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)

Reactive oxygen metabolites have been reported to affect platelet aggregation. However, this phenomenon is still poorly understood. In the present study we investigated the effects of superoxide radical and hydrogen peroxide (H2O2) on platelet function in vitro and correlated those effects to possible changes of platelet concentrations of cyclic nucleotides and thromboxane, since these systems play a key role in the response of platelets to activating stimuli. Human platelets were exposed to xanthine-xanthine oxidase (X-XO), a system that generates both superoxide radicals and H2O2. Sixty seconds of incubation with X-XO impaired aggregation in response to ADP (by 48%), collagen (by 71%), or the thromboxane mimetic U-46619 (by 50%). This effect was reversible and occurred in the absence of cell damage. Impairment of aggregation in platelets exposed to X-XO was due to H2O2 formation, since it was prevented by catalase but not by superoxide dismutase. Similarly, incubation with the pure H2O2 generator glucose-glucose oxidase also markedly inhibited ADP-induced platelet aggregation in a dose-dependent fashion. Impaired aggregation by H2O2 was accompanied by a > 10-fold increase in platelet concentrations of guanosine 3',5'-cyclic monophosphate (cGMP), whereas adenosine 3',5'-cyclic monophosphate levels remained unchanged. The inhibitory role of increased cGMP formation was confirmed by the finding that H2O2-induced impairment of platelet aggregation was largely abolished when guanylate cyclase activation was prevented by incubating platelets with the guanylate cyclase inhibitor, LY-83583. Different effects were observed when arachidonic acid was used to stimulate platelets. Exposure to a source of H2O2 did not affect aggregation to arachidonate. Furthermore, in the absence of exogenous H2O2, incubation with catalase, which had no effects on platelet response to ADP, collagen, or U-46619, virtually abolished platelet aggregation and markedly reduced thromboxane B2 production (to 44% of control) when arachidonic acid was used as a stimulus. In conclusion, our data demonstrate that H2O2 may exert complex effects on platelet function in vitro. Low levels of endogenous H2O2 seem to be required to promote thromboxane synthesis and aggregation in response to arachidonic acid. In contrast, exposure to larger (but not toxic) concentrations of exogenous H2O2 may inhibit aggregation to several agonists via stimulation of guanylate cyclase and increased cGMP formation.
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PMID:Modulation of platelet function by reactive oxygen metabolites. 804 96

The present study investigates the mechanism(s) of action of relaxations induced by bradykinin and by electrical field stimulation (EFS) in isolated rat anococcygeus muscle, where contractile tone has been elevated with clonidine. Bradykinin, EFS, and the bradykinin B1 receptor agonist, des-Arg9-bradykinin, produced quantitatively and qualitatively similar relaxations. Bradykinin B1 receptor antagonist, [des-Arg9,Leu8]-bradykinin (1 microM), attenuated the relaxation responses of bradykinin B1 receptor agonist and inhibited bradykinin and EFS-induced relaxation responses. Bradykinin B2 receptor antagonist, [beta-(2-thienyl)-Ala5,8,D-Phe7]-bradykinin (1 microM), significantly inhibited the relaxation responses of bradykinin, EFS, and bradykinin B1 receptor agonist. Methylene blue (30 microM) and N-methylhydroxylamine (1 mM) significantly inhibited the bradykinin- and EFS-induced relaxation responses. The relaxation responses of bradykinin and EFS were not affected by captopril (5 microM), superoxide dismutase (100 U/ml), and catalase (100 U/ml). Nitric oxide synthase inhibitor, L-NG-nitro-arginine (L-NOARG, 30 microM), significantly inhibited the EFS- and bradykinin-induced relaxation responses. L-arginine (100 microM) reversed the inhibitory effect of L-NOARG on the relaxation responses of EFS and bradykinin. In addition, L-arginine potentiated the relaxation responses of EFS and bradykinin. The data of the present study suggests that bradykinin, similar to EFS, generates an endogenous nitrate, probably nitric oxide, which subsequently activates guanylate cyclase and relaxes the rat anococcygeus muscle.
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PMID:Analysis of bradykinin-induced relaxations in the rat isolated anococcygeus muscle. 812 Dec 44

