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)

This study examined whether a clinically relevant concentration of the volatile anaesthetic halothane modifies the endothelium-dependent relaxation produced by acetylcholine (3 nM-10 microM), histamine (1 pM-0.1 microM) and anti-human immunoglobulin E (1:1000) in human isolated pulmonary arteries submaximally precontracted with noradrenaline. An inhibitor of nitric oxide formation, N(G)-nitro-L-arginine (100 microM), attenuated acetylcholine-induced relaxation but failed to inhibit histamine- and anti-human immunoglobulin E-induced relaxation. Indomethacin (2.8 microM, a cyclooxygenase inhibitor) preferentially reduced the relaxation to histamine and anti-human IgE. Halothane (2%) significantly attenuated the relaxation to acetylcholine but had no significant effect on the relaxation elicited by histamine and anti-human IgE. Halothane (2%) enhanced the basal release of prostaglandin I2 by human pulmonary arteries (control 0.31 +/- 0.04 ng mg(-1); treated tissues 0.50 +/- 0.06 ng mg(-1); n = 5; P < 0.05). Halothane (2%) did not alter the responsiveness and sensitivity of preparations to relaxants acting through activation of adenylyl cyclase (forskolin) or guanylyl cyclase (sodium nitroprusside) or by the opening of K(ATP) channels (cromakalim). In conclusion, halothane inhibits the endothelium-dependent relaxation of human pulmonary arteries to acetylcholine by interfering with the nitric oxide pathway at a site before activation of soluble guanylyl cyclase in vascular smooth muscle.
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PMID:Halothane inhibits endothelium-dependent relaxation elicited by acetylcholine in human isolated pulmonary arteries. 919 70

Noradrenergic contractions induced by electrical field stimulation (EFS) of the rabbit anococcygeus muscle and the human and rabbit corpus cavernosum did not occur until termination of stimulation, even when EFS was applied for long periods (10 min). After treatment with a nitric oxide synthase inhibitor, a scavenger of NO, or a specific inhibitor of the soluble guanylate cyclase, EFS-induced contraction began as soon as stimulation commenced and its magnitude and duration were increased. In the presence of a cGMP-phosphodiesterase inhibitor, the lag period between the end of EFS and the onset of contraction was longer, and the response was smaller. Even when the concentration of endogenous noradrenaline was increased with cocaine, the contraction still did not occur during EFS and the lag period was unchanged, although the response was enhanced. When tissue tone was elevated, relaxation occurred during EFS followed by a contraction. After blockade of neuronal noradrenaline release with guanethidine, contractions of the tissues to increasing concentrations of exogenous noradrenaline were significantly reduced by EFS, an effect that was reversible by inhibition of NO synthase. In contrast, in the rat and mouse anococcygeus muscles contraction began immediately with EFS, and nitrergic stimulation by EFS did not affect the responses elicited by high concentrations of exogenous noradrenaline. These results suggest that the human and rabbit genitourinary organs have a powerful nitrergic innervation that does not merely modulate, but actually controls, the sympathetic responses. Our observations may increase understanding of the balance between nitrergic and sympathetic systems in humans, disruption of which may contribute to certain pathological conditions.
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PMID:Nitrergic control of peripheral sympathetic responses in the human corpus cavernosum: a comparison with other species. 922 43

This study has evaluated the possible role played by the L-arginine-nitric oxide pathway in the vasorelaxant action of the hydroalcoholic extract from Eugenia uniflora, and fractions from the extract, in rings of rat thoracic aorta. The addition of an increasing cumulative concentration of hydroalcoholic extract from E. uniflora (1-300 micrograms mL-1) caused a concentration-dependent relaxation response in intact endothelium-thoracic aorta rings pre-contracted with noradrenaline (30-100 nM). The IC50 value, with its respective confidence limit, and the maximum relaxation (Rmax) were 7.02 (4.77-10.00) micrograms mL-1 and 83.94 +/- 3.04%, respectively. The removal of the endothelium completely abolished these responses. The nitric oxide synthase inhibitors N omega-nitro-L-arginine (L-NOARG, 30 microM) and N omega-nitro-L-arginine methyl ester (L-NAME, 30 microM), inhibited the relaxation (Rmax) to -10.43 +/- 7.81% and -3.69 +/- 2.62%, respectively. In addition, L-arginine (1 mM), but not D-arginine (1 mM), completely reversed inhibition by L-NOARG. Methylene blue (30 microM), a soluble guanylate cyclase inhibitor, reduced the relaxation induced by the extract to 14.60 +/- 7.40%. These data indicate that in the rat thoracic aorta the hydroalcoholic extract, and its fractions, from the leaves of E. uniflora have graded and endothelium-dependent vasorelaxant effects.
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PMID:Analysis of the role of nitric oxide in the relaxant effect of the crude extract and fractions from Eugenia uniflora in the rat thoracic aorta. 923 44

