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:2.3.1.21 (CPT)
4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

A number of data are consistent with the hypothesis that increases in intracellular Na+ concentration (Na+i) during ischemia and early reperfusion lead to calcium overload and exacerbation of myocardial injury. However, the mechanisms underlying the increased Na+i remain unclear. 23Na nuclear magnetic resonance spectroscopy was used to monitor Na+i in isolated rat hearts perfused with a high concentration of fatty acid as can occur under some pathological conditions. Whole-cell patch-clamp experiments were also performed on isolated cardiomyocytes in order to investigate the role of voltage-gated sodium channels. Na+i increased to substantially above control levels during no-flow ischemia. The results show that a pharmacological reduction of Na+i increase by cariporide (1 micromol/L, a Na+/H+ exchange blocker) is not the only protection against ischemia-reperfusion damage, but that such protection may also be brought about by metabolic action aimed at reducing fatty acid utilization by myocardial cells. This action was obtained in the presence of etomoxir (0.1 micromol/L), an inhibitor of carnitine palmitoyltransferase-1 (the key enzyme involved in fatty acid uptake by the mitochondria) which also decreases long-chain acyl carnitine accumulation. The possibility of Na+ channels participating in Na+i increase as a consequence of alterations in cardiac metabolism was studied in isolated cells. Sustained I(Na) was stimulated by the presence of lysophosphatidylcholine (LPC, 10 micromol/L) whose accumulation during ischemia is, at least partly, dependent on increased long-chain acyl carnitine. Current activation was particularly significant in the range of potentials between -60 and -20 mV. This may have particular relevance in ischemia. The quantity of charge carried by sustained I(Na) was reduced by 24% in the presence of 1 micromol/L cariporide. Therefore, limitation of long-chain fatty acid metabolism, and consequent limitation of ischemia-induced long-chain acyl carnitine accumulation, may contribute to reducing intracellular Na+ increase during ischemia-reperfusion.
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PMID:Different pathways for sodium entry in cardiac cells during ischemia and early reperfusion. 1261 73

Activation of renal sensory nerves involves PGE2-mediated release of substance P (SP) via activation of the cAMP-PKA pathway. The PGE2-mediated SP release is suppressed by a low- and enhanced by a high-sodium (Na+) diet, suggesting an inhibitory effect of ANG. We now examined whether ANG II is present in the pelvic wall and inhibits PGE2-mediated SP release by blocking PGE2-mediated increases in cAMP. ANG II levels in renal pelvic tissue were 710 +/- 95 and 260 +/- 30 fmol/g tissue in rats fed a low- and high-Na+ diet, respectively. In a renal pelvic preparation from high-Na+-diet rats, 0.14 microM PGE2 produced an increase in SP release from 7 +/- 1 to 19 +/- 3 pg/min that was blocked by 15 nM ANG II. Treating pelvises with pertussis toxin (PTX) abolished the effects of ANG II. In pelvises from low-Na+ rats, neither basal nor bradykinin-mediated SP release was altered by PGE2. However, the bradykinin-mediated release of SP was enhanced by the permeable cAMP analog CPT-cAMP, from 4 +/- 1 to 11 +/- 2 pg/min, a response similar to that in normal-Na+-diet rats. In vivo, renal pelvic administration of PGE2 enhanced the afferent renal nerve activity (ARNA) response to bradykinin in normal- but not in low-Na+ diet rats. CPT-cAMP produced similar enhancement of the ARNA responses to bradykinin in normal- and low-Na+-diet rats, 1,670 +/- 490 and 1,760 +/- 400%.s (area under the curve of ARNA vs. time). Similarly, the ARNA responses to increases in renal pelvic pressure were similarly enhanced by CPT-cAMP in normal- and low-Na+-diet rats. In conclusion, renal pelvic ANG II modulates the responsiveness of renal sensory nerves by suppressing PGE2-mediated activation of adenylyl cyclase via a PTX-sensitive mechanism.
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PMID:Angiotensin blocks substance P release from renal sensory nerves by inhibiting PGE2-mediated activation of cAMP. 1274 58

