Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In isolated, constant-pressure perfused rat kidneys at basal vascular tone, injected P2 purinoceptor agonists evoked vasoconstriction (alpha, beta-methylene ATP > beta, gamma-methylene ATP > ATP-gamma-S > 2-methylthio ATP > ATP > ADP = UTP). In kidneys with raised tone, the nucleotides produced vasodilatation at low doses (2-methylthio ATP > ADP = ATP = ATP-gamma-S > UTP; alpha, beta-methylene ATP and beta, gamma-methylene ATP, inactive), and constriction at high doses (alpha, beta-methylene ATP > beta, gamma-methylene ATP > ATP-gamma-S > 2-methylthio ATP > ADP = ATP > UTP). Removal of the endothelium abolished the dilator responses to the agonists. NG-Nitro-L-arginine methylester (L-NAME, 5 x 10(-5) M) abolished vasorelaxation in response to 2-methylthio ATP, a response which could be restored by additional L-arginine (3 x 10(-3) M). Both vasodilatation and constriction due to the nucleotides remained unaffected by indomethacin (3 x 10(-6) M), S-(p-nitrobenzyl)-6-thioinosine (3 x 10(-5) M) and 8-phenyltheophylline (3 x 10(-6) M). Pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 1-3 x 10(-6) M), inhibited vasoconstriction caused by alpha, beta-methylene ATP, 2-methylthio ATP and UTP, but not by ATP. Suramin (3 x 10(-5) M) caused a rightward shift of the dose-response curves for constriction caused by alpha, beta-methylene ATP (27-fold) and 2-methylthio ATP (5-fold), whereas the ATP curve was shifted to the left (20-fold). With Evans blue (10(-5) M), vasodilatation due to the nucleotides was abolished and the dose-response curves for vasoconstriction caused by ATP and UTP were shifted left more than 100-fold, the effect to both could not be antagonized by PPADS (3 x 10(-6) M). These results suggest: (1) the different rank orders of P2 purinoceptor agonist potencies for constrictor and dilator responses in perfused rat kidney are consistent with mediation via P2x and P2Y purinoceptors, respectively; (2) P2X purinoceptors, selectively sensitive to blockade by PPADS, are located on vascular smooth muscle; (3) endothelial P2Y purinoceptor stimulation results in vasodilatation involving NO synthesis but not release of prostanoids; (4) Evans blue, which appears to combine selective P2Y purinoceptor blockade and strong inhibition of ecto-nucleotidases, potentiates vasoconstriction in response to the degradable nucleotides, ATP, 2-methylthio ATP and UTP; (5) additionally, Evans blue unmasks a PPADS-insensitive P2U purinoceptor where the nearly equipotent nucleotides, ATP and UTP, can produce vasoconstriction.
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PMID:Characterization of vascular P2 purinoceptors in the rat isolated perfused kidney. 881 26

1. The aim of this study was to characterize P2 receptors in the arterial vascular bed of human perfused placental cotyledons. Vasoconstrictor responses to bolus injections of purine and pyrimidine nucleotides were tested at basal tone, and vasodilator responses in preparations with tone raised by perfusion with prostaglandin F2alpha (PGF2alpha; 10-50 nM). 2. At basal tone, bolus injections of the P2X-selective agonist alpha,beta-methylene ATP (alpha,beta-meATP; 0.5-500 nmol) elicited dose-dependent vasoconstriction. ATP (0.005-5 micromol) also elicited dose-dependent vasoconstriction, but was less potent than alpha,beta-meATP. Vasoconstriction was also elicited by other nucleotides, but only at the highest dose tested (5 micromol): UTP > CTP = ITP (n = 6). GTP and TTP did not cause vasoconstriction. 3. Constrictor responses to bolus injections of alpha,beta-meATP were resistant to desensitization and were not significantly affected when carried out in the presence of 1 microM alpha,beta-meATP added to the perfusate. However, responses to bolus injections of alpha,beta-meATP were partially blocked by perfusion with 10 microM alpha,beta-meATP. In contrast, responses to ATP and UTP were unaffected by 10 microM alpha,beta-meATP. The P2X receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; 10 and 100 microM) had no significant effect on vasoconstriction mediated by alpha,beta-meATP and ATP. 4. Removal of the endothelium had no significant effect on constrictor responses to alpha,beta-meATP, ATP and UTP. Inhibition of nitric oxide (NO) synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME; 100 microM) had no significant effect on vasoconstriction to ATP and alpha,beta-meATP. 