Rats were vaccinated with saline (control) or one of the two commercially available Pasteurella haemolytica vaccines Presponse or Precon-PH. Animals were killed 3 days later and thoracic aorta removed for evaluation of the ex vivo biophysical responses to carbachol (CCh). In some experiments, vascular endothelium was mechanically removed. Vaccination of rats impairs the endothelial-dependent relaxation to CCh. In vessels with endothelium removed, the contractile response to CCh is converted into a relaxation following vaccination. Treatment of endothelial-denuded vascular rings ex vivo with methylene blue, a guanylate cyclase inhibitor, reduced the vaccination effect. Treatment of vascular rings with the superoxide dismutase inhibitor diethyldithiocarbamate, impairs the relaxant response of de-endothelialized vessels to CCh in Presponse vaccinated rats while enhancing the relaxation response of vessels from Precon-PH vaccinated rats. De-endothelialized vessels from vaccinated rats, but not control rats, relaxed in the presence of N-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of nitric oxide synthetase. Furthermore, in the presence of L-NMMA, the relaxant response to CCh is significantly enhanced by Precon-PH but not Presponse. The normal relaxant response to hydrogen peroxide is converted into a contraction following vaccination. Results suggest that exposure to commercially available P. haemolytica vaccines alters vascular smooth muscle reactivity to CCh and that several independent pathways may be altered.
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PMID:Disturbances in ex vivo vascular smooth muscle responses following exposure to Pasteurella haemolytica vaccines. 812 61

The effects of angiotensin-converting enzyme (ACE) inhibitors on vascular reactivity were investigated using isolated canine femoral arteries with and without endothelium. N-N-(S)-1-carboxy-3-phenylpropyl-L-alanyl-N-(indan-2-yl)glycine (M-1; an active metabolite of delapril, a nonsulfhydryl ACE inhibitor) and captopril (a sulfhydryl ACE inhibitor, 10(-8) to 10(-5) M) relaxed in a dose-dependent manner canine femoral arterial rings precontracted with prostaglandin F2 alpha in the presence of endothelium only. The endothelium-dependent relaxations by M-1 and captopril were completely blocked by methylene blue, an inhibitor of soluble guanylate cyclase; NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis; and oxyhemoglobin, an inactivator of nitric oxide; they were partially blocked by aspirin, an inhibitor of cyclooxygenase and were enhanced by superoxide dismutase, a radical scavenger. The inhibitory effect of L-NMMA on the relaxations by M-1 and captopril were reversed by a high dose of L-arginine. Moreover, a bradykinin antagonist partially inhibited these relaxations. These results suggest that endothelium-dependent relaxations by M-1 and captopril in canine femoral arteries are mediated through the release of both prostanoids and endothelium-derived nitric oxide via endogenous bradykinin.
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PMID:Endothelium-dependent relaxation by angiotensin-converting enzyme inhibitors in canine femoral arteries. 814 60

