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 1,4-dihydropyridine BAY-K-8644 [methyl-1,4-dihydro-2, 6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate] acts as both a calcium channel agonist and antagonist by stimulating or inhibiting inward calcium current. In AtT-20 mouse pituitary tumor cells, BAY-K-8644 both stimulates and blocks adrenocorticotropin (ACTH) secretion. Because in several cell systems the cytoplasmic enzyme guanylate cyclase is activated, presumably by calcium entry, the effect of BAY-K-8644 on cyclic GMP (cGMP) synthesis in AtT-20 cells was assessed. BAY-K-8644 increased cGMP accumulation in a time-dependent manner. The concentrations of BAY-K-8644, however, required to increase cGMP formation were not associated with its stimulatory effects on secretion but rather with its ability to antagonize basal and (-)-isoproterenol-induced ACTH secretion. The inhibitory effect of BAY-K-8644 on ACTH secretion was not mimicked by 8-Br-cGMP. The cGMP response to BAY-K-8644 was not mimicked by the cationophore, A-23187, or depolarizing concentrations of K+. Other calcium channel antagonists such as nifedipine or verapamil had markedly smaller effects on cGMP formation compared to BAY-K-8644. Sodium nitroprusside and sodium azide both increased cGMP synthesis in AtT-20 cells and both inhibited, to a lesser extent than BAY-K-8644, both basal- and (-)-isoproterenol-stimulated ACTH release. The data suggest that BAY-K-8644 stimulates cGMP synthesis by binding to sites less accessible or poorly activated by other dihydropyridines, and that stimulation of guanylate cyclase is independent of inward calcium current.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:BAY-K-8644-stimulated cyclic GMP synthesis in mouse pituitary tumor cells. 241 44

The contractile and intracellular responses to acetylcholine (ACh) were measured in isolated segments of the guinea pig circumflex coronary artery. ACh (10(-5) M) led to hyperpolarization of the membrane in the presence or absence of the H1-receptor agonist 2-(2-aminoethyl)pyridine (AEP). This hyperpolarization was associated with relaxation of vessels precontracted with AEP. Hyperpolarization and relaxation were abolished after complete removal of the endothelium. Less endothelial coverage was required to obtain a relaxation with ACh (10(-5) M) than with bradykinin (BK, 10(-7) M). BK did not initiate hyperpolarization. A23187 (10(-8) to (10(-5) M) did not relax vessels precontracted with AEP. Three muscarinic antagonists were compared and the following order of potency was obtained: atropine greater than pirenzapine greater than AFDX116. Although atropine (10(-7) M) reduced the ACh (10(-5) M)-induced hyperpolarization by 83%, this same concentration of pirenzapine had no effect on hyperpolarization. Oxyhemoglobin (10(-5) M) significantly reduced relaxation to nitroglycerine but not ACh. Methylene blue (10(-5) or 5 x 10(-5) M) inhibited relaxation to submaximal but not maximal concentrations of ACh. In vessels precontracted with elevated potassium, ACh (10(-5) M) caused contraction rather than relaxation. The onset and time to peak hyperpolarization with carbachol was more rapid with luminal as opposed to adventitial application of drug. It is concluded that relaxation and hyperpolarization with ACh in the coronary artery are mediated via the endothelium. The results are compatible with the hypothesis that relaxation is initiated by both endothelial-derived relating factor stimulation of guanylate cyclase activity and hyperpolarization of the smooth muscle.
...
PMID:Effect of ACh on electrical and mechanical activity in guinea pig coronary arteries. 280 72

