| Abstrakt: |
The effects of the putative selective P purinoceptor agonist, β,γ-methylene- l-adenosine 5′-triphosphate (βγme- l-ATP), were determined at rat neuronal and smooth muscle P 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 P purinoceptor agonist, α, β methylene ATP (αβmeATP;1-100 μM), produced concentration-related depolarisation responses with a mean EC 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 [H]Lx βmeATP binding sites, with mean pIC 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 pIC 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 EC 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 [H]αβmeATP exhibited high affinity for ββ γme- l-ATP, αβmeATP and βγme- d-ATP with mean PIC values of 7.7, 8.4 and 7.3, respectively. These results indicate that βγme- l-ATP exhibits neither agonist nor antagonist properties at P purinoceptors on rat vagal neurones and possesses only very low affinity for [H]αβmeATP binding sites in rat brain. In contrast, βγme- l-ATP is a potent, high affinity agonist at smooth muscle P purinoceptors of the rat vas deferens. This selective agonist action of βγme- l-ATP suggests that P purinoceptors in smooth muscle and neurones are different and represent distinct P purinoceptor subtypes. [ABSTRACT FROM AUTHOR] |
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