1. Makatoxin I (MkTx I) is a new toxin purified from the venom of the scorpion Buthus martensi Karsch. Contractile (excitatory, adrenergic) and relaxant (inhibitory, nitrergic) responses of the rat isolated anococcygeus muscle (Acm) to MkTx I were investigated. 2. MkTx I (0.28 microM) produced a rapid and very marked rise in the tone of the Acm which then gradually wanted to the control baseline. Phentolamine (5 microM), guanethidine (5 microM), tetrodotoxin (2 microM) and reserpine pretreatment in vivo (5 mg kg-1 s.c. at 24 hr and 5 mg kg-1 i.p. at 3 h) completely blocked the contractile responses of the Acm to MkTx I. The responses to noradrenaline (NA) were blocked by phentolamine, but were potentiated by guanethidine. 3. MkTx I (0.28 microM) also marked and rapidly relaxed the tone of the carbachol (CCh; 3 microM), precontracted Acm. The addition of sodium nitroprusside (SNP; 1 microM) also produced a marked and rapid relaxation of the Acm. TTx (2 microM) or NG-nitro-L-arginine methylester (L-NAME, 50 microM) markedly inhibited the relaxant responses of the Acm to field stimulation (FS) as well as to MkTx I, but not the responses to SNP. 4. Therefore, the contractile responses of the rat anococcygeus muscle to MkTx I can be attributed to the release of transmitter NA on postjunctional alpha-adrenoceptors, whereas the relaxant responses of the Acm to MkTx I involve the release of nitric oxide as the neurotransmitter which, presumably, results in the activation of the enzyme guanylate cyclase leading to relaxation of the muscle.
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PMID:Adrenergic and nitrergic responses of the rat isolated anococcygeus muscle to a new toxin (makatoxin I) from the venom of the scorpion Buthus martensi Karsch. 923 83

Alcohol suppresses reproduction in humans, monkeys and small rodents by suppressing release of luteinizing hormone (LH). The major action is on the hypothalamus to decrease release of LH-releasing hormone (LHRH). The release of LHRH is controlled by nitric oxide (NO). The hypothesized pathway is via norepinephrine-induced release of NO from NOergic neurons which activates LHRH release. We have evaluated details of this process in male rats by incubating medial basal hypothalamic (MBH) explants in vitro and examining the release of NO and metabolites generated by NO which control LHRH release. Norepinephrine increased release of NO as measured by determining the content of the enzyme at the end of the experiment (30 min) by adding [14C]arginine to the homogenate and measuring its conversion to [14C]citrulline since this is formed in equimolar quantities with NO by nitric oxide synthase (NOS). Since this increase in content presumably caused by activation of the enzyme by norepinephrine was blocked by the alpha 1 receptor blocker prazosin, it appears that alpha 1 receptors activate NOS by increasing intracellular free calcium in the NOergic neuron which combines with calmodulin to activate nitric oxide synthase. The release of LHRH induced by nitroprusside (NP), a donor of NO, results in an increase in cyclic (c)GMP in the medium supporting the activation of guanylate cyclase by nitroprusside. This activation is important in releasing LHRH since addition of 8-monobutyryl cGMP also released the peptide. Ethanol had no effect on the content of NO or the increase in content induced by norepinephrine indicating that it did not act on NOS. Earlier experiments indicated that prostaglandin E2 (PGE2) was important in releasing LHRH. PGE2 is produced by activation of cyclooxygenase by NO since this could occur following addition of the NO donor nitroprusside. Not only does NP increase PGE2 release, but also the conversion of [14C]arachidonic acid to its metabolites, particularly PGE2. Ethanol acts at this step since it completely blocks the release of LHRH induced by NP and the increase in PGE2 induced by NP. Therefore, the results support the theory that norepinephrine acts to stimulate NO release from NOergic neurons. This NO diffuses to the LHRH terminals, where it activates guanylate cyclase, leading to an increase in cGMP. At the same time, it also activates cyclooxygenase. The increase in cGMP increases intracellular free calcium, required for activation of phospholipase A2. Phospholipase A2 converts membrane phospholipids into arachidonic acid, the substrate for conversion by the activated cyclooxygenase to PGE2 which then activates the release of LHRH. Since alcohol inhibits conversion of labeled arachidonic acid to PGE2, it must act either directly to inhibit cyclooxygenase or by some other mechanism which, in turn, inhibits the enzyme.
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PMID:The mechanism of action of alcohol to suppress gonadotropin secretion. 932 22