To examine the effect of a prior episode of anoxia on subsequent anoxia-mediated vasorelaxation, norepinephrine-precontracted endothelium-intact rat aortic rings were first exposed to anoxia (95% N2-5% CO2 for 5, 15, or 30 min) then to normoxia (95% O2-5% CO2 for 15 min). These rings were exposed again to anoxia for 30 min. First exposure of rings to anoxia for 30 min resulted in 77 +/- 4% decrease in tone (vasorelaxation), whereas second exposure resulted in only 10 +/- 4% relaxation (n = 11, P < 0.001 vs. relaxation during first exposure). First exposure of rings to anoxia for 5 or 15 min also diminished relaxation to 59 +/- 3 and 19 +/- 8%, respectively, on second exposure to anoxia (both P < 0.01 vs. relaxation during 1st anoxia). Attenuation of vasorelaxation by prior episode of anoxia was not affected by treatment of rings with indomethacin (10(-5) M), the Ca2+ channel blocker felodipine (10(-6) M), the superoxide anion scavenger superoxide dismutase (100 micrograms/ml), or adenosine A1 and A2 blockers (each 10(-6) M). To examine the role of intact functional endothelium in attenuation of vasorelaxation during second anoxic exposure, rings were deendothelialized and treated with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 10(-4) M) or the guanylate cyclase inhibitor methylene blue (MB; 2 x 10(-5) M). In all deendothelialized rings, vasorelaxation during second anoxic exposure was similar to that during first anoxic exposure (100 +/- 0 vs. 98 +/- 3%, P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prior episode of anoxia attenuates vasorelaxation in response to subsequent episode of anoxia. 816 Aug 46

Nitric oxide synthase(NOS) inhibitor,N omega-nitro-L-arginine methyl ester (L-NAME, 10-300 mg/kg) and L-NG-monomethyl-arginine (L-NMMA, 30-300 mg/kg) suppressed the swellings of adjuvant-injected paw of rats (25-54%) at day 2 and 8 when dosed intraperitoneally and orally for 4 days from day -1 to day 2 after adjuvant. L-NAME (30-300 mg/kg) also suppressed the edema of the non adjuvant-injected paws (15-42%) at day 28. Local injection of this inhibitor (2 and 10 mg/kg) was without effect. L-arginine (1 g/kg, i.p.), impaired the suppression by L-NAME. Bovine blood Cu, Zn-superoxide dismutase (SOD, 3 mg/kg, i.p.: 28% suppression) and L-NAME (30 mg/kg i.p.: 36% suppression) showed additive effect (52%) in adjuvant-injected paws at day 8 when co-injected. As the effect of 30 mg/kg L-NAME corresponded nearly to that of 10 mg/kg VoltarenR, this NOS inhibitor would be worth considering as an anti-inflammatory agent. Sodium nitroprusside (NO-donor) and methylene blue (guanylate cyclase inhibitor) had no effect. L-NAME was also suppressive when dosed after adjuvant inoculation and NO is involved in the development and maintenance of swelling.
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PMID:Nitric oxide and superoxide radical are involved in both initiation and development of adjuvant arthritis in rats. 816 99

The modulatory actions of nitric oxide on sensory nerves were investigated on dilator responses of the perfused rat mesentery to transmural nerve stimulation. N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, caused a significant augmentation of vasodilator responses to transmural nerve stimulation, an effect which was abolished by L-arginine. L-NAME had no effect on vasodilator responses to exogenous calcitonin gene-related peptide. In preparations without endothelium L-NAME still caused potentiation of vasodilator responses to transmural nerve stimulation. Methylene blue, an inhibitor of guanylate cyclase, also significantly enhanced vasodilator responses to transmural nerve stimulation. After pretreatment with diethyldithiocarbamate to inhibit superoxide dismutase, vasodilator responses to transmural nerve stimulation were also potentiated. This response was abolished by exogenous superoxide dismutase. These findings suggest that endogenous nitric oxide modulates, in an inhibitory fashion, the actions of sensory nerves in the rat mesentery. The results also suggest that endogenous superoxide dismutase may participate in the regulation of the actions of sensory nerves via control of cellular superoxide anion level.
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PMID:Nitric oxide modulates responses to sensory nerve activation of the perfused rat mesentery. 822 87

