Purinergic Receptors in Visceral Smooth Muscle

Maguire, M. Helen; Satchell, D.G.

doi:10.1007/978-94-009-5816-6_2

Cited by 12 publications

(11 citation statements)

References 107 publications

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“…L-AMP-PCP (100 jiM) was completely resistant to degradation, and no breakdown products could be detected even after 60 min ( Figure 5). In the case of ATP and of AMP-PCP, somewhat less adenosine was detected after the longer incubation times than would have been expected from the corresponding breakdown of the starting materials (Figures 3 and 5), and this is presumably due to some uptake of adenosine by the muscle (Maguire & Satchell, 1981). ATP (100 tiM) incubated with Krebs solution alone for 60 min was completely unchanged, and there was no detectable release of nucleotides or nucleosides by the muscle after 60 min incubation.…”

Section: Degradation Studiesmentioning

confidence: 83%

“…The pharmacological actions of adenosine 5'-triphosphate (ATP) on many smooth muscle systems may be complicated by the breakdown of ATP to adenosine, which is less active than, or in some cases has the opposite action to ATP (Burnstock & Brown, 1981;Maguire & Satchell, 1981). This complication has been partly overcome by the use of analogues which are thought to be more resistant to enzymatic degradation by the tissue, such as adenylyl 5'-(P,-ymethylene)-diphosphonate (AMP-PCP), in which one of the ester oxygen linkages between the phosphate groups has been replaced by a methylene linkage (Maguire & Satchell, 1979).…”

Section: Introductionmentioning

confidence: 99%

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Some pharmacological and biochemical interactions of the enantiomers of adenylyl 5′‐(β, γ‐methylene)‐diphosphonate with the guinea‐pig urinary bladder

Cusack

Hourani

1984

British J Pharmacology

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Adenosine 5′‐triphosphate (ATP) and adenylyl 5′‐(β,γ methylene)‐diphosphonate (AMP‐PCP) both contracted the guinea‐pig urinary bladder, but the response to AMP‐PCP was much greater. We synthesized the enantiomer of AMP‐PCP, L‐adenylyl 5′‐(β,γ‐methylene)‐diphosphonate (L‐AMP‐PCP), and tested it on the guinea‐pig bladder. L‐AMP‐PCP contracted the guinea‐pig bladder, and was more potent than AMP‐PCP and much more potent than ATP. The potential breakdown product of L‐AMP‐PCP, L‐adenosine, unlike adenosine (the breakdown product of AMP‐PCP), did not inhibit contractions of the guinea‐pig bladder. ATP and its enantiomer L‐adenosine 5′‐triphosphate (L‐ATP) were rapidly degraded by the muscle, and AMP‐PCP was also degraded, but more slowly. L‐AMP‐PCP, however, was completely resistant to degradation. L‐AMP‐PCP would appear to be a useful ATP analogue, as it is potent and resistant to degradation, and its potential breakdown product, L‐adenosine, is inactive.

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Section: Degradation Studiesmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Some pharmacological and biochemical interactions of the enantiomers of adenylyl 5′‐(β, γ‐methylene)‐diphosphonate with the guinea‐pig urinary bladder

Cusack

Hourani

1984

British J Pharmacology

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“…an interaction between them, whereby activation of ectonu cleotidase influences ATP-receptor binding, also cannot be ruled out. It has been proposed that the P2y-purinoccptor and ecto-ATPase are the same molecule [27,31]. This conclusion was based on the observation that most of the nonhydrolyzable ATP analogs are much less potent, on a molar basis, than ATP; thus, ectonucleotidase activity may be required for complete P2y-purinoceptor activa tion.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Flow-Mediated Signal Transduction in Endothelial Cells: Kinetics of ATP Surface Concentrations

1992

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Intracellular free calcium ([Ca²⁺]_i) was measured in single cells of a confluent endothelial monolayer subjected to defined flow. Flow medium containing adenosine triphosphate (ATP) was used to study the influence of flow forces upon agonist-response coupling as mediated via the P2_y-purinoceptor. [Ca²⁺]_i responses were highly sensitive to the fluid motion at the cell surface; consecutive small increases of flow stimulated large [Ca²⁺]i transients with the levels returning to baseline at the new flow rate within 250 s. The characteristics of [Ca²⁺]_i transients were also influenced by decreasing flow. Since potent ecto-nucleotidases at the endothelial cell surface rapidly degrade ATP, we postulated that a combination of flow and degradative enzymes regulates the mass transport of ATP in the boundary layer. The hypothesis predicts that step increases of flow exceed the capacity of the ectonucleotidases and allow ATP to reach the receptor. Experiments were conducted to compare ATP and ADP_βS, a nonhydrolyzable ATP analog that resists degradation by surface ectonucleotidases, and calculations of ATP mass transport to the cell surface were compared to estimates of surface clearance rates. Calculations of mass transport coefficients for ATP in the boundary layer demonstrated that changes of flow which elicited a prominent [Ca²⁺]_i response represented 26-73 % changes in the mass transport of ATP from the bulk fluid. When steady-state mass transport coefficients for ATP under various flow conditions were compared with the estimated rate constant for surface degradation of ATP, ratios close to unity were obtained. These results suggest that both boundary layer mass transport and ATP clearance rates can be rate-limiting for flow-mediated activation of the P_2y-receptor. The experiments provide evidence for differential signal transduction responses in the endothelium driven by diffusion gradients (derived from both the blood and the vessel wall), which are likely to vary widely in the complex flow fields encountered in vivo.

