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: CAS:113-59-7 (CPT)
3,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have demonstrated that functional interaction between endothelin (ET)-1 and nitric oxide (NO) involves changes in Ca(2+) mobilization and cytoskeleton in human brain microvascular endothelial cells. The focus of this investigation was to examine the possible existence of analogous interplay between these vasoactive substances and elucidate their signal transduction pathways in human brain capillary endothelial cells. The results indicate that ET-1-stimulated Ca(2+) mobilization in these cells is dose-dependently inhibited by NOR-1 (an NO donor). This inhibition was prevented by ODQ (an inhibitor of guanylyl cyclase) or Rp-8-CPT-cGMPS (an inhibitor of protein kinase G). Treatment of endothelial cells with 8-bromo-cGMP reduced ET-1-induced Ca(2+) mobilization in a manner similar to that observed with NOR-1 treatment. In addition, NOR-1 or cGMP reduced Ca(2+) mobilization induced by mastoparan (an activator of G protein), inositol 1,4,5-trisphosphate, or thapsigargin (an inhibitor of Ca(2+)-ATPase). Interestingly, alterations in endothelial cytoskeleton (actin and vimentin) were associated with these effects. The data indicate for the first time that the cGMP-dependent protein kinase colocalizes with actin. These changes were accompanied by altered levels of phosphorylated vasodilator-stimulated phosphoprotein, which were elevated in endothelial cells incubated with NOR-1 and significantly reduced by ODQ or Rp-8-CPT-cGMPS. The findings indicate a potential mechanism by which the functional interrelationship between ET-1 and NO plays a role in regulating capillary tone, microcirculation, and blood-brain barrier function.
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PMID:ET-1- and NO-mediated signal transduction pathway in human brain capillary endothelial cells. 1252 47

Cyclic AMP-stimulating agents are powerful vasodilators, but our knowledge of the signal transduction mechanisms of these agents, particularly in human arteries, is limited. We now report direct molecular effects of prostaglandin E(2) (PGE(2)) on cultured human coronary artery smooth muscle cells (HCASMC). Patch-clamp studies revealed that 10 microM PGE(2) opens a high-conductance (approximately 200 pS), calcium-stimulated potassium (BK(Ca)) channel in intact HCASMC. In contrast, PGE(2) had no direct effect on channels in cell-free patches, indicating involvement of a soluble second messenger. Enzyme immunoassay demonstrated that PGE(2) enhances production of cAMP in HCASMC, but does not increase [cGMP]. Furthermore, forskolin, CPT-cAMP, or CPT-cGMP mimicked the stimulatory effect of PGE(2) on BK(Ca) channel activity. Interestingly, the response to PGE(2) was unaffected by inhibiting the cAMP-dependent protein kinase, but was antagonized by inhibitors of the cGMP-dependent protein kinase (PKG). Furthermore, cAMP-stimulated PKG activity mimicked the effect of PGE(2). These studies suggest a novel PGE(2) action in human arteries: opening of BK(Ca) channels via cAMP cross-activation of PKG in HCASMC. It is proposed that this signaling mechanism may mediate the vasodilatory response to cAMP-dependent agents in the human coronary and other vascular beds.
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PMID:PGE2 action in human coronary artery smooth muscle: role of potassium channels and signaling cross-talk. 1256 73

Adenosine (ADO) is a potent cerebral vasodilator and has been proposed as a metabolic regulator of cerebral blood flow. However, the signal transduction pathway by which ADO causes vasodilation in cerebral microvessels is currently unknown. The current study was designed to investigate the role of cyclic nucleotides and cyclic nucleotide-dependent protein kinases in ADO-induced dilation of resistance-sized rat cerebral arterioles that develop spontaneous tone. Arterioles were cannulated and perfused intraluminally at constant flow (2 microl/min) and pressure (60 mm Hg). ADO (29.7 +/- 2.0%; 1 microM), CGS-21680 (16 +/- 4%, 1 microM), 8-bromo-cyclic guanosine monophosphate (8 Br-cGMP; 29.9 +/- 3.9%; 100 microM), sodium nitroprusside (SNP; 30.6 +/- 3.3%, 1 microM), cyclic guanine monophosphate-dependent protein kinase activator (Sp-8-pCPT-cGMPS, 25.9 +/- 4.2%; 10 microM), forskolin (30.5 +/- 5.9%; 0.1 microM), and pH 6.8 all produced large dilations. The selective cGMP-dependent protein kinase inhibitor, Rp-8-pCPT-cGMPS (10 microM), had no effect on resting diameter or reactivity to acidic pH, but significantly ( < 0.05) attenuated arteriolar dilations to ADO (59%, n = 8), CGS-21680 (60%, n = 4), SNP (62%, n = 3), 8 Br-cGMP (88%, n = 3), and Sp-8-pCPT-cGMPS (98%, n = 3). H8, the less-selective cyclic nucleotide-dependent protein kinase inhibitor, had similar effects as Rp-8-pCPT-cGMPS. Additionally, the inhibitor of the soluble guanylate cyclase, 1H-[1,24]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), blocked the response to SNP (70% inhibition) and significantly inhibited the ADO response (43% inhibition). In contrast, inhibition of the cyclic ADO monophosphate (cAMP)-dependent protein kinase Rp-8-CPT-cAMPS had no effect on the ADO, SNP, or pH responses, but significantly blocked forskolin-induced vasodilation (53%). It is concluded that ADO-induced vasodilation in cerebral microvessels, at least in part, involves cGMP and cGMP-dependent protein kinase, but not cAMP or cAMP-dependent kinase. Our data therefore provides a new insight into mechanisms by which ADO invokes vasodilation in cerebral microvascular arterioles.
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PMID:cGMP-dependent and not cAMP-dependent kinase is required for adenosine-induced dilation of intracerebral arterioles. 1260 23

