta. It is concluded that the relaxation elicited by PLA2 in the rat aorta is endothelium-independent and partially mediated by lipoxygenase product(s) and cyclic GMP whereas the relaxation induced by ACh was endothelium-dependent, mediated by lipoxygenase product(s) and cyclic GMP, and blocked by atropine.
...
PMID:Relaxant effect of phospholipase A2 from Vipera russelli snake venom on rat aorta. 408 46

The mechanism of activation of intestinal guanylate cyclase by Escherichia coli heat-stable enterotoxin (STa) has been studied by using isolated rat intestinal epithelial cells and purified brush border membrane (BBM) preparations. Inhibitors of prostaglandin biosynthesis, quinacrine and 5,8,11,14-eicosatetraynoic acid (ETYA), significantly reduced intracellular levels of cyclic guanosine 3', 5'-monophosphate in isolated cells treated with STa. Although these data suggested that activation of phospholipase A2 and metabolism of arachidonic acid are involved in the mechanism of action of STa, other data ruled out such a mechanism. (i) The rate of release of [3H]arachidonic acid by prelabeled intestinal cells incubated with STa was the same as control cells not treated with STa. (ii) Thin-layer chromatography of lipid extracts of intestinal cells treated with STa and untreated cells did not reveal any quantitative or qualitative differences in free fatty acids, neutral lipids, and phospholipids. (iii) Amounts of prostaglandin PGE2, prostaglandin PGF2 alpha, and thromboxane B2 in intestinal cells and BBM incubated with STa did not increase compared with controls not incubated with STa. When purified BBM preparations were incubated with phospholipase A2 inhibitors (p-bromophenacyl bromide and quinacrine) or cyclooxygenase inhibitors (ETYA and indomethacin), basal and STa-induced guanylate cyclase activities were significantly reduced. Inhibitors of calcium-calmodulin-mediated reactions (EGTA [ethylene glycol-bis(beta-aminoethyl ether)-N,N-tetraacetic acid], trifluoperazine, and chlorpromazine) and calcium channel blockers (verapamil and nifedipine) also nonspecifically inhibited both basal and STa-stimulated guanylate cyclase in BBM preparations. Lanthanum, a competitive inhibitor of membrane-bound calcium, did not affect either basal or STa-stimulated guanylate cyclase of BBM preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Characterization of the mechanism of action of Escherichia coli heat-stable enterotoxin. 614 30

Previous research indicates that norepinephrine and dopamine stimulate release of luteinizing hormone (LH)-releasing hormone (LHRH), which then reaches the adenohypophysis via the hypophyseal portal vessels to release LH. Norepinephrine exerts its effect via alpha 1-adrenergic receptors, which stimulate the release of nitric oxide (NO) from nitricoxidergic (NOergic) neurons in the medial basal hypothalamus (MBH). The NO activates guanylate cyclase and cyclooxygenase, thereby inducing release of LHRH into the hypophyseal portal vessels. We tested the hypothesis that these two catecholamines modulate NO release by local feedback. MBH explants were incubated in the presence of sodium nitroprusside (NP), a releaser of NO, and the effect on release of catecholamines was determined. NP inhibited release of norepinephrine. Basal release was increased by incubation of the tissue with the NO scavenger hemoglobin (20 micrograms/ml). Hemoglobin also blocked the inhibitory effect of NP. In the presence of high-potassium (40 mM) medium to depolarize cell membranes, norepinephrine release was increased by a factor of 3, and this was significantly inhibited by NP. Hemoglobin again produced a further increase in norepinephrine release and also blocked the action of NP. When constitutive NO synthase was inhibited by the competitive inhibitor NG-monomethyl-L-arginine (NMMA) at 300 microM, basal release of norepinephrine was increased, as was potassium-evoked release, and this was associated in the latter instance with a decrease in tissue concentration, presumably because synthesis did not keep up with the increased release in the presence of NMMA. The results were very similar with dopamine, except that reduction of potassium-evoked dopamine release by NP was not significant. However, the increase following incubation with hemoglobin was significant, and hemoglobin, when incubated with NP, caused a significant elevation in dopamine release above that with NP alone. In this case, NP increased tissue concentration of dopamine along with inhibiting release, suggesting that synthesis continued, thereby raising the tissue concentration in the face of diminished release. When the tissue was incubated with NP plus hemoglobin, which caused an increase in release above that obtained with NP alone, the tissue concentration decreased significantly compared with that in the absence of hemoglobin, indicating that, with increased release, release exceeded synthesis, causing a fall in tissue concentration. When NO synthase was blocked by NMMA, the release of dopamine, under either basal or potassium-evoked conditions, was increased. Again, in the latter instance the tissue concentration declined significantly, presumably because synthesis did not match release. Therefore, the results were very similar with both catecholamines and indicate that NO acts to suppress release of both amines. Since both catecholamines activate the release of LHRH, the inhibition of their release by NO serves as an ultra-short-loop negative feedback by which NO inhibits the release of the catecholamines, thereby reducing the activation of the NOergic neurons and decreasing the release of LHRH. This may be an important means for terminating the pulses of release of LHRH, which generate the pulsatile release of LH that stimulates gonadal function in both male and female mammals.
...
PMID:Nitric oxide inhibits the release of norepinephrine and dopamine from the medial basal hypothalamus of the rat. 747 83