5. In preparations with tone raised with PGF2alpha (10-50 nM) vasodilatation was elicited by nucleotides with the following order of potency: 2MeSATP = ADP >> ATP > UTP > CTP = GTP = ITP = TTP. pD2 values were: 2MeSATP, 10.03+/-0.26 (n=7); ADP, 9.97+/-0.40 (n=5); ATP, 8.89+/-0.18 (n=7); UTP, 7.79+/-0.35 (n=7). Maximal responses to 2MeSATP and ADP were similar and were approximately 40% greater than maximal responses to ATP and UTP. 6. Vasodilator responses to nucleotides were abolished by L-NAME (100 microM) and by removal of the endothelium. 7. In conclusion, contractile responses mediated by alpha,beta-meATP and ATP in human placental smooth muscle are resistant to desensitization and insensitive to PPADS and, thus, show a dissimilar pharmacological profile to the classic smooth muscle P2X1 receptor. There may be two subtypes of smooth muscle P2 receptor based on differential antagonism of alpha,beta-meATP and ATP with alpha,beta-meATP. A smooth muscle P2 receptor mediates vasoconstriction to UTP, and may indicate a further subtype. Endothelium-dependent, NO-dependent, vasodilatation to 2MeSATP and ADP may be mediated by P2Y1 receptors, while endothelial P2Y2 receptors are likely to mediate NO-dependent relaxation to ATP and UTP.
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PMID:Characterization of P2 receptors for purine and pyrimidine nucleotides in human placental cotyledons. 924 47

1. The dilator effect of extracellular adenosine triphosphate (ATP) has mainly been characterized as a direct effect on smooth muscle or as an endothelium-dependent effect mediated by nitric oxide (NO) or prostaglandins. We tested the hypothesis that endothelium-derived hyperpolarizing factor (EDHF) may also be involved. Dilator effects were studied in vitro by continuous recording of isomeric tension in cylindrical segments of rat blood vessels precontracted by noradrenaline (NA), in the presence of indomethacin (10 microM). 2. By screening different blood vessels in the rat we found that both acetylcholine (ACh) and ATP dilate mesenteric arteries with a resting tone of 1 mN by an endothelium-dependent non-NO mechanism. With an increased resting tone (4 mN) the dilatation was mediated by NO. Thus by varying the resting tension the different dilator mechanisms could be examined. However, in the carotid artery the dilatation was solely mediated by an endothelium-dependent NO mechanism, even at different resting tones (1 and 4 mN). 3. The N-nitro-L-arginine methyl ester (L-NAME)-resistant dilatation to ACh and ATP was further inhibited by the NO-scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO), indicating L-NAME insensitive NO-synthesis. 4. In carotid arteries and mesenteric arteries at high resting tones (4 mN) the ATP-dilatation was totally inhibited by endothelium removal or L-NAME (10(-3) M). In mesenteric arteries at low resting tone (1 mN) the ATP, UTP (uridine-triphosphate) and 2-MeSATP (2methylthioATP)-dilatation was totally inhibited by endothelium removal. However, L-NAME in combination with indomethacin attenuated only 5% of the UTP dilatation, 70% of the ATP dilatation but all of the 2-MeSATP-dilatation. The inhibitors of Ca2+-activated K+ channels charybdotoxin (0.5 x 10(-7) M) together with apamin (10(-6) M), and the cytochrome P450 inhibitor, SKF 525A (10(-4) M), each in combination with indomethacin. L-NAME and PTIO (0.5 x 10(-3) M) totally abolished the remaining ATP and UTP-dilatation. This indicates a dilatation mediated by an endothelium-dependent non-NO factor, probably EDHF. 5. Agonist potency (UTP>ATP>>2-MeSATP), indicates that the EDHF-mediated dilatation was stimulated by a P2U-receptor, possibly by a selective pyrimidine-receptor. In contrast, a P2Y-receptor stimulated NO-mediated dilatation (2-MeSATP=ATP>UTP). 6. In conclusion, the dilator effects of ATP and especially UTP can be mediated by an endothelium-dependent non-NO-mediated mechanism, probably EDHF, mediated by a P2U-receptor, possibly a selective pyrimidine-receptor, while NO-mediated dilatation is stimulated mainly by a P2Y1-receptor. Furthermore, the EDHF-dilatation is dependent on the resting tone of the blood vessel.
