The inhibitory adenosine receptor at the neuromuscular junction and hippocampus of the rat: antagonism by 1,3,8‐substituted xanthines

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Abstract
1 The ability of 1,3,8-substituted xanthines to antagonize the inhibitory effects of adenosine receptor agonists on the amplitude of nerve-evoked twitches of the rat phrenic-diaphragm and on the amplitude of orthodromically-evoked population spikes, recorded from the CA1 pyramidal cells of rat hippocampal slices, was investigated. 2 1,3-Dipropyl-8-cyclopenthylxanthine (DPCPX), 1,3-dipropyl-8-(carboxymethyloxyphenyl)xanthine (XCC), 1,3-dipropyl-8-(4-((2-aminoethyl)amino)carbonylmethyloxyphenyl)xanthine (XAC), 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX), 8-phenyltheophylline (8-PT), 1,3-diethyl-8-phenylxanthine (DPX) and PD 115,199, in concentrations virtually devoid of effect on neuromuscular transmission, shifted to the right in a near parallel manner the log concentration-response curve for the inhibitory effect of 2-chloroadenosine (CADO) on nerve-evoked twitches of the phrenic-diaphragm. Linear Schild plots with slopes near to unity were obtained for all the xanthines. 3 The order of potency of the xanthines as antagonists of the effect of CADO in the phrenic-diaphragm was DPCPX (Ki = 0.54 nm) > XCC (Ki = 10 nm), XAC (Ki = 11 nm), PACPX (Ki = 13 nm) > DPX (Ki = 22 nm), 8-PT (Ki = 25 nm) > PD 115,199 (Ki = 57 nm). The potency of DPCPX in antagonizing the inhibitory effects of R-N6-phenylisopropyladenosine (R-PIA) and 5′-N-ethylcarboxamide adenosine (NECA) on nerve-evoked twitch responses was not statistically different from its potency in antagonizing the inhibitory effect on CADO. 4 In the hippocampal slices, DPCPX, XCC and XAC, used in concentrations virtually devoid of effect on population spike amplitude, shifted to the right in a near parallel manner the log concentration-response curve for the inhibitory effect of CADO on the amplitude of the population spikes. The Schild plots were linear with slopes near unity. 5 The potencies of DPCPX (Ki = 0.45 nm) and XAC (Ki = 11 nm) in antagonizing the inhibitory adenosine receptor at the hippocampus were similar to their potencies for antagonism of the inhibitory adenosine receptor at the phrenic-diaphragm. XCC was only slightly more potent (Ki = 5.4 nm) as an antagonist of the adenosine receptor in the hippocampus than in the phrenic-diaphragm. 6 The results suggest that the inhibitory adenosine receptors in the phrenic-diaphragm and in the hippocampus of the rat are similar, and that according to the antagonist potencies, these receptors belong to the A1-adenosine receptor subtype.

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