1. In rat aortic rings contracted by phenylephrine, acetylcholine relaxation was partly inhibited by: iberiotoxin, a Ca(2+)-activated K(KCa) channel inhibitor; glyburide, an ATP-dependent K(KATP) channel inhibitor; and 4-aminopyridine, a voltage-dependent K(KV) channel inhibitor, and was almost abolished by the removal of endothelium. 2. NG-nitro-L-arginine (NOARG), a NO synthase inhibitor, markedly reduced acetylcholine relaxation and abolished the inhibitory effects of iberiotoxin and glyburide on the acetylcholine relaxation. The inhibitory effect of 4-aminopyridine on acetylcholine relaxation was partly reduced by NOARG. 3. Methylene blue, a guanylate cyclase inhibitor, markedly inhibited acetylcholine relaxation and also abolished the inhibitory effects of iberiotoxin and glyburide and partly inhibited that of 4-amino-pyridine on acetylcholine relaxation. 4. Metyrapone, a cytochrome P-450-dependent monooxygenase inhibitor, and AA861, a 5-lipoxygenase inhibitor, but not indomethacin, a cyclooxygenase inhibitor, partly inhibited acetylcholine relaxation and reduced the inhibitory effect of 4-aminopyridine on acetylcholine relaxation. 5. These results indicate that, in rat aortic rings, acetylcholine relaxation may be dependent on the activation of KCa, KATP and KV channels. The activations of KCa and KATP channels may also be dependent on NO synthesis and subsequent formation of cGMP. The activation of KV channels may also be dependent on NO synthesis and subsequent activation of guanylate cyclase. In addition, the activation of KV channels may be dependent on the metabolism of arachidonic acid through 5-lipoxygenase and cytochrome P-450-dependent on the monooxygenase pathways.
...
PMID:The involvement of KCa, KATP and KV channels in vasorelaxing responses to acetylcholine in rat aortic rings. 906 90

Soluble guanylate cyclase (sGC) was isolated from bovine lung, and its resonance Raman (RR) spectra were investigated for the reduced, CO-bound (CO-sGC), NO-bound (NO-sGC), oxidized, and oxidized NO-bound forms in the presence and absence of GTP. The enzyme was purified by more than 12 000-fold in terms of specific activity than the supernatant of homogenates, and the heme content was determined with the pyridine hemochoromogen method and Bradford's protein assay to be 0.8 per heterodimer (alpha, Mr = 74 000; beta, Mr = 69 000). The RR spectra of sGC and CO-sGC including the Fe-His stretch at 203 cm-1 and the Fe-CO stretch at 473 cm-1 were unaltered by binding of GTP and cGMP, but apparent RR spectra of NO-sGC in the presence of GTP changed with time and concentrations of GTP. In the absence of GTP, the RR bands of the N-O stretch (nuNO) and the Fe-NO stretch (nuFe-NO) were observed at 1681 and 521 cm-1, respectively. In its presence, however, two nuNO bands were observed at 1700 and 1681 cm-1, which exhibited 15NO isotopic frequency shifts of 32 and 34 cm-1, respectively. Similar Raman spectral changes were observed with the same amount of cGMP but not with PPi or GTP analogues including ATP, GMPPNP, and GTPgammaS. This suggests that GTP or cGMP binds to the distal side of the heme in the proximity of bound NO, possibly regulating NO binding.
...
PMID:Effects of GTP on bound nitric oxide of soluble guanylate cyclase probed by resonance Raman spectroscopy. 925 12

Soluble guanylate cyclase (sGC) consisting of two different subunits (alpha: Mr = 74,000, beta: Mr = 69,000) was purified more than 12,000-fold in terms of specific activity from the supernatant of bovine lung homogenates and characterized. The heme content determined with the pyridine hemochromogen method and Bradford's protein assay was 0.8 heme per dimer. Cholera, pertussis, and botulinum C3 toxins modified exclusively the beta-subunit of sGC, yielding the ADP-ribose-bound compound with 1:1 stoichiometry, and Vmax for the cyclase reaction was increased 10 times by this modification. When the ADP-ribosylation of sGC was performed simultaneously with two or three bacterial toxins which have distinct amino acid specificities, the resultant enzyme had only one ADP-ribose, and the activity was the same as that of the enzyme modified with one toxin. When NO was incorporated into the reaction mixture containing the ADP-ribosylated sGC, the cyclase activity noticeably increased by approximately the same amount as that seen for the unmodified enzyme. Such effects were not seen with CO. When ADP-ribosylated sGC was incubated with Mn2+, the enzyme activity was synergistically increased. The heme-deleted sGC was also ADP-ribosylated by bacterial toxins and its activity was raised. These findings suggest that sGC has an ADP-ribosylation site near the GTP binding site, like other GTP-binding proteins, and that the beta-subunit regulates the activity.
...
PMID:Purification of bovine soluble guanylate cyclase and ADP-ribosylation on its small subunit by bacterial toxins. 934 80