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PMID:P2U-receptor mediated endothelium-dependent but nitric oxide-independent vascular relaxation. 951 92

The main aim of this study was to determine the functional effect of 2-methyl-thio-adenosine diphosphate (2MeS-ADP) on vascular purinoceptors, in comparison with that of a characterised agonist of the P2Y1 receptor, 2-methyl-thio-adenosine triphosphate (2MeS-ATP), and of the P2Y2 receptor, uridine triphosphate (UTP). On phenylephrine-precontracted rat aortic rings, mounted isometrically in organ baths, we found that 2MeS-ADP (10(-9) to 10(-6) M) induced concentration-dependent relaxation of rings with a functional endothelium. Mechanical removal of the endothelium abolished the relaxant effect of 2MeS-ADP. The 2MeS-ADP-induced relaxation of phenylephrine-precontracted rings was inhibited by Nomega-nitro-L-arginine methyl ester (L-NAME) (100 microM) but not by indomethacin (100 microM) or aspirin (1 mM), indicating that the 2MeS-ADP-induced relaxation was nitric oxide (NO) synthase-mediated but not cyclooxygenase-dependent. Repeated stimulation with 2MeS-ADP resulted in desensitisation of the receptor. Under these conditions, the relaxant effect of 2MeS-ATP was abolished. On the contrary, UTP-induced relaxation was not affected, showing that 2MeS-ADP and 2MeS-ATP but not UTP shared the same receptor. Suramin (100 microM), a non-specific P2 inhibitor, abolished the effect of 2MeS-ADP, 2MeS-ATP and UTP. In contrast, pyridoxal-phosphate-6-azophenyl-2'-4'-disulphonic acid (PPADS) and adenosine-3'-phosphate-5'-phosphosulphate (A3P5PS) abolished only the vasodilator responses to 2MeS-ADP and 2MeS-ATP and did not affect the relaxant effect of UTP, showing that 2MeS-ADP acted through the P2Y1 receptor. Clopidogrel, a potent platelet ADP receptor antagonist, at a dose that strongly inhibited ADP-induced platelet aggregation ex vivo, did not modify the relaxant responses to 2MeS-ADP or 2MeS-ATP. In conclusion, these results showed that 2MeS-ADP induces endothelium-dependent, NO-mediated relaxation of rat aortic rings. This effect, resistant to clopidogrel treatment, occurred through activation of the P2Y1 receptor.
