Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracellular signaling pathways involved in the survival of proliferating L1210 leukemia cells were investigated by using specific modulators. Among the various inhibitors tested, only 1H-[1,2,4]oxadiazole [4,3-a]quinoxalin-1-one (ODQ), a soluble guanylate cyclase (sGC) inhibitor, was found to induce a marked increase in caspase activity, which was associated with a loss of cell viability and a reduction in cGMP content. ODQ also provoked the processing of caspases-3 and -9, release of cytochrome c and, as early events, reduction of Bcl-2 content and dephosphorylation of Bad at Ser 112. Furthermore, YC-1, an sGC activator, and 8-Br-cGMP, a cell-permeant analogue of cGMP, exerted some protection against various apoptotic stimuli, such as serum deprivation or spermine accumulation. Although PD98059 (2'-amino-3'-methoxyflavone), an inhibitor of the p44/42 mitogen-activated protein kinase (MAPK) pathway, did not increase basal caspase activity, and ODQ did not affect p44/42 MAPK phosphorylation significantly, phorbol myristate acetate stimulated p44/42 MAPK and reduced caspase activation induced by ODQ, serum deprivation, and spermine in a p44/42-dependent manner. SB203580 (4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)1H-imidazole), a p38 MAPK inhibitor, also partially protected against ODQ-induced apoptosis by increasing p44/42 MAPK phosphorylation. In conclusion, these results suggest that sGC may be relevant both for survival of L1210 cells under basal growing conditions and for protection against various apoptotic stimuli. p44/42 MAPK activation may also confer some protection from apoptosis, but apparently through a pathway largely independent of cGMP.
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PMID:Control of survival of proliferating L1210 cells by soluble guanylate cyclase and p44/42 mitogen-activated protein kinase modulators. 1143 4

This study was designed to characterise the muscarinic receptor subtype responsible for acetylcholine-mediated in vitro pulmonary artery relaxation in rats and the importance of the presence of neostigmine (an anti-cholinesterase) during receptor characterisation. Cumulative administration of acetylcholine elicited concentration-dependent relaxation of phenylephrine (1 microM) precontracted preparations. Inclusion of neostigmine (10 microM) caused a parallel leftward shift with an increase of the pD(2) value (7.09 vs. 6.43) of the concentration-response curve of acetylcholine. The magnitude of maximum relaxation, however, was not affected. Using a range of conventional muscarinic receptor antagonists (atropine, pirenzepine, methoctramine, p-FHHSiD and tropicamide) and the highly selective Green Mamba muscarinic toxins (MT-3 and MT-7), it was found that muscarinic M(3) receptors are probably responsible for endothelium-dependent relaxation of the pulmonary artery upon acetylcholine challenge. Preincubation with N(G)-nitro-L-arginine methyl ester (L-NAME, 20 microM, a nitric oxide synthase inhibitor), but not N(G)-nitro-D-arginine methyl ester (D-NAME, 20 microM), abolished acetylcholine-elicited relaxation. Moreover, 6-anilino-5,8-quinolinedione (LY 83583, 1 microM) and methylene blue (1 microM) (both are guanylate cyclase inhibitors) markedly attenuated acetylcholine-elicited relaxation. However, the presence of indomethacin (3 microM, a cyclo-oxygenase inhibitor), (-)-perillic acid (30 microM, a p21(ras) blocker), 2-[2'-amino-3'-methoxy-phenyl]-oxana-phthalen-4-one (PD 98059) (10 microM, a p42/p44 mitogen-activated protein kinase inhibitor), 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB 203580) (1 microM, a p38 mitogen-activated protein kinase blocker), wortmannin (500 nM, a phosphatidylinositol-3 kinase inhibitor) and genistein (10 microM, a tyrosine kinase blocker) failed to alter acetylcholine-provoked pulmonary arterial relaxation. These results suggest that acetylcholine caused pulmonary arterial relaxation through the activation of muscarinic M(3) receptors in the endothelium. Moreover, the p21(ras)/mitogen-activated protein kinase pathway seems to play no role in mediating acetylcholine-elicited relaxation.
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PMID:Role of mitogen-activated protein kinase pathway in acetylcholine-mediated in vitro relaxation of rat pulmonary artery. 1175 66