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“…The potential pharmacological complications produced by such processes are generally 2-fold: to convert the applied agonist to other chemical species which may be active as agonists or antagonists at the receptor under study or at other receptors in the tissue preparation and to reduce the concentration of the agonist available to interact with the receptors under study so that the applied agonist concentration does not reflect the active one. Although there are a number of reports describing effects at purinoceptors of the former kind (Maguire & Satchell, 1981), evidence for the pharmacological impact of the latter is limited (Welford et al, 1987). However, studies conducted in other receptor systems, for example adrenoceptors and muscarinic receptors, show that problems of this kind manifest as incorrect determination of agonist potency orders (Kenakin, 1980) and cause difficulties in the quantitative analysis of antagonist effects (Kenakin & Beek, 1985).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological analysis of ecto‐ATPase inhibition: evidence for combined enzyme inhibition and receptor antagonism in P_2X‐purinoceptor ligands

Crack

Beukers

McKechnie

et al. 1994

British J Pharmacology

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1 Previous studies have shown that suramin and FPL 66301 are competitive antagonists at the P2x-purinoceptor in the rabbit ear artery. Those studies employed ax,-methylene ATP, a poorly hydrolysable ATP analogue, as the agonist. In this study these compounds have been tested using ATP as the agonist. 2 Suramin, in the concentration range 30-1000 IM, potentiated the contractile effects of ATP, producing a 3-fold leftward shift of the ATP E/[AJ curves. FPL 66301, in the concentration range 100-1000 jM, produced a significant but small (;3-fold) rightward shift of the ATP curves. These results are in marked contrast with previous studies using a,-methylene ATP in which 30-fold rightward shifts were achieved using the same concentration ranges of suramin and FPL 66301. 3 Suramin and FPL 66301 were tested as ecto-ATPase inhibitors in a human blood cell assay. Suramin inhibited the enzyme with a pICQ0 of 4.3, FPL 66301 with a pIC50 of 3.3.4 The pharmacological data were analysed using a theoretical model describing the action of a compound with dual enzyme inhibitory and receptor antagonistic properties on the effects of an agonist susceptible to enzymatic degradation. The model was found to fit the data well using the known pKB estimates for suramin and FPL 66301 and similar relative (but not absolute) pK, estimates to those obtained for the compounds in the enzyme assay. 5 From this analysis it was concluded that the limited shifts of ATP E/[A] curves produced by suramin and FPL 66301 were the result of 'self-cancellation' of the potentiating (enzyme inhibitory) and rightward-shifting (receptor antagonistic) properties. 6 The analysis also indicated that the presence of ecto-ATPase activity in the rabbit ear artery preparation has a marked effect on the apparent potency of ATP. The experimental p[A50] was 3.4, whereas the 'true' value, that is the value which would be obtained in the absence of ecto-ATPase activity, was 6.0, some 400-fold higher. 7 Two conclusions are drawn from this study. Firstly, caution must be exercised in the use of suramin and FPL 66301 as tools for receptor classification. Absence of overt antagonism by these compounds when metabolically unstable agonists are used could lead to erroneous claims for receptor subtypes.Secondly, the agonist potency order currently used to designate P2X-purinoceptors may require modification.

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Purinergic Receptors in Visceral Smooth Muscle

Cited by 12 publications

References 107 publications

Some pharmacological and biochemical interactions of the enantiomers of adenylyl 5′‐(β, γ‐methylene)‐diphosphonate with the guinea‐pig urinary bladder

Some pharmacological and biochemical interactions of the enantiomers of adenylyl 5′‐(β, γ‐methylene)‐diphosphonate with the guinea‐pig urinary bladder

Mechanisms of Flow-Mediated Signal Transduction in Endothelial Cells: Kinetics of ATP Surface Concentrations

Pharmacological analysis of ecto‐ATPase inhibition: evidence for combined enzyme inhibition and receptor antagonism in P_2X‐purinoceptor ligands

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Purinergic Receptors in Visceral Smooth Muscle

Cited by 12 publications

References 107 publications

Some pharmacological and biochemical interactions of the enantiomers of adenylyl 5′‐(β, γ‐methylene)‐diphosphonate with the guinea‐pig urinary bladder

Some pharmacological and biochemical interactions of the enantiomers of adenylyl 5′‐(β, γ‐methylene)‐diphosphonate with the guinea‐pig urinary bladder

Mechanisms of Flow-Mediated Signal Transduction in Endothelial Cells: Kinetics of ATP Surface Concentrations

Pharmacological analysis of ecto‐ATPase inhibition: evidence for combined enzyme inhibition and receptor antagonism in P2X‐purinoceptor ligands

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Product

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Pharmacological analysis of ecto‐ATPase inhibition: evidence for combined enzyme inhibition and receptor antagonism in P_2X‐purinoceptor ligands