We have investigated the differences between the nitric oxide synthase inhibitor (NOSI), L-NMMA, and the guanylate cyclase inhibitors (GCI), methylene blue and LY 83583, in their abilities to increase vasoconstrictor responses in vitro and in vivo. In rat small mesenteric arterial rings, 1 h exposure to the NOSI, L-NMMA (100 microM), and the GCI, methylene blue (10 microM), alone or in combination with L-NMMA, caused a significant reduction in the maximum relaxation to ACh in mesenteric arteries pre-contracted with the thromboxane mimetic U46619 (10 microM). Hence, both NOSI and GCI inhibit endothelium-dependent relaxations to ACh in rat small mesenteric artery. However, 1 h exposure to L-NMMA and L-NNA (both 100 microM), but not methylene blue (10 microM), significantly increased the contractile response to U-46619 (10 microM) in rat small mesenteric artery. It was decided to investigate further this difference between NOSI and methylene blue. In rat small mesenteric arterial rings, L-NMMA (10 microM) and LY 83583 (1-10 microM) significantly increased the contractile response to KCl (40 mM) or to noradrenaline (10 microM), when administered during the contraction. However, methylene blue (1-10 microM) increased the contractile response to KCl but not noradrenaline. In rat aortic rings, L-NMMA (100 microM), methylene blue (1-10 microM) and LY 83583 (1-10 microM) significantly increased the contractile response to KCl (40 mM) or to noradrenaline (1 microM). In the pithed rat preparation, L-NMMA (40.3 micromol kg(-1), i.v.) significantly increased the pressor response both to bolus injection of noradrenaline (3.13 nmol kg[-1]) and to spinal pressor nerve stimulation. However, methylene blue (3.13-15.6 micromol kg[-1]) or LY 83583 (4.0-40.0 micromol kg[-1]), failed to affect pressor responses to either NA or pressor nerve stimulation. Hence, there are differences between NOSI and GCI in their abilities to increase vasoconstrictor responses, especially when comparing responses in vitro and in vivo. This suggests that nitric oxide has actions in addition to activation of guanylate cyclase to modulate vasoconstrictor responses, presumably by membrane hyperpolarisation, and that this action may be more important in vivo.
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PMID:Comparison of the effects of nitric oxide synthase inhibition and guanylate cyclase inhibition on vascular contraction in vitro and in vivo in the rat. 934 35

