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  • Articles  (4)
  • Nodose ganglion neurones  (2)
  • SRIF-binding  (2)
  • 1995-1999  (4)
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  • Articles  (4)
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  • 1995-1999  (4)
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  • 1
    ISSN: 1432-1912
    Keywords: Key words P2X Purinoceptor ; βγ-Methylene-L-ATP ; Rat vagus nerve ; Nodose ganglion neurones ; Rat vas deferens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The effects of the putative selective P2X purinoceptor agonist, β,γ-methylene-L-adenosine 5′-triphosphate (βγme-L-ATP), were determined at rat neuronal and smooth muscle P2X purinoceptors. βγMe-L-ATP had no effect on the extracellularly recorded membrane potential of the rat isolated vagus nerve preparation at concentrations up to 300 μM. In contrast, the archetypal P2X purinoceptor agonist, α,β-methylene ATP (αβmeATP; 1–100 μM), produced concentration-related depolarisation responses with a mean EC50 value of 10.8 μM. The depolarising effects of αβmeATP were not attenuated by βγme-L-ATP (100 μM). In voltage clamp experiments on single nodose ganglion neurones, ATP (100 μM), but not βγme-L-ATP (1–300 μM), evoked rapid (〈20 ms onset) inward currents when applied using a concentration-clamp method. In receptor binding studies to rat brain membranes, βγme-D-ATP and αβmeATP competed with high affinity for [3H]αβmeATP binding sites, with mean pIC50 values of 7.7 and 8.3, respectively. However, βγme-L-ATP possessed low affinity for these sites and competed only at concentrations in excess of 10 μM (mean pIC50 value 4.1). In prostatic segments of the rat vas deferens, βγme-L-ATP (1–100 μM) and αβmeATP (0.3–100 μM) each produced concentration-related contractile responses with mean EC50 values of 17.1 and 3.6 μM, respectively. βγMe-L-ATP (1–10 μM) evoked fast inward currents in freshly dispersed vas deferens smooth muscle cells, indicative of an action at ligand-gated ion channels. Binding sites in vas deferens membranes labelled using 1 nM [3H]αβmeATP exhibited high affinity for βγme-L-ATP, αβmeATP and βγme-D-ATP with mean pIC50 values of 7.7, 8.4 and 7.3, respectively. These results indicate that βγme-L-ATP exhibits neither agonist nor antagonist properties at P2X purinoceptors on rat vagal neurones and possesses only very low affinity for [3H]αβmeATP binding sites in rat brain. In contrast, βγme-L-ATP is a potent, high affinity agonist at smooth muscle P2X purinoceptors of the rat vas deferens. This selective agonist action of βγme-L-ATP suggests that P2X purinoceptors in smooth muscle and neurones are different and represent distinct P2X purinoceptor subtypes.
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  • 2
    ISSN: 1432-1912
    Keywords: P2X Purinoceptor ; βγ-Methylene-l-ATP ; Rat vagus nerve ; Nodose ganglion neurones ; Rat vas deferens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of the putative selective P2X purinoceptor agonist, β,γ-methylene-l-adenosine 5′-triphosphate (βγme-l-ATP), were determined at rat neuronal and smooth muscle P2X purinoceptors. βγMe-l-ATP had no effect on the extracellularly recorded membrane potential of the rat isolated vagus nerve preparation at concentrations up to 300 μM. In contrast, the archetypal P2X purinoceptor agonist, α, β methylene ATP (αβmeATP;1–100 μM), produced concentration-related depolarisation responses with a mean EC50 value of 10.8 μM. The depolarising effects of αβmeATP were not attenuated by βγme-l-ATP (100 μM). In voltage clamp experiments on single nodose ganglion neurones, ATP (100 μM), but not βγme-l.-ATP (1–300 μM), evoked rapid ( 〈 20 ms onset) inward currents when applied using a concentration-clamp method. In receptor binding studies to rat brain membranes, βγme-d-ATP and αβmeATP competed with high affinity for [3H]Lx βmeATP binding sites, with mean pIC50 values of 7.7 and 8.3, respectively. However, βγme-l-ATP possessed low affinity for these sites and competed only at concentrations in excess of 10 μM (mean pIC50 value 4.1). In prostatic segments of the rat vas deferens, βγme-l-ATP (1–100 μM) and αβmeATP (0.3–100 μM) each produced concentration-related contractile responses with mean EC50 values of 17.1 and 3.6 μM, respectively. βγMe-l-ATP (1–10 μM) evoked fast inward currents in freshly dispersed vas deferens smooth muscle cells, indicative of an action at ligand-gated ion channels. Binding sites in vas deferens membranes labelled using 1 nM [3H]αβmeATP exhibited high affinity for ββ γme-l-ATP, αβmeATP and βγme-d-ATP with mean PIC50 values of 7.7, 8.4 and 7.3, respectively. These results indicate that βγme-l-ATP exhibits neither agonist nor antagonist properties at P2X purinoceptors on rat vagal neurones and possesses only very low affinity for [3H]αβmeATP binding sites in rat brain. In contrast, βγme-l-ATP is a potent, high affinity agonist at smooth muscle P2X purinoceptors of the rat vas deferens. This selective agonist action of βγme-l-ATP suggests that P2X purinoceptors in smooth muscle and neurones are different and represent distinct P2X purinoceptor subtypes.