Isolated perfused rat kidney was used to examine the possible mechanisms involved in the hypotensive/vasodilator actions of cryptolepine. In kidneys preconstricted by phenylephrine (PE 5-7.5 x 10(-7) M), cryptolepine at bolus doses of 2.5, 5, and 10 micrograms elicited dose-dependent reductions in perfusion pressure by 29.8 +/- 4.1, 43.3 +/- 3.9, and 54.3 +/- 4.9 mm Hg, respectively. In the presence of indomethacin, cryptolepine-induced reduction in perfusion pressure was not significantly changed, suggesting a lack of a cyclooxygenase-mediated component in its renal vasodilator response. Removal of the endothelium with p-bromophenacyl bromide (p-BPB 10 microM) inhibited the vasodilator response to cryptolepine 2.5, 5, and 10 micrograms to 10.2 +/- 1.8, 15.9 +/- 1.5, and 20.2 +/- 2.0 mm Hg, respectively (p < 0.01). The vasodilator response to acetylcholine (ACh 50 ng) was also reduced from a control value of 56.7 +/- 4.5 to 15.3 +/- 1.9 mm Hg (p < 0.01); responses to sodium nitroprusside (SNP 5 micrograms) and isoprenaline (1 microgram) were not affected. In kidneys treated with hydroquinone (10(-5) and 10(-4) M), a specific inhibitor of endothelium-dependent vasodilation, cryptolepine- and ACh-induced vasodilation were inhibited dose dependently (p < 0.01). N omega-nitro-L-arginine (L-NNA 10(-5)-10(-4) M), a specific inhibitor of the synthesis/release of endothelium-derived relaxing factor/nitric oxide (EDRF/NO), attenuated the vasodilator response to cryptolepine and ACh (50 ng) dose dependently. At 10(-4) M L-NNA, cryptolepine-induced vasodilation was reduced to 6.6 +/- 2.2 (2.5 micrograms), 10.9 +/- 2.2 (5 micrograms), and 13.3 +/- 1.4 mm Hg (10 micrograms). L-Arginine (10(-4) and 3 x 10(-4) M) but not D-arginine (10(-4) M) inhibited the effects of L-NNA, with vasodilatory effects of cryptolepine returning to control values, suggesting that the vasodilator material released by cryptolepine is EDRF, possibly NO. Methylene blue (MB 10(-4) M), the inhibitor of soluble guanylate cyclase which inhibited 50 ng ACh and 5 micrograms SNP-induced vasodilation also reduced the vasodilatory responses to cryptolepine to 0.8 +/- 0.8 (2.5 micrograms), 4.2 +/- 4.2 (5 micrograms), and 10.8 +/- 6.2 mm Hg (10 micrograms) suggesting that the effector pathway for cryptolepine-induced vasodilation is soluble guanylate cyclase-linked increase in cyclic GMP of vascular smooth muscle.
...
PMID:Role of the endothelium and cyclic GMP in renal vasodilator responses to cryptolepine in rats. 751 10

Endothelium-dependent modulation of vascular tone was investigated in isolated porcine and bovine basilar arteries. L-Nitro-arginine (NO synthase inhibitor) and methylene blue (soluble guanylate cyclase inhibitor) increased, but indomethacin (cyclooxygenase inhibitor) decreased the vascular tone in the basilar arteries from both species. Bradykinin evoked relaxation of precontracted porcine basilar artery, but not bovine basilar artery. Sodium fluoride (endothelial G-protein activator) produced relaxation of precontracted basilar arteries from both species. The effects of bradykinin and sodium fluoride were completely abolished by endothelial denudation and markedly inhibited by L-nitro-arginine and methylene blue, but not by indomethacin. Sodium nitroprusside (guanylate cyclase activator) evoked relaxation of precontracted endothelium-denuded basilar arteries from both species. These results suggest that there is species variation in endothelium-dependent modulation of vascular tone in the basilar artery.
...
PMID:Endothelial modulation of vascular tone in isolated porcine and bovine basilar arteries. 753 39

To investigate the possible neuromodulatory role of nitric oxide (NO) in the gastrointestinal tract, an examination was made of the effects of NG-nitro-L-arginine (L-NOARG), an inhibitor of NO synthase, on the intestinal response to [Met5]-enkephalin (ENK) by recording the mechanical activity of the isolated duodenum from rats. [Met5]-enkephalin elicited a biphasic response of the duodenum, i.e. transient relaxation followed by contraction. The relaxation induced by ENK was blocked by naloxone, an opioid receptor antagonist, but not by tetrodotoxin (TTX). The contractile response of the duodenum to ENK was blocked by TTX but not by naloxone. The contractile response was not affected by hyoscine, a muscarinic antagonist, or guanethidine, an adrenergic neuron blocking agent, indicating mediation by non-adrenergic, non-cholinergic (NANC) nerves. The contractile but not the relaxant response to ENK was blocked by L- but not D-NOARG. The contractile response was also inhibited by methylene blue, an inhibitor of both NO synthase and guanylate cyclase, and by indomethacin, a cyclooxygenase inhibitor. Thus, endogenous NO and prostaglandins are involved in the contractile response to ENK. Endogenous NO may modulate the release of excitatory NANC transmitters via a prejunctional mechanism.
...
PMID:Involvement of endogenous nitric oxide in non-adrenergic, non-cholinergic contraction elicited by [Met5]-enkephalin in rat isolated duodenum. 753 16


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---