The effects of various spontaneous nitric oxide (NO) donors and NO synthase inhibitors on endothelin- production were examined using porcine cultured aortic endothelial cells. NO donors such as (+/-)-(E)-4-methyl-2-[(E)-hydroxyimino]-5-nitro-3-hexanamide (NOR 2), (+/-)-(E)-4-ethyl-2-[( E)-hydroxyimino]-5-nitro-3-hexanamide (NOR 3) and (+/-)-N-[(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexen-1- yl]-3-pyridine carboxamide (NOR 4) suppressed effectively the release of endothelin-1 from the cells. Endothelin-1 mRNA expression was also attenuated by these compounds. Other NO donors such as 3-[2-hydroxy-1-(1-methylethyl)-2-nitrosohydrazino]-1-propanamin e (NOC 5), 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (NOC 18), s-nitroso-n-acetyl-DL-penicillamine, N-morpholino sydnonimine (SIN-1) had no effects on endothelin-1 production. Endothelial intracellular cyclic guanosine monophosphate (cGMP) levels were significantly increased by all NO donors. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective soluble guanylyl cyclase inhibitor, had no effect on the NOR 3-induced decrease in endothelin-1 secretion, although cGMP production was abolished by ODQ. NOR 3 also inhibited endothelin-1 secretion even in the presence of 2-(4-carboxyphenyl)-4,4,5,5-tetrametylimidazole-1-oxyl 3-oxide (carboxy-PTIO), a NO scavenger. NOR 3-induced inhibitory effects on endothelin-1 secretion were abolished by preincubation of the compound in phosphate-buffered saline (37 degrees C, 4 h), a procedure by which about 98% of the parent compound's ability to release NO was lost. NO synthase inhibitors such as N(G)-nitro-L-arginine, N(G)-monomethyl-L-arginine and N(G)-nitro-L-arginine methyl ester (L-NAME) enhanced prepro endothelin-1 mRNA expression and significantly increased endothelin-1 release from endothelial cells. Endothelin-1 secretion was also increased effectively by carboxy-PTIO or ODQ. When the cells were exposed to L-NAME with carboxy-PTIO or ODQ, no significant further increase in endothelin-1 release was observed. These results suggest that endogenous NO inhibits endothelin-1 production through guanylyl cyclase/cGMP-dependent mechanisms. In contrast, it seems unlikely that exogenous NO has an inhibitory effect on endothelin-1 production in endothelial cells. NOR compounds inhibit endothelin-1 production perhaps through NO/cGMP-independent mechanisms, i.e., through an unknown effect of the parent compound itself.
...
PMID:Effects of endogenous and exogenous nitric oxide on endothelin-1 production in cultured vascular endothelial cells. 992 Jan 86