The amiloride-sensitive epithelial sodium channel (ENaC) plays a key role in sodium reabsorption in the collecting ducts. We examined ENaC mRNA distribution along the nephron and acute effects of vasopressin and hyperosmolality on ENaC mRNA expression. ENaCalpha, beta, and gamma mRNA expressions were observed in cortical, outer medullary and initial inner medullary collecting ducts (CCD, OMCD and ilMCD, respectively). ENaCalpha mRNA expression was also observed in medullary and cortical thick ascending limbs (MAL and CAL, respectively), while ENaCbeta and gamma mRNA expressions were not observed. Furthermore, ENaCalpha mRNA expression in MAL but not in collecting ducts was stimulated by acute exposure to arginine vasopressin (AVP), 8-(4-chlorophenylthio) (CPT)-cAMP and hyperosmolality. However, the physiological significance of these effects is not known, since ENaC protein is reported to be absent in MAL. These data suggest that ENaCalpha mRNA expression in MAL but not in collecting ducts is acutely regulated by AVP and hyperosmolality. The absence of stimulation of ENaCalpha mRNA expression in collecting ducts suggests the physiological significance of ENaCbeta and gamma mRNA for acute regulation by vasopressin. Determining the physiological significance of the acute effect of vasopressin in MAL will require further investigations.
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PMID:Acute regulation of the epithelial sodium channel gene by vasopressin and hyperosmolality. 1456 2

In tissue or nerve injury, proinflammatory mediators are released that can modulate a variety of ion channels found in nociceptors. The changes in channel activity, which primarily occurs through changes in intracellular pathways, may lead to the pathological states of hyperalgesia and allodynia. To understand further the regulatory mechanisms underlying the changes in channel activity, we used whole cell patch-clamp recordings from capsaicin-sensitive nociceptive neurons in rat trigeminal ganglion neurons to examine how the cGMP-dependent pathways may regulate ion channel function. Addition of the 8-(4-chlorophenylthio)-3',5' (CPT)-cGMP, a membrane permeant modulator of ion channels, decreased the number of evoked action potentials by 36% and inhibited the tetrodotoxin-resistant (TTX-R) sodium currents and IA potassium currents by 37 and 32%, respectively. Delayed rectifier potassium (IK) currents were unaffected, suggesting that the effects of CPT-cGMP are unlikely to arise from a nonspecific effect on channel activity as a consequence of the adsorption of amphipathic CPT-cGMP molecules to the membrane's bilayer component. This conclusion was reinforced by the lack of changes in gramicidin A channel function in the presence of CTP-cGMP. In summary, the activation of the cGMP-dependent pathways reduces nociceptor excitability, in part, by decreasing the activity of voltage-gated TTX-R sodium channels. This pathway may be a target for efforts to produce selective analgesics.
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PMID:Voltage-gated ion channels in nociceptors: modulation by cGMP. 1517 69