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PMID:Relaxant effect of 2-methyl-thio-adenosine diphosphate on rat thoracic aorta: effect of clopidogrel. 1007 99

Early reports indicated that ECV304 was a spontaneously-transformed line derived from a Japanese human umbilical vein endothelial cells (HUVEC) culture. Many morphological, immunochemical, and genetic studies provided further evidence that ECV304 was a valuable biomedical research tool and could be used to study processes that include angiogenesis in vitro and signal transduction by a variety of G protein-coupled receptors. However, several distinct differences between ECV304 and HUVEC are now apparent and recent reports have indicated genetic similarity between ECV304 and T24/83, a human bladder cancer cell line. To further assess the utility of ECV304 as a human endothelial cell model, we compared the functional responses of ECV304 and T24/83 to a range of G protein-coupled receptor agonists. We also used DNA fingerprinting to karyotype both ECV304 and T24/83. Both ATP and uridine triphosphate (UTP) stimulated inositol phosphate metabolism in ECV304 without alteration of cAMP levels. Comparative data using selective P2Y receptor agonists indicated that this response, leading to calcium mobilization from intracellular stores, was predominantly mediated by the activation of P2Y2 receptors. Similar responses were recorded from both ECV304 and T24/83 cells. ECV304 expressed a relatively high basal activity of NOS that was reduced by L-NAME and stimulated by P2Y2 receptor agonists. In contrast, P2Y2 receptor activation did not induce prostaglandin synthesis in ECV304. Both ECV304 and T24/83 express receptors for adenosine, adrenaline, and calcitonin, which stimulate adenylate cyclase. Proliferation of ECV304 and T24/83 cells, measured by the incorporation of [3H]thymidine into DNA, was largely serum-independent. This was in contrast to parallel experiments with porcine and bovine aortic endothelial cells that indicated a marked serum-dependent increase in DNA synthesis. Genetic analysis confirmed that ECV304 and T24/83 are identical. ECV304 displays some endothelial characteristics and is useful for the study of receptor pharmacology. However, ECV304 is not of HUVEC origin and is therefore an inappropriate cell line to study endothelial cell biology.
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PMID:Critical evaluation of ECV304 as a human endothelial cell model defined by genetic analysis and functional responses: a comparison with the human bladder cancer derived epithelial cell line T24/83. 1065 1

The purine nucleotide ATP mediates pulmonary vasodilation at birth by stimulation of P2Y purine receptors in the pulmonary circulation. The specific P2Y receptors in the pulmonary circulation and the segmental distribution of their responses remain unknown. We investigated the effects of purine nucleotides, ATP, ADP, and AMP, and pyrimidine nucleotides, UTP, UDP, and UMP, in juvenile rabbit pulmonary arteries for functional characterization of P2Y receptors. We also studied the expression of P2Y receptor subtypes in pulmonary arteries and the role of nitric oxide (NO), prostaglandins, and cytochrome P-450 metabolites in the response to ATP. In conduit size arteries, ATP, ADP, and AMP caused greater relaxation responses than UTP, UDP, and UMP. In resistance vessels, ATP and UTP caused comparable vasodilation. The response to ATP was attenuated by the P2Y antagonist cibacron blue, the NO synthase antagonist N(omega)-nitro-l-arginine methyl ester (l-NAME), and the cytochrome P-450 inhibitor 17-octadecynoic acid but not by the P2X antagonist alpha,beta-methylene ATP or the cyclooxygenase inhibitor indomethacin in conduit arteries. In the resistance vessels, l-NAME caused a more complete inhibition of the responses to ATP and UTP. Responses to AMP and UMP were NO and endothelium dependent, whereas responses to ADP and UDP were NO and endothelium independent in the conduit arteries. RT-PCR showed expression of P2Y(1), P2Y(2), and P2Y(4) receptors, but not P2Y(6) receptors, in lung parenchyma, pulmonary arteries, and pulmonary artery endothelial cells. These data suggest that distinct P2Y receptors mediate the vasodilator responses to purine and pyrimidine nucleotides in the juvenile rabbit pulmonary circulation. ATP appears to cause NO-mediated vasodilation predominantly through P2Y2 receptors on endothelium.
