Article date: November 1991
By: S.M.O. Hourani, S.J. Bailey, J. Nicholls, I. Kitchen, in Volume 104, Issue 3, pages 685-690
Previous results obtained with the rat colon muscularis mucosae, which contracts in response to adenosine and adenosine 5′‐triphosphate (ATP), had suggested that adenylyl 5′‐(β,γ‐methylene)diphosphonate (AMPPCP), a stable ATP analogue, acted on P1‐purinoceptors rather than, as expected, on P2‐purinoceptors. This possibility has been examined in two tissues in which adenosine and ATP both cause relaxation, the guinea‐pig taenia caeci and the rat duodenum.
ATP, 2‐methylthio‐ATP (2‐MeSATP), AMPPCP, adenosine 5′‐(α,β‐methylene)triphosphonate (AMPCPP) and adenosine each relaxed the taenia caeci and the duodenum, and the order of potency of the nucleotides in each tissue was 2‐MeSATP > ATP > AMPCPP > AMPPCP, indicating that these effects were mediated by P2Y‐purinoceptors.
The P1 antagonist 8‐(p‐sulphophenyl)theophylline (8‐SPT) (100 μm) did not affect the responses to ATP, 2‐MeSATP or AMPCPP in either tissue, but inhibited the responses of adenosine and of AMPPCP in both tissues. In the duodenum a lower concentration of 8‐SPT caused a parallel shift to the right of the concentration‐response curve to adenosine and to AMPPCP but to different extents, with AMPPCP being inhibited more powerfully than adenosine. A dose‐ratio of around 5 was observed for adenosine and AMPPCP at concentrations of 8‐SPT of 20 μm and 2 μm respectively, but Schild analysis resulted in plots with slopes greater than unity. In the taenia caeci, however, 8‐SPT inhibited adenosine more powerfully than AMPPCP, and a range of concentrations (10–20 μm) only caused a two fold shift in the concentration‐response curve for AMPPCP, although the concentration‐response curve to adenosine was shifted in a concentration‐dependent manner and Schild analysis gave a pA2 value of 5.13 with a slope of 0.90.
As has been shown in other tissues, including the guinea‐pig taenia caeci, ATP (100 μm) was rapidly dephosphorylated by enzymes present in the rat duodenum, with less than 10% remaining after 20 min incubation, whereas AMPPCP (100 μm) was resistant to degradation, with greater than 90% remaining at the same time point.
AMPPCP therefore has pronounced but variable agonist actions on P1‐purinoceptors, and appears to act entirely via these receptors on the rat duodenum although in the guinea‐pig taenia caeci this action is less important and it acts largely via P2Y‐purinoceptors. These P1‐purinoceptor effects of AMPPCP are direct and are not due to its degradation to adenosine.
Previous results obtained with the rat colon muscularis mucosae, which contracts in response to adenosine and adenosine 5′‐triphosphate (ATP), had suggested that adenylyl 5′‐(β,γ‐methylene)diphosphonate (AMPPCP), a stable ATP analogue, acted on P1‐purinoceptors rather than, as expected, on P2‐purinoceptors. This possibility has been examined in two tissues in which adenosine and ATP both cause relaxation, the guinea‐pig taenia caeci and the rat duodenum.
ATP, 2‐methylthio‐ATP (2‐MeSATP), AMPPCP, adenosine 5′‐(α,β‐methylene)triphosphonate (AMPCPP) and adenosine each relaxed the taenia caeci and the duodenum, and the order of potency of the nucleotides in each tissue was 2‐MeSATP > ATP > AMPCPP > AMPPCP, indicating that these effects were mediated by P2Y‐purinoceptors.
The P1 antagonist 8‐(p‐sulphophenyl)theophylline (8‐SPT) (100 μm) did not affect the responses to ATP, 2‐MeSATP or AMPCPP in either tissue, but inhibited the responses of adenosine and of AMPPCP in both tissues. In the duodenum a lower concentration of 8‐SPT caused a parallel shift to the right of the concentration‐response curve to adenosine and to AMPPCP but to different extents, with AMPPCP being inhibited more powerfully than adenosine. A dose‐ratio of around 5 was observed for adenosine and AMPPCP at concentrations of 8‐SPT of 20 μm and 2 μm respectively, but Schild analysis resulted in plots with slopes greater than unity. In the taenia caeci, however, 8‐SPT inhibited adenosine more powerfully than AMPPCP, and a range of concentrations (10–20 μm) only caused a two fold shift in the concentration‐response curve for AMPPCP, although the concentration‐response curve to adenosine was shifted in a concentration‐dependent manner and Schild analysis gave a pA2 value of 5.13 with a slope of 0.90.
As has been shown in other tissues, including the guinea‐pig taenia caeci, ATP (100 μm) was rapidly dephosphorylated by enzymes present in the rat duodenum, with less than 10% remaining after 20 min incubation, whereas AMPPCP (100 μm) was resistant to degradation, with greater than 90% remaining at the same time point.
AMPPCP therefore has pronounced but variable agonist actions on P1‐purinoceptors, and appears to act entirely via these receptors on the rat duodenum although in the guinea‐pig taenia caeci this action is less important and it acts largely via P2Y‐purinoceptors. These P1‐purinoceptor effects of AMPPCP are direct and are not due to its degradation to adenosine.
DOI: 10.1111/j.1476-5381.1991.tb12489.x
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