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  • 3
    ISSN: 1432-1912
    Keywords: Somatostatin ; BIM-23027 ; Rat colonic mucosa ; sst2 receptors ; SRIF-binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have previously shown that the somatostatin (SRIF) sst2 receptor-selective peptide, BIM-23027, is a potent antisecretory agent in rat isolated distal colonic mucosa (RDCM) and in radioligand binding studies in RDCM membranes, it only maximally inhibited approximately 40% of [125I]-Tyr11-SRIF-14 binding (McKeen ES, Feniuk W, Humphrey PPA (1995) Naunyn-Schmiedeberg's Arch Pharmacol 352:402–411). The aim of this study was to characterise the BIM-23027-sensitive and -insensitive SRIF binding sites in more detail and to compare their properties with those of the recombinant sst2 receptor stably expressed in mouse fibroblast (Ltk−) cells. SRIF-14, SRIF-28, CGP-23996 and D Trp8-SRIF-14 abolished [125I]-Tyr11-SRIF-14 binding (pIC50 values, 8.7–9.7) but the competition curves had Hill slopes which were less than unity. Octreotide and L-362,855 inhibited binding over a wide concentration range (0.1 nM-1 μM) and inhibition of binding was incomplete at the highest concentration studied. BIM-23056 (PIC50 〈6.5) was a weak inhibitor of [125]-Tyr11-SRIF-14 binding. GTPγS decreased [125I]-Tyr11-SRIF-14 binding by 40%. Further binding experiments with [125I]-Tyr11-SRIF-14 were carried out in RDCM in the continuous presence of BIM-23027 (1 μM). Under these conditions, seglitide had no effect on [125I]-Tyr11-SRIF-14 binding at concentrations up to 10 μM, whilst SRIF-14 and SRIF-28 abolished specific [125I]-Tyr11-SRIF-14 binding in a manner which was consistent with the ligand binding to two sites. SRIF-14 and SRIF-28 displayed high affinity (pIC50 values of 9.8 and 9.3 respectively) for approximately 70% of these binding sites and low affinity (pIC50 values of 7.8 and 7.3) for the remaining sites. Octreotide, L-362,855 and BIM-23056 were weak inhibitors of [125I]-Tyr11-SRIF-14 binding (PIC50 〈6.5). [125I]-BIM-23027 labelled a single population of SRIF binding sites in RDCM membranes and mouse fibroblast (Ltk−) cells stably expressing the human recombinant sst2 receptor. There was a significant correlation between the affinitestimates of a range of SRIF analogues at inhibiting [125I]-BIM-23027 binding in RDCM membranes and binding to the recombinant sst2 receptor in Ltk− cells, suggesting that the sites labelled by [125I]-BIM-23027 in RDCM are similar to the sst2 receptor. GTPγS (100 μM) decreased [125I]-BIM-23027 binding in RDCM by 60%. The results from these studies demonstrate that [125I]-Tyr11-SRIF-14 labels a heterogeneous population of high affinity SRIF binding sites in RDCM membranes. The majority of these sites are insensitive to GTPγS and display negligible affinity for the cyclic hexapeptides, BIM-23027 and seglitide. The remaining high affinity binding sites can be selectively labelled with [125I]-BIM-23027, are sensitive to GTPγS and show similar characteristics to the recombinant sst2 receptor which appears to mediate the antisecretory effects of SRIF in the mucosa (McKeen ES, Feniuk W, Humphrey PPA (1995) Naunyn-Schmiedeberg's Arch Pharmacol 352:402–411).