The role of reactive oxygen species in the vascular pathology associated with atherosclerosis was examined by testing the hypothesis that impaired vascular reactivity results from the reaction of nitric oxide (.NO) with superoxide (O2-), yielding the oxidant peroxynitrite (ONOO-). Contractility studies were performed on femoral arteries from rabbits fed a cholesterol-supplemented diet. Cholesterol feeding shifted the EC50 for acetylcholine (ACh)-induced relaxation and impaired the maximal response to ACh. We used pH-sensitive liposomes to deliver CuZn superoxide dismutase (SOD; superoxide:superoxide oxidoreductase, EC 1.15.1.1) to critical sites of .NO reaction with O2-. Intravenously injected liposomes (3000 units of SOD per ml) augmented ACh-induced relaxation in the cholesterol-fed group to a greater extent than in controls. Quantitative immunocytochemistry demonstrated enhanced distribution of SOD in both endothelial and vascular smooth muscle cells as well as in the extracellular matrix. SOD activity in vessel homogenates of liposome-treated rabbits was also increased. Incubation of beta very low density lipoprotein with ONOO- resulted in the rapid formation of conjugated dienes and thiobarbituric acid-reactive substances. Our results suggest that the reaction of O2- with .NO is involved in the development of atherosclerotic disease by yielding a potent mediator of lipoprotein oxidation, as well as by limiting .NO stimulation of vascular smooth muscle guanylate cyclase activity.
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PMID:Superoxide and peroxynitrite in atherosclerosis. 830 29

Segments of endothelium-denuded pulmonary arterial and aortic rings and strips of corpus cavernosum from rabbits were superfused with Krebs solution alone and then Krebs medium containing 0.1-0.5 mM N omega-Nitro-L-Arginine. Photorelaxation in response to ultraviolet light (366 nm) was significantly enhanced by 50 microM methylene blue in all preparations; 25 microM methylene blue also increased photorelaxation in corpus cavernosum and pulmonary artery. Enhanced photorelaxation was associated with increased tissue cGMP. This effect was significantly attenuated by 10 microM hemoglobin and was associated with decreased tissue cGMP but was unaffected by superoxide dismutase. We speculate that UV-generated free radicals convert the phenothiazine moiety of methylene blue to a phenyl radical which activates guanylate cyclase and thus enhances smooth muscle relaxation.
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PMID:Methylene blue enhanced photorelaxation in aorta, pulmonary artery and corpus cavernosum. 838 Dec 79

Lactate was found to produce a relaxation of isolated endothelium-removed calf pulmonary arteries precontracted with 20-30 mM K+. Examination of the mechanism of this response indicates that it appears to be O2 dependent and mediated via guanosine 3',5'-cyclic monophosphate (cGMP), since it is reduced by hypoxia (N2 atmosphere, PO2 = 8-10 Torr) and because the relaxation was both eliminated by inhibition of soluble guanylate cyclase activation with methylene blue and enhanced by an antagonist of cGMP-selective phosphodiesterases (M & B 22948). Relaxation to lactate is not mediated via prostaglandin formation or arginine-derived nitric oxide, since indomethacin or nitro-L-arginine, respectively, did not alter the response. Lucigenin-elicited chemiluminescence, a potential detector of superoxide anion, was significantly increased by lactate only after inhibition of Cu-Zn-superoxide dismutase (via pretreatment with diethyldithiocarbamate). Pyruvate (5 mM) produced only minimal relaxation and did not significantly increase chemiluminescence. In the homogenate fraction of the arterial smooth muscle, NAD plus lactate or NADH was required to observe increased chemiluminescence. The calf pulmonary arterial smooth muscle contraction to hypoxia and relaxation to posthypoxic reoxygenation was observed to be increased by lactate, associated with a reduced level tone generation under O2 but not N2 atmosphere. Thus lactate, but not pyruvate, appears to cause a cGMP-mediated relaxation in the calf pulmonary artery through an increased intracellular H2O2 generation via the NADH-dependent production of superoxide anion, and activation of this relaxing mechanism modulates O2-elicited tone responses.
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PMID:O2-dependent modulation of calf pulmonary artery tone by lactate: potential role of H2O2 and cGMP. 838 45


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