Soluble guanylyl cyclase (sGC) is a cGMP-generating enzyme carrying a heme prosthetic group that functions as a nitric oxide (NO) sensor. sGC is present in most cells types, including the vascular endothelium, where its biological functions remain largely unexplored. Herein, we have investigated the role of sGC in angiogenesis and angiogenesis-related properties of endothelial cells (EC). Initially, we determined that sGC was present and enzymatically active in the chicken chorioallantoic membrane (CAM) during the days of maximal angiogenesis. In the CAM, inhibition of endogenous sGC inhibited neovascularization, whereas activation promoted neovessel formation. Using zebrafish as a model for vascular development, we did not detect any effect on vasculogenesis upon sGC blockade, but we did observe an abnormal angiogenic response involving the cranial and intersegmental vessels, as well as the posterior cardinal vein. In vitro, pharmacological activation of sGC or adenovirus-mediated sGC gene transfer promoted EC proliferation and migration, whereas sGC inhibition blocked tube-like network formation. In addition, sGC inhibition blocked the migratory response to vascular EC growth factor. Cells infected with sGC-expressing adenoviruses exhibited increased extracellular signal-regulated kinase 1/2 and p38 MAPK activation that was sensitive to sGC inhibition by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, suggesting that these mitogen-activated protein kinases are downstream effectors of sGC in EC. A functional role for p38 in cGMP-stimulated migration was demonstrated using SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole]; pharmacological inhibition of p38 attenuated BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine] and sGC overexpression-induced EC mobilization. We conclude that sGC activation promotes the expression of angiogenesis-related properties by EC and that sGC might represent a novel target to modulate neovessel formation.
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PMID:Soluble guanylyl cyclase activation promotes angiogenesis. 1694 Apr 34

N,N'-Dialkyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamines show structural analogy with estrogens and selective estrogen receptor modulators. Because the vasodilator properties of these compounds are unknown, we investigated their potential to relax porcine coronary arteries and determined the mechanism(s) of relaxation. Isolated porcine coronary arterial rings were suspended in organ chambers, precontracted with KCl (30 mM), and the relaxant response was determined by measurement of changes in isometric force. Dependent on the chemical structure, the drugs induced concentration-dependent relaxation in rings with and without endothelium. N,N'-Dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine (8) was most potent and showed a 12- to 15-fold higher vasodilatory effect than 17beta-estradiol (E2). The vasorelaxation was independent of endothelium. Calcium concentration-dependent contractions in high-potassium depolarizing medium were insurmountably inhibited by 8. The effect of the L-type Ca2+ channel activator (S)-(-)-Bay K 8644 [(S)-(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridine-carboxylic acid methyl ester], which induced a leftward shift of Ca2+ contraction, was blocked by 8. The relaxant response to 8 was unaffected by the estrogen receptor antagonist ICI 182,780 (7alpha-[9-[(4,4,5,5,5-pentafluoropentyl]-sulfinyl]nonyl]-estra-1,3,5(10)-triene-3,17beta-diol) and K+ channel blockers, i.e., TEA, glibenclamide, and 4-aminopyridine. Furthermore, the vasodilatory effect of 8 was unaffected by the adenylyl cyclase inhibitor SQ 22536 [9-(tetrahydro-2-furanyl)-9H-purin-6-amine], the guanylyl cyclase inhibitor ODQ [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one], the protein kinase A inhibitor KT 5720 [(9S,10S,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg: 3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid hexyl ester], the protein kinase G inhibitor KT 5823 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester], and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB 203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole]. Western blot analysis demonstrated that 8, unlike E2, raloxifene, and tamoxifen, failed to stimulate p38 MAPK. It is concluded that N,N'-dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine induces endothelium-independent relaxation of coronary arteries; the mechanism apparently involves inhibition of L-type Ca2+ channels. The drug may be protective against cardiovascular diseases.
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PMID:Characterization of the relaxant response to N,N'-dipropyl-1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine in porcine coronary arteries. 1732 23