NO and cGMP have antigrowth and anti-inflammatory effects on the vessel wall in response to injury. It is well established that after vascular injury proinflammatory cytokines are involved in vascular wall remodeling. The purpose of this study was to ascertain the signaling mechanisms involved in cGMP-dependent protein kinase (PKG) suppression by inflammatory cytokines in primary bovine aortic vascular smooth muscle cells (VSMC). Interleukin (IL)-Ibeta, tumor necrosis factor (TNF)-alpha, and LPS decreased the mRNA and protein levels of PKG in VSMC. IL-Ibeta, TNF-alpha, and LPS increased inducible nitric oxide synthase (iNOS) expression and cGMP production. Treatment of cells with selective inhibitors of iNOS or soluble guanylate cyclase (sGC) reversed the downregulation of PKG expression induced by cytokines and LPS. The NO donor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA NONOate) and 3-(5-hydroxymethyl-2-furyl)-1-benzylindazole (YC-1), a NO-independent sGC activator, decreased PKG mRNA and protein expression in bovine aortic VSMC. Cyclic nucleotide analogs [8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate (CPT-cGMP) and 8-(4-chlorophenylthio)adenosine 3,5'-cyclic monophosphate (CPT-cAMP)] also suppressed PKG mRNA and protein expression. However, CPT-cAMP was more effective than CPT-cGMP in decreasing PKG mRNA levels. Selective inhibition of PKA with the Rp isomer of 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphorothioate (Rp-8p-CPT cAMPS) prevented the downregulation of PKG by LPS. In contrast, the Rp isomer of 8-(4-chlorophenylthio)guanosine 3,5'-cyclic monophosphorothioate (Rp-8p-CPT cGMPS; inhibitor of PKG) had no effect on LPS-induced inhibition of PKG mRNA and protein expression. These studies suggest that cross-activation of PKA in response to iNOS expression by inflammatory mediators downregulates PKG expression in bovine aortic VSMC.
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PMID:Downregulation of cGMP-dependent protein kinase expression by inflammatory cytokines in vascular smooth muscle cells. 1498 34

The endothelial cells (EC) of the microvasculature in the brain form the anatomical basis of the blood-brain barrier (BBB). In the present study, the effects of agents that modify the permeability of a well-established in vitro model of the human BBB were studied. The monolayers formed by confluent human brain microvessel endothelial cell (HBMEC) cultures are impermeable to the macromolecule tracer horseradish peroxidase (HRP) and have high electrical resistance. Exposure of HBMEC to various cytokines including TNF-alpha, IL-1beta, interferon gamma (IFN-gamma), or lipopolysaccharide (LPS) decreased transendothelial electrical resistance (TEER) mainly by increasing the permeability of the tight junctions. Primary cultures of HBMEC express endothelial nitric oxide synthase (eNOS) and produce low levels of NO. Treatment with the NO donors sodium nitroprusside (SNP) and DETA NONOate or the cGMP agonist 8-Br-cGMP significantly increased monolayer resistance. Conversely, inhibition of soluble guanylyl cyclase with ODQ rapidly decreased the resistance, and pretreatment of HBMEC with Rp-8-CPT-cGMPS, an inhibitor of cGMP-dependent protein kinase, partially prevented the 8-Br-cGMP-induced increase in resistance. Furthermore, NO donors and 8-Br-cGMP could also reverse the increased permeability of the monolayers induced by IL-1beta, IFN-gamma, and LPS. These results indicate that NO can decrease the permeability of the human BBB through a mechanism at least partly dependent on cGMP production and cGMP-dependent protein kinase activation.
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PMID:Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood-brain barrier. 1553 Aug 83