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  • 4
    ISSN: 1432-1912
    Keywords: Key words Somatostatin ; BIM-23027 ; Rat colonic mucosa ; sst2 receptors ; SRIF-binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have previously shown that the somatostatin (SRIF) sst2 receptor-selective peptide, BIM-23027, is a potent antisecretory agent in rat isolated distal colonic mucosa (RDCM) and in radioligand binding studies in RDCM membranes, it only maximally inhibited approximately 40% of [125I]-Tyr11-SRIF-14 binding (McKeen ES, Feniuk W, Humphrey PPA (1995) Naunyn-Schmiedeberg‘s Arch Pharmacol 352:402–411). The aim of this study was to characterise the BIM-23027-sensitive and -insensitive SRIF binding sites in more detail and to compare their properties with those of the recombinant sst2 receptor stably expressed in mouse fibroblast (Ltk–) cells. SRIF-14, SRIF-28, CGP-23996 and D Trp8-SRIF-14 abolished [125I]-Tyr11-SRIF-14 binding (pIC50 values, 8.7–9.7) but the competition curves had Hill slopes which were less than unity. Octreotide and L-362,855 inhibited binding over a wide concentration range (0.1 nM-1 μM) and inhibition of binding was incomplete at the highest concentration studied. BIM-23056 (pIC50 〈6.5) was a weak inhibitor of [125]-Tyr11-SRIF-14 binding. GTPγS decreased [125I]-Tyr11-SRIF-14 binding by 40%. Further binding experiments with [125I]-Tyr11-SRIF-14 were carried out in RDCM in the continuous presence of BIM-23027 (1 μM). Under these conditions, seglitide had no effect on [125I]-Tyr11-SRIF-14 binding at concentrations up to 10 μM, whilst SRIF-14 and SRIF-28 abolished specific [125I]-Tyr11-SRIF-14 binding in a manner which was consistent with the ligand binding to two sites. SRIF-14 and SRIF-28 displayed high affinity (pIC50 values of 9.8 and 9.3 respectively) for approximately 70% of these binding sites and low affinity (pIC50 values of 7.8 and 7.3) for the remaining sites. Octreotide, L-362,855 and BIM-23056 were weak inhibitors of [125I]-Tyr11-SRIF-14 binding (pIC50 〈6.5). [125I]-BIM-23027 labelled a single population of SRIF binding sites in RDCM membranes and mouse fibroblast (Ltk–) cells stably expressing the human recombinant sst2 receptor. There was a significant correlation between the affinity estimates of a range of SRIF analogues at inhibiting [125I]-BIM-23027 binding in RDCM membranes and binding to the recombinant sst2 receptor in Ltk– cells, suggesting that the sites labelled by [125I]-BIM-23027 in RDCM are similar to the sst2 receptor. GTPγS (100 μM) decreased [125I]-BIM-23027 binding in RDCM by 60%. The results from these studies demonstrate that [125I]-Tyr11-SRIF-14 labels a heterogeneous population of high affinity SRIF binding sites in RDCM membranes. The majority of these sites are insensitive to GTPγS and display negligible affinity for the cyclic hexapeptides, BIM-23027 and seglitide. The remaining high affinity binding sites can be selectively labelled with [125I]-BIM-23027, are sensitive to GTPγS and show similar characteristics to the recombinant sst2 receptor which appears to mediate the antisecretory effects of SRIF in the mucosa (McKeen ES, Feniuk W, Humphrey PPA (1995) Naunyn-Schmiedeberg‘s Arch Pharmacol 352:402–411).
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