KRN2391 is a cyanoamidine derivative with a pyridine ring and a nitroxyl group. This gives the molecule a dual pharmacological action as both an ATP-sensitive K channel (K(ATP)) opener and an organic nitrate. In cerebrovascular disease with endothelial dysfunction, such a compound could be advantageous to prevent the negative consequences of a reduced synthesis of endogenous nitric oxide and endothelium-derived hyperpolarizing factor. The objective of this study was to characterise the vasodilator action of KRN2391 in a cerebral artery. As shown in the rabbit basilar artery contracted by endothelin-1 KRN2391 elicited a concentration-dependent relaxation. KRN2391 was unable to relax arteries contracted by a 60 mM K solution. The KRN2391-induced relaxation of endothelin-1-contracted arteries was unaffected by N(G)-nitro-L-arginine (0.1 mM), indomethacin (10 microM) or removal of the endothelium. The guanylate cyclase inhibitors ODQ (10 microM) and LY53583 (10 microM), and the cGMP phosphodiesterase inhibitor zaprinast (10 microM) each had no effect on the KRN2391-induced relaxation. Glibenclamide (1 microM), a blocker of K(ATP), caused a rightward shift of the concentration-response curve for KRN2391. The relaxation induced by the prototype K(ATP) opener levcromakalim was inhibited to a similar extent by glibenclamide. Addition of ODQ or LY53583, or the calcium-sensitive K channel blockers apamin (0.1 microM) and charybdotoxin (0.1 microM) in the presence of glibenclamide did not produce a significant further inhibition of the KRN-induced relaxation. KRN2391 (10 microM) did not influence the content of cGMP in the basilar artery, whereas the nitric oxide donor 3-morpholino-sydnonimine (0.1 mM) increased the cGMP level three-fold. Thus, KRN2391 is an effective vasodilator of the rabbit basilar artery, acting mainly through opening of KATP . The nitro-moiety of the molecule does not seem to contribute to the relaxant effect in this artery.
...
PMID:Vasodilator action in the nitroxylated cyanoamidine derivative, KRN2391, in rabbit basilar artery. 1048 89

Nitric oxide (NO) released under inflammatory and infectious conditions has been implicated in the down-regulation of many cytochrome P450 genes, but its mechanism of action remains unknown. We showed that the expression of the CYP2D6 gene is down-regulated at the transcriptional level by NO in HepG2 cells. The NO donor (+/-)-N-[(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexene-1-yl]-3-pyridine carboxamide (NOR4) decreased the expression of CYP2D6 mRNA in a concentration-dependent manner. Using a CYP2D6 promoter-luciferase construct, we found that NOR4 and another NO donor, S-nitrosoglutathione (GSNO), reduced the luciferase activity in a concentration-dependent manner. A guanylate-cyclase inhibitor failed to prevent suppression of CYP2D6 promoter activity by GSNO, indicating that the activity of the CYP2D6 promoter is suppressed via an NO-guanylate cyclase-independent pathway. Deletion analysis of the CYP2D6 promoter revealed that the -80 to +65 region, which contains the nuclear receptor hepatocyte nuclear factor-4 (HNF4) binding site, was responsible for the suppression of CYP2D6 promoter activity by NO. Therefore, we examined NO responsiveness of the HNF4 binding site by electrophoretic mobility-shift assays and site-direct mutagenesis. The DNA-binding activity of HNF4 was directly inhibited by NO donors, GSNO, and S-nitroso-N-acetyl-penicillamine in a concentration-dependent manner. Mutation of the HNF4 binding site in the CYP2D6 promoter partially restored the suppression of the promoter activity by NO donors. These results demonstrated that NO down-regulates CYP2D6 gene expression, at least in part, by directly inhibiting HNF4 binding to the CYP2D6 promoter.
...
PMID:Contribution of hepatocyte nuclear factor-4 to down-regulation of CYP2D6 gene expression by nitric oxide. 1175 21