Increases in endothelial cGMP prevent oxidant-mediated endothelial barrier dysfunction, but the downstream mechanisms remain unclear. To determine the role of cGMP-dependent protein kinase (PKG)(I), human pulmonary artery endothelial cells (HPAEC) lacking PKG(I) expression were infected with a recombinant adenovirus encoding PKG(Ibeta) (Ad.PKG) and compared with uninfected and control-infected (Ad.betagal) HPAEC. Transendothelial electrical resistance (TER), an index of permeability, was measured after H(2)O(2) (250 microM) exposure with or without pretreatment with 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate (CPT-cGMP). HPAEC infected with Ad.PKG, but not Ad.betagal, expressed PKG(I) protein and demonstrated Ser(239) and Ser(157) phosphorylation of vasodilator-stimulated phosphoprotein after treatment with CPT-cGMP. Adenoviral infection decreased basal permeability equally in Ad.PKG- and Ad.betagal-infected HPAEC compared with uninfected cells. Treatment with CPT-cGMP (100 microM) caused a PKG(I)-independent decrease in permeability (8.2 +/- 0.6%). In all three groups, H(2)O(2) (250 microM) caused a similar approximately 35% increase in permeability associated with increased actin stress fiber formation, intercellular gaps, loss of membrane VE-cadherin, and increased intracellular Ca(2+) concentration ([Ca(2+)](i)). In uninfected and Ad.betagal-infected HPAEC, pretreatment with CPT-cGMP (100 microM) partially blocked the increased permeability induced by H(2)O(2). In Ad.PKG-infected HPAEC, CPT-cGMP (50 microM) prevented the H(2)O(2)-induced TER decrease, cytoskeletal rearrangement, and loss of junctional VE-cadherin. CPT-cGMP attenuated the peak [Ca(2+)](i) caused by H(2)O(2) similarly (23%) in Ad.betagal- and Ad.PKG-infected HPAEC, indicating a PKG(I)-independent effect. These data suggest that cGMP decreased HPAEC basal permeability by a PKG(I)-independent process, whereas the ability of cGMP to prevent H(2)O(2)-induced barrier dysfunction was predominantly mediated by PKG(I) through a Ca(2+)-independent mechanism.
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PMID:Role of protein kinase G in barrier-protective effects of cGMP in human pulmonary artery endothelial cells. 1633 78

Natriuretic peptides and nitric oxide (NO) activate the cGMP/cGMP-dependent protein kinase (PKG) signaling pathway and play an important role in bone development and adult bone homeostasis. The cytokine IL-6 regulates bone turnover and osteoclast and osteoblast differentiation. We found that C-type natriuretic peptide and the NO donor Deta-NONOate induced IL-6 mRNA expression in primary human osteoblasts, an effect mimicked by the membrane-permeable cGMP analog 8-chlorophenylthio-cGMP (8-CPT-cGMP). Similar results were obtained in rat UMR106 osteosarcoma cells, where C-type natriuretic peptide and 8-CPT-cGMP stimulated transcription of the human IL-6 promoter and increased IL-6 secretion into the medium. Cotransfection of type I PKG enhanced the cGMP effect on the IL-6 promoter, whereas small interfering RNA-mediated silencing of PKG I expression prevented the cGMP effect on IL-6 mRNA expression. Step-wise deletion of the IL-6 promoter demonstrated a cAMP response element to be critical for transcriptional effects of cGMP, and experiments with dominant interfering proteins showed that cGMP activation of the promoter required cAMP response element binding-related proteins, and, to a lesser extent, proteins of the CAAT enhancer-binding protein and activator protein-1 (Fos/Jun) families. 8-CPT-cGMP induced nuclear translocation of type I PKG and increased cAMP response element binding-related protein phosphorylation on Ser(133). PKG regulation of the IL-6 promoter appeared to be of physiological significance, because inhibitors of the NO/cGMP/PKG signaling pathway largely prevented fluid shear stress-induced increases of IL-6 mRNA in UMR106 cells.
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PMID:Guanosine 3',5'-cyclic monophosphate (cGMP)/cGMP-dependent protein kinase induce interleukin-6 transcription in osteoblasts. 1734 96

We examined the effects of acute hypoxia on vascular tone and coronary blood flow (CBF) in rabbit coronary arteries. In the pressurized arterial preparation of small arteries (<100 mum) and the Langendorff-perfused rabbit hearts, hypoxia induced coronary vasodilation and increased CBF in the presence of glibenclamide (K(ATP) channel blocker), Rp-8-Br-PET-cGMPs [cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibitor, Rp-cGMPs], and methionyl transfer RNA synthetase (MRS) 1334 (adenosine A(3) receptor inhibitor); these increases were inhibited by the inward rectifier K(+) (Kir) channel inhibitor, Ba(2+). These effects were blocked by the adenylyl cyclase inhibitor SQ 22536 and by the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) inhibitors Rp-8-CPT-cAMPs (Rp-cAMPs) and KT 5720. However, cGMP-dependent protein kinase was not involved in the hypoxia-induced increases of the vascular diameter and CBF. In summary, our results suggest that acute hypoxia can induce the opening of Kir channels in coronary artery that has small diameter (<100 mum) by activating the cAMP and PKA signalling pathway, which could contribute to vasodilation and, therefore, increased CBF.
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PMID:Acute hypoxia induces vasodilation and increases coronary blood flow by activating inward rectifier K(+) channels. 1748 61