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PMID:P2Y purine receptor responses and expression in the pulmonary circulation of juvenile rabbits. 1496 41

The neurotransmitter(s) that generate the inhibitory junctional potential (IJP) in the circular muscle of hamster distal colon and their mechanisms have not been elucidated. The aim of the present study, therefore, was to determine the contributing roles of the non-adrenergic, non-cholinergic (NANC) inhibitory transmitter(s) including nitric oxide (NO), adenosine 5'-triphosphate (ATP) and vasoactive intestinal polypeptide (VIP) in the generation of IJP in the hamster distal colon. For this purpose, the effects of the corresponding blockers of these putative NANC inhibitory mediators have been investigated using microelectrode technique. Intracellular membrane potential recordings were made from smooth muscle cells at 35 degrees C in Tyrode's solution that contained atropine (0.5microM), guanethidine (3microM) and nifedipine (0.5microM). Single electrical stimuli (0.5ms, 50V) as well as trains of two and five pulses (20Hz at the same duration and voltage) elicited NANC IJP consisted of initial fast (IJP-F) followed by a slow hyperpolarization (IJP-S). The response had been abolished by tetrodotoxin (TTX, 0.3microM). The nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 200microM) blocked IJP-S but enhanced IJP-F. The later had been blocked with suramin, a universal P2 receptor antagonist, or with CBF3GA, a P2Y receptor antagonist at dose-dependent fashions. The IJP-F had been markedly inhibited by desensitization of P2Y receptor with its putative agonist 2-methylthio-ATP (2-meSATP, 50microM for 30min). IJP-F was sensitive to the P2Y1 receptor specific antagonist A3P5PS (10microM) and to the G-protein inhibitor, pertussis toxin (PTX, 400ng/ml for 2h) as well as to the small and intermediate Ca(2+) sensitive K(+) channels blocker, apamin (0.3microM). IJP-S was blocked by the guanylate cyclase (GC) inhibitor, 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10microM) and was partially sensitive to apamin. Exogenously applied ATP (100microM-1mM) produced typical hyperpolarization that was blocked by suramin, CBF3GA and 2-meSATP desensitization; while exogenously applied NO (3-10microM) produced slowly developing hyperpolarization that was not blocked by L-NAME but ODQ. In the presence of both purinergic and nitrergic inhibitors, stimulation using a train of eight pulses at 25Hz evoked a small slow hyperpolarization that was sensitive to the VIP antagonist (VIP 6-28, 1microM). Exogenous application of VIP (1-10microM) produced similar response that was not evident in the presence of VIP 6-28. These data indicate that NANC IJP that is generated in the circular muscle cells of hamster distal colon is mediated by ATP and NO via P2Y1/P2Y2 receptor and GC-dependent pathways, respectively. A masked role for VIP is also indicated.
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PMID:NANC inhibitory neuromuscular transmission in the hamster distal colon. 1703 41

We investigated the mechanism of synaptic suppression by P2Y receptors in mixed hippocampal cultures wherein networked neurons exhibit synchronized Ca(2+) oscillations (SCO) due to spontaneous glutamatergic synaptic transmission. Pharmacological studies suggested that SCO suppression was mediated by P2Y2/P2Y4 receptors. Immunostaining studies and characterization of ATP/UTP-stimulated Ca(2+) responses in solitary neurons and astrocytes revealed that the SCO attenuation was effectuated by astrocytes. We demonstrate that nitric oxide released from activated astrocytes causes synaptic suppression by inhibiting neurotransmitter release. Physiological concentrations of ATP and UTP evoked NO production in astrocytes. SCO suppression was considerably diminished by removal of extracellular NO by membrane-impermeable scavenger c-PTIO or by pretreatment of cells with nitric oxide synthase inhibitor L-NAME. The nitric oxide donor DETA/NO effectively suppressed the SCO. ATP/UTP inhibited KCl-induced exocytosis at presynaptic terminals in an NO-dependent manner. In the absence of exogenously added ATP/UTP, both the NO scavenger and NOS inhibitor enhanced the frequency of SCO, implying that astrocytes release NO during spontaneous synaptic activity and exert a suppressive effect. We report for the first time that under physiological conditions astrocytes use NO as a messenger molecule to modulate the synaptic strength in the networked neurons.
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PMID:Nitric oxide-mediated modulation of synaptic activity by astrocytic P2Y receptors. 1872 29