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

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 101M, 166Ho-DOTMP, 3-AP; Abatacept, abetimus sodium, ACR-16, adefovir dipivoxil, alefacept, AMD-070, aminolevulinic acid hexyl ester, anatumomab mafenatox, anti-CTLA-4 MAb, antigastrin therapeutic vaccine, AP-12009, AP-23573, APC-8024, aripiprazole, ATL-962, atomoxetine hydrochloride; Bevacizumab, bimatoprost, bortezomib, bosentan, BR-1; Calcipotriol/betamethasone dipropionate, cinacalcet hydrochloride, clofazimine, colchicine, cold-adapted influenza vaccine trivalent, CRM197; Desloratadine, desoxyepothilone B, diethylhomospermine; Edodekin alfa, efalizumab, elcometrine, eletriptan, enfuvirtide, entecavir, EP-2101, eplerenone, erlotinib hydrochloride, etoricoxib, everolimus, exherin, ezetimibe; Febuxostat, fluorescein lisicol, fosamprenavir calcium, frovatriptan; Hemoglobin raffimer, HSPPC-96, human insulin; Imatinib mesylate, insulin detemir, insulin glargine, IRX-2, istradefylline, IV gamma-globulin, ixabepilone; Kahalalide F; L-759274, levodopa/carbidopa/entacapone, licofelone, lonafarnib, lopinavir, lurtotecan, LY-156735; MAb G250, mecasermin, melatonin, midostaurin, muraglitazar; Nesiritide, nitronaproxen; O6-Benzylguanine, olmesartan medoxomil, olmesartan medoxomil/hydrochlorothiazide, omapatrilat, oral insulin; Parecoxib sodium, PCK-3145, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon alfa-2b/ ribavirin, pemetrexed disodium, peptide YY3-36, PG-CPT, phenoxodiol, pimecrolimus, posaconazole; Rasagiline mesilate, rDNA insulin, RG228, rimonabant hydrochloride, rosuvastatin calcium, rotigotine hydrochloride; S-3304, safinamide mesilate, salcaprozic acid sodium salt, SDZ-SID-791, SGN-30, soblidotin, squalamine; Telmisartan/hydrochlorothiazide, testosterone gel, TF(c)-KLH conjugate vaccine, TH-9507, theraloc, tipifarnib, tocilizumab, travoprost; ValboroPro, valdecoxib, veglin, voriconazole; Ximelagatran.
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PMID:Gateways to clinical trials. 1553 46

Dietary fatty acids regulate the abundance and activity of various proteins involved in the regulation of fat oxidation by functioning as regulators of gene transcription. To determine whether the transcription of key lipid metabolic proteins necessary for fat metabolism within human skeletal muscle are regulated by acute elevations in circulating free fatty acid (FFA) concentrations, 7 healthy men underwent 3 randomized resting infusions of Intralipid (20%) with heparin sodium, saline and heparin sodium, or saline only for 5 hours. These infusions significantly elevated plasma FFA concentrations by 15-fold (to 1.67 +/- 0.13 mmol/L) in the Intralipid infusion trial, with modest elevations observed in the saline and heparin sodium and saline alone infusion groups (0.67 +/- 0.09 and 0.49 +/- 0.087 mmol/L, P < .01 both vs Intralipid infusion). Analysis of messenger RNA (mRNA) concentration demonstrated that pyruvate dehydrogenase kinase isoform 4 (PDK4) mRNA, a key negative regulator of glucose oxidation, was increased in all trials with a 24-fold response after Intralipid infusion, 15-fold after saline and heparin infusion, and 9-fold after saline alone. The PDK4 increases were not significantly different between the 3 trials. The mRNA concentration of the major uncoupling protein within skeletal muscle, uncoupling protein 3, was not elevated in parallel to the increased plasma FFA as similar ( approximately 2-fold) increases were evident in all trials. Additional genes involved in lipid transport (fatty acid translocase/CD36), oxidation (carnitine palmitoyltransferase I), and metabolism (1-acylglycerol-3-phosphate O -acyltransferase 1, hormone-sensitive lipase, and peroxisomal proliferator-activated receptor-gamma coactivator-1alpha) were not altered by increased circulating FFA concentrations. The present data demonstrate that of the genes analyzed that encode proteins that are key regulators of lipid homeostasis within skeletal muscle, only the PDK4 gene is uniquely sensitive to increasing FFA concentrations after increased plasma FFA achieved by intravenous lipid infusion.
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PMID:Effect of elevated lipid concentrations on human skeletal muscle gene expression. 1598 7