The aim of the present study was to investigate the mechanisms underlying the vasorelaxation induced by the selective phosphodiesterase 5 (PDE5) inhibitor vardenafil in rat penile small arteries. Segments of the rat dorsal penile artery were mounted in microvascular myographs for isometric tension recording. Concentration-response curves for vardenafil (1 nM-3 microM) and other PDE inhibitors (sildenafil, rolipram and milrinone) were constructed by adding cummulative concentrations of the drugs to arteries precontracted with phenylephrine. The effect of mechanical endothelial cell removal and of selective blockers of the nitric oxide (NO)/cGMP pathway and K+ channels were evaluated on the vardenafil relaxant responses. Vardenafil was the most potent of the four PDE inhibitors tested that maximally relaxed penile arteries, pD2 and maximum relaxation being 6.96+/-0.08 and 97+/-1% (n=48), respectively. Blockade of guanylate cyclase with ODQ (5 microM), mechanical removal of the endothelium or inhibition of NO synthase with l-NOARG (100 microM) markedly reduced vardenafil-induced relaxations, without altering maximum response. Inhibitors of both the cGMP-dependent (PKG) and the cAMP-dependent (PKA) protein kinases, Rp-8-Br-PET-cGMPS (5 microM) and Rp-8-CPT-cAMPS (50 microM), respectively, both reduced vardenafil relaxant responses and the later abolished that of rolipram. Vardenafil-elicited relaxation was reduced by the selective inhibitor of the large-conductance Ca2+-activated K+ channels (BK(Ca)), iberiotoxin (30 nM) and also by the ATP-sensitive K+ channel (K(ATP)) inhibitor, glibenclamide (1 microM). Vardenafil induces a potent vasodilatation in rat penile arteries that is partially dependent on the endothelium and the NO/cGMP pathway and involves activation of both BK(Ca) and K(ATP) channels.
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PMID:Mechanisms of the relaxant effect of vardenafil in rat penile arteries. 1842 Jan 89

Epithelial sodium channels (ENaC) are regulated by protein kinase A, in addition to a broad spectrum of other protein kinases. It is not clear whether cGMP/PKG signaling might regulate ENaC activity. We examined the responses of alphabetagamma-ENaC channels expressed in Xenopus oocytes to 8-(4-chlorophenylthio)-cGMP (8-pCPT-cGMP), a cell-permeable cGMP analog. This compound stimulated human alphabetagamma-ENaC activity in a dose-dependent fashion, but cell-impermeable cGMP had no effect. Similar stimulatory effects of cGMP were observed in oocytes expressing either mouse or rat alphabetagamma-ENaC channels. The identical ion selectivity and amiloride sensitivity of the 8-pCPT-cGMP-activated currents to those of alphabetagamma-ENaC channels suggest that the cGMP-activated currents are associated with expressed ENaC. The PKGI activator Sp isomer of beta-phenyl-1,N(2)-etheno-8-bromo-cGMP did not elicit a rise in ENaC current and that the 8-pCPT-cGMP-induced activation of ENaC channels was blocked by incubating oocytes with a PKG inhibitor, but not with other cGMP-sensitive kinase inactivators for PKA, MEK, MAP, and PKC. Surprisingly, both site-directed mutation of putative consensus PKG phosphorylation sites and truncation of entire cytosolic NH(2)- and COOH-terminal tails did not alter the response to 8-pCPT-cGMP. The ENaC activity was activated to the same extent by 8-pCPT-cGMP in cells in which PKGII expression was knocked down using small interfering RNA. Analog to 8-CPT-cAMP, 8-pCPT-cGMP was capable of activating ENaC in the identical manner in cell-free outside-out patches. We conclude that the rapid upregulation of human alphabetagamma-ENaC activity in oocytes by external 8-pCPT-cGMP and 4-chlorothiolphenol-cAMP depends on the para-chlorophenylthiol and the hydroxy groups, and 8-pCPT-cGMP may serve as a novel ENaC ligand in addition to activating PKG signal.
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PMID:8-pCPT-cGMP stimulates alphabetagamma-ENaC activity in oocytes as an external ligand requiring specific nucleotide moieties. 2000 51


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