We evaluated the role of receptor desensitization, activation of AT(2) receptors, and enzymatic degradation of angiotensin II (Ang II) by amino/neutral endopeptidases in rat anococcygeus smooth muscle (ASM) relaxation. Ang II (0.3 nM to 10 microM) produced contractions (E(max) = 21.50 +/- 5.73%) followed by passive relaxations (E(max) reduced to 9.08 +/- 2.55%). Contractions were inhibited (E(max) = 13.67 +/- 2.03%) by losartan (0.1 microM; AT(1) antagonist) but not by PD123,319 [S-(+)-1-([4-(dimethylamino)-3-methylphenyl]methyl)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid] (0.1 microM; AT(2) antagonist). Conversely, the passive relaxation was inhibited (E(max) = 18.00 +/- 3.45%) by PD123,319 but not by losartan. Ang II (0.3 microM to 100 microM) produced initial contractions (E(max) = 11.49 +/- 9.39%) followed by active relaxations [I(max) (maximum inhibition elicited by the agonist) = 47.85 +/- 4.23%] on strips precontracted by bethanechol (100 microM). A second administration of Ang II on the background of bethanechol (1 h later) resulted in stronger relaxations (I(max) = 64.03 +/- 5.47%) without the initial contractions. N(G)-Nitro-l-arginine methyl ester [nitric-oxide synthase (NOS) inhibitor], ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; guanylate cyclase inhibitor), PD123,319, and tetrodotoxin (neurotoxin) inhibited the relaxations. The presence of AT(1) and AT(2) receptors was confirmed by Western blot. Experiments with amastatin (1 microM) and thiorphan (1 microM), aminopeptidase, and neutral endopeptidase inhibitors, respectively, excluded the involvement of enzymatic degradation in Ang II-induced relaxation of ASM. In conclusion, the rat ASM relaxation by Ang II is the result of active and passive relaxations. The passive relaxation depends on desensitization of excitatory AT(1) receptors, and the active relaxation is mediated by stimulation of AT(2) receptors and activation of the neuronal NOS/soluble guanylate cyclase pathway.
...
PMID:Angiotensin II-induced relaxation of anococcygeus smooth muscle via desensitization of AT1 receptor, and activation of AT2 receptor associated with nitric-oxide synthase pathway. 1517 97

The effect of histamine on the pressure-induced constriction was characterized in rat cerebral arteries and mechanisms were investigated. Rat cerebral arteries were pressurized to 70 mm Hg in an arteriograph and the effect of histamine on myogenic tone was studied. Histamine and amthamine, a selective histamine H(2)-receptor agonist, concentration-dependently decreased myogenic tone, which was unchanged in the absence of endothelium. 2-(2-aminoethyl) pyridine, a selective histamine H(1)-receptor agonist, produced concentration-dependent constriction of arteries that was significantly increased in the absence of endothelium. Imetit, a selective histamine H(3)-receptor agonist, has no effect on myogenic tone. The dilation to histamine was antagonized by tiotidine, a selective antagonist of histamine H(2)-receptor subtype, giving a pK(B) of 7.86 that was not altered in the absence of endothelium. The histamine-mediated dilation was significantly antagonized by NF 449, a reversible inhibitor of Gs-protein activation but was not affected by ODQ and SQ 22536. Dilations to histamine and amthamine were accompanied by a decrease in arterial wall calcium measured by fura-2 ratios. The dilation to histamine was significantly reduced by partial depolarization of smooth muscle by 25 mM KCl (control 91+/-5%, 25 mM KCl 53+/-5%, P<0.002) and was not observed in the presence of strongly depolarizing 60 mM KCl. The histamine dilation was not affected by iberiotoxin, barium chloride and glibenclamide but was strongly antagonized by 4-aminopyridine (0.3 mM) and tetraethylammonium chloride (10 mM) (pEC(50): control: 5.6+/-0.1, 4-aminopyridine: 4.1+/-0.1 (P<0.001); tetraethylammonium chloride: 3.2+/-0.2 (P<0.0001)). These results suggest that histamine-mediated reversal of myogenic tone in rat cerebral arteries is endothelium-independent, mediated by histamine H(2)-receptor subtype with no involvement of guanylyl cyclase or adenylyl cyclase activation and most likely involves activation of K(V) potassium channels.
...
PMID:Histamine decreases myogenic tone in rat cerebral arteries by H2-receptor-mediated KV channel activation, independent of endothelium and cyclic AMP. 1692 98


1 2 3 Next >>

---