1. The effect of Tityus serrulatus scorpion venom and its toxin components on the rabbit isolated corpus cavernosum was investigated by use of a bioassay cascade. 2. Tityus serrulatus venom (3-100 microg), acetylcholine (ACh; 0.3-30 nmol) and glyceryl trinitrate (GTN; 0.5-10 nmol) dose-dependently relaxed rabbit isolated corpus cavernosum preparations precontracted with noradrenaline (3 microM). The selective soluble guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3,-alquinoxalin-1-one] (ODQ; 30 microM) increased the basal tone of the rabbit isolated corpus cavernosum and abolished the relaxations induced by the agents mentioned above. Methylene blue (30 microM) also inhibited the relaxations induced by Tityus serrulatus venom but, in contrast to ODQ, the inhibition was irreversible. 3. The non-selective NO synthase (NOS) inhibitors Nomega-nitro-L-arginine methyl ester (L-NAME; 10 microM) and NG-iminoethyl-L-ornithine (L-NIO; 30 microM) also increased the tone of the rabbit isolated corpus cavernosum and markedly reduced both ACh- and Tityus serrulatus venom-induced relaxations without affecting those evoked by GTN. The inhibitory effect was reversed by infusion of L-arginine (300 microM), but not D-arginine (300 microM). The neuronal NOS inhibitor 1-(2-trifluoromethylphenyl) imidazole (TRIM, 100 microM) did not affect either the tone of the rabbit isolated corpus cavernosum or the relaxations induced by ACh, bradykinin (Bk), Tityus serrulatus venom and GTN. TRIM was approximately 1,000 times less potent than L-NAME in inhibiting rabbit cerebellar NOS in vitro, as measured by the conversion of [3H]-L-arginine to [3H]-L-citrulline. 4. The protease inhibitor aprotinin (Trasylol; 10 microg ml[-1]) and the bradykinin B2 receptor antagonist Hoe 140 (D-Arg-[Hyp3,Thi5,D-Tic7, Oic8]-BK; 50 nM) did not affect the rabbit isolated corpus cavernosum relaxations induced by Tityus serrulatus venom. The ATP-dependent K+ channel antagonist glibenclamide (10 microm) and the Ca2+-activated K+ channel antagonists apamin (0.1 microM) and charybdotoxin (0.1 microM) also failed to affect the venom-induced relaxations. Similarly, the K+ channel blocker tetraethylammonium (TEA; 10 microM) had no effect on the venom-induced relaxations. 5. Capsaicin (3 and 10 nmol) relaxed the rabbit isolated corpus cavernosum in a dose-dependent and non-tachyphylactic manner. Ruthenium red (30 microM), an inhibitor of capsaicin-induced responses, markedly reduced the relaxations caused by capsaicin, but failed to affect those induced by Tityus serrulatus venom. L-NAME (10 microM) had no effect on the capsaicin-induced relaxations of the rabbit isolated corpus cavernosum. 6. The sodium channel blocker tetrodotoxin (TTX; 1 microM) abolished the relaxations of the rabbit isolated corpus cavernosum induced by Tityus serrulatus venom without affecting those evoked by capsaicin, ACh and GTN. Tetrodotoxin (1 microM) also promptly reversed the response to the venom when infused during the relaxation phase. 7. The bioassay cascade of the toxin components purified from Tityus serrulatus venom revealed that only fractions X, XI and XII caused dose-dependent relaxations of the rabbit isolated corpus cavernosum and these were markedly reduced by either TTX (1 microM) or L-NAME (10 microM). 8. Our results indicate that Tityus serrulatus scorpion venom (and the active fractions X, XI and XII) relaxes rabbit corpus cavernosum via the release of NO. This release is specifically triggered by the activation of capsaicin-insensitive cavernosal non-adrenergic non-cholinergic (NANC) fibres, that may possibly be nitrergic neurones. Tityus serrulatus venom may therefore provide an important tool for understanding further the mechanism of NANC nitrergic nerve activation.
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PMID:Effect of Tityus serrulatus scorpion venom on the rabbit isolated corpus cavernosum and the involvement of NANC nitrergic nerve fibres. 950 84

1. The effects of the K+ channel opener levcromakalim, the guanylate cyclase stimulant nitroprusside and the dual drug nicorandil (K+ channel opener and guanylate cyclase stimulant) were analysed in piglet isolated endothelium-denuded pulmonary (PA) and mesenteric (MA) arteries stimulated by noradrenaline (NA) or by the thromboxane A2 mimetic U46619. 2. Nicorandil, levcromakalim and verapamil were less potent in PA than in MA, the efficacy of levcromakalim was also reduced in PA. The effects of nicorandil and levcromakalim were similar in arteries pre-contracted by NA and U46619, whereas verapamil was more potent in arteries pre-contracted by NA. Nitroprusside was equipotent in MA pre-contracted by either NA or U46619 and in PA pre-contracted by NA whereas in PA pre-contracted by U46619, nitroprusside showed lower potency and efficacy. 3. The relaxant effects of levcromakalim and nitroprusside were inhibited by 10(-5) M glibenclamide and 10(-6) M ODQ, respectively. Nicorandil-induced relaxation was inhibited by ODQ in all experimental conditions, whereas glibenclamide had inhibitory effects in PA and MA pre-contracted by U46619, had no effect in PA pre-contracted by NA and in MA pre-contracted by NA it was only inhibitory in the presence of ODQ. 4. No apparent interactions were found between nitroprusside and levcromakalim as indicated by the lack of effects of pretreatment with one of them (producing 20-35% relaxation) on the potency of the relaxant response to the other. However, in PA pre-contracted by U46619, where nitroprusside or levcromakalim induced only partial relaxation, the combination of both mechanisms (either by combining nitroprusside plus levcromakalim or by nicorandil) was able to induce full vasodilatation. 5. In conclusion, K+ channel opening and guanylate cyclase stimulation are independent pathways that induce additive vasorelaxation in piglet PA and MA. The mechanism of action of nicorandil is dependent on the artery and on the nature of the agonist employed to precontract the artery. The relative efficacy of K+ channel opening vs guanylate cyclase stimulation may partially explain the preferential contribution of each mechanism to the relaxant effects of nicorandil.
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PMID:Role of K+ channel opening and stimulation of cyclic GMP in the vasorelaxant effects of nicorandil in isolated piglet pulmonary and mesenteric arteries: relative efficacy and interactions between both pathways. 953 12