Previously we showed that when the gill muscles of the venerid clam Mercenaria mercenaria are stimulated to contract by 5-hydroxytryptamine (5HT), the contraction is about doubled when another identical dose of 5HT is applied after washout. Furthermore, this "endogenous potentiation" is mimicked by nitric oxide (NO), which is synthesized in the gill. We now report that the isolated gills also synthesize H2S; the basal rate of synthesis was 0.70 micromol.g(-1).h(-1) (se = 0.14; n = 24), but in the presence of 5HT (10(-2) M), the rate increased markedly to 35.82 micromol.g(-1).h(-1) (se = 4.93; n = 4). In addition, dithiothreitol (DTT; 2.2 mM) increased the rate of synthesis significantly to 4.9 micromol.g(-1).h(-1) (se = 0.8; n = 8). Stimulation of H2S synthesis by 5HT (5 x 10(-3) M) was seasonal; that is, the rates measured monthly from December through June are significantly lower than those measured from July through November. We also found that if isolated gills were pretreated with the H2S donor, sodium hydrosulfide (NaHS), their contractions in response to 5HT were potentiated. The threshold of the potentiation was 10(-8) M NaHS, and the largest effect was at 10(-6) M. During August, however, when endogenous and NO-induced potentiations are both absent, 10(-6) M NaHS was also ineffective. Like the effect of NO, that of NaHS (10(-6) M) was blocked by oxadiasoloquinoxalin (ODQ; 5 x 10(-5) M), an inhibitor of soluble guanylate cyclase (sGC). Moreover, Rp-8-CPT-cGMPS (10(-5) M), which inhibits protein kinase-G, also blocked the effect of NaHS (10(-6) M). When isolated gills were treated with 2.2 mM DTT, the endogenous potentiation of a second 5HT-induced contraction more than doubled in comparison to untreated controls. In conclusion, H2S is synthesized in the gill and, along with NO, is a seasonal, endogenous modulator of branchial muscle contraction; its action may be mediated through a sGC/cGMP signaling cascade.
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PMID:Hydrogen sulfide is synthesized in the gills of the clam Mercenaria mercenaria and acts seasonally to modulate branchial muscle contraction. 1611 90

1. We developed a novel method to isolate nonpigmented epithelial (NPE) cells from porcine eyes in order to examine Na,K-ATPase responses to nitric oxide (NO) donors specifically in the epithelium. 2. Cells were treated with NO donors and other test compounds for 20 min prior to Na,K-ATPase activity measurement. 3. NO donors, sodium nitroprusside (SNP, 1 microM-1 mM), sodium azide (100 nM-1 microM) and S-nitroso-N-acetylpenicillamine (1 microM-1 mM) caused significant concentration-dependent inhibition of Na,K-ATPase activity. Detection of nitrite in the medium of L-arginine and SNP-treated NPE confirmed NO generation. 4. Concentration-dependent inhibition of Na,K-ATPase was also obtained by L-arginine (1-3 mM), a physiological precursor of NO and 8p-CPT-cGMP (1-100 microM), a cell permeable analog of cGMP. The L-arginine effect was abolished when the NO synthesizing enzyme, NO-synthase, was inhibited by L-NAME (100 microM). 5. The inhibitory effect of SNP or sodium azide on Na,K-ATPase activity was suppressed by soluble guanylate cyclase (sGC) inhibitors, ODQ (10 microM) or methylene blue (10 microM). 6. The inhibitory effect of 8p-CPT-cGMP on Na,K-ATPase was abolished by protein kinase G (PKG) inhibitors, H-8 (1 microM) and H-9 (20 microM), but not by the protein kinase A (PKA) inhibitor H-89 (100 nM). H-8 and H-9 partially suppressed the inhibitory effect of SNP on Na,K-ATPase. 7. Taken together the results indicate that Na,K-ATPase inhibition response to NO donors involves activation of sGC, generation of cGMP and activation of PKG. These findings suggest that Na,K-ATPase inhibition in NPE may contribute to the ability of NO donors to reduce aqueous humor secretion.
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PMID:NO donors inhibit Na,K-ATPase activity by a protein kinase G-dependent mechanism in the nonpigmented ciliary epithelium of the porcine eye. 1677 Mar 22


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