Inhibitory responses to exogenous adenosine in murine proximal and distal colon”

Abstract

1 The aims of the present study were firstly, to characterize pharmacologically the subtypes of P1 purinoreceptors involved in the inhibitory effects induced by exogenous adenosine in longitudinal smooth muscle of mouse colon, and secondly, to examine differences in the function and distribution of these receptors between proximal and distal colon. 2 Adenosine (100 μM–3 mM) caused a concentration-dependent reduction of the amplitude of spontaneous contractions in the proximal colon, and muscular relaxation in the distal colon. In the proximal colon, adenosine effects were antagonized by a selective A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10 nM), but were not modified by 3,7-dimethyl-1-propargylxanthine (DMPX, 10 μM) or by 9-chloro-2-(2-furanyl)-5-((phenylacetyl)amino)- [1,2,4]triazolo[1,5-c]quinazoline (MRS 1220, 0.1 μM), selective A2 and A3 receptor antagonists, respectively. In the distal colon, adenosine effects were antagonized by DPCPX, DMPX, and by a selective A2B receptor antagonist, 8-[4-[((4-cyanophenyl)carbamoylmethyl)oxy]phenyl]-1,3-di(n-propyl) xanthine (MRS 1754, 10 μM), but not by 8-(3-chlorostyryl)-caffeine (CSC, 10 μM), a selective A2A receptor antagonist, or by MRS 1220. 3 Tetrodotoxin (TTX 1 μM), the nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 100 μM), or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 μM), an inhibitor of soluble guanylyl cyclase, reduced adenosine effects only in distal colon. In addition, L-NAME induced