1. The aim of the present study was to explore the contribution of adrenergic, sensory and nitrergic innervations to the inhibitory effects of the beta2-adrenoceptor agonist clenbuterol on responses to electrical field stimulation (EFS, 200 mA, 0.3 ms, 1-16 Hz, for 30 s, at 1 min interval) in rat mesenteric artery segments without endothelium and the possible involvement of adrenergic, sensory and nitrergic innervations. 2. Clenbuterol (1 microM) reduced EFS-induced contractile responses, and this effect was reversed by the beta-antagonist propranolol (1 microM) (contraction at 16 Hz expressed as % of 75 mM K+-induced contraction was: control, 69+/-9, clenbuterol, 31+/-6, n=13, P<0.001; control, 83+/-5, clenbuterol+propranolol 70+/-7, n=11, P>0.05). 3. In arteries preincubated with [3H]-noradrenaline (NA), clenbuterol did not modify the tritium overflow evoked by EFS (200 mA, 0.3 ms, 4 Hz, for 60 s; ratio between tritium release in the second and first stimuli was: control, 0.80+/-0.05 and clenbuterol added before second stimulus, 0.91+/-0.11, n=5, P>0.05). 4. The nitric oxide (NO) synthase inhibitors NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME) (10 and 100 microM), and the guanylate cyclase inhibitor methylene blue (10 microM) increased the contractions caused by EFS (% contraction at 16 Hz, control, 81+/-7, n=26; 10 microM L-NMMA, 109+/-12, n=8, P<0.05; methylene blue, 119+/-6, n=6, P<0.05). However, these contractions were decreased by the NO synthase substrate L-arginine 10 microM (14+/-6%, n=6, P<0.001), but not modified by either the sensory neurones toxin capsaicin (0.5 microM, 75+/-6%, n=6, P>0.05) or the protein synthesis inhibitor cycloheximide (10 microM, 83+/-6%, n=8, P>0.05). None of these drugs altered the concentration-response curves to exogenous NA (n=7). 5. Pretreatment with capsaicin or cycloheximide did not modify the reduction of the EFS-evoked contraction provoked by clenbuterol. However the presence of L-NMMA (or L-NAME) or methylene blue did decrease the effect of clenbuterol (% contraction at 16 Hz, clenbuterol, 31+/-6, n=13; clenbuterol+10 microM L-NMMA, 93+/-11, n=8, P<0.05; clenbuterol+methylene blue, 90+/-7, n=6, P<0.05). 6. These results suggest that the reduction caused by clenbuterol in the contraction induced by EFS in rat mesenteric arteries seems to be mediated by NO release, through the activation of beta2-adrenoceptors probably present on nitrergic nerves.
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PMID:Effect of clenbuterol on non-endothelial nitric oxide release in rat mesenteric arteries and the involvement of beta-adrenoceptors. 964 70

We investigated the effects of nitric oxide (NO) donors, S-nitroso-N-acetylpenicillamine and sodium nitroprusside on basal and K+-evoked release of [3H]noradrenaline from superfused synaptosomes from the rat cerebral cortex. Both substances produced concentration-dependent increases in the release of the labeled transmitter under basal and depolarized conditions. The effects of the donors on basal release were Ca2+-independent but were not inhibited by the carrier-uptake blocker, desipramine; the effects were abolished by hemoglobin (an NO scavenger). Thirty-five minutes after stimulation with sodium nitroprusside, the synaptosomes were still responsive to KCl stimulation, indicating that the donor's effects were not caused by damage to the synaptosome membrane. The cGMP analogue, 8-bromo-cGMP, had no effect on basal release, and the enhanced release produced by sodium nitroprusside was not inhibited by the specific inhibitor of soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one, indicating that NO's effects on basal release of the neurotransmitter are guanylate cyclase-independent. Both of the NO donors had more marked effects on release of [3H]noradrenaline during K+-stimulated depolarization. The NO-mediated increase in this case was partially antagonized by 10 microM LH-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one, and 8-Br-cGMP was also capable of producing concentration-dependent increases in the K+-stimulated release of the transmitter. These findings indicate that the effects of the NO donors on [3H]noradrenaline release during depolarization are partially mediated by the activation of guanylate cyclase.
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PMID:Effects of nitric oxide donors on basal and K+-evoked release of [3H]noradrenaline from rat cerebral cortex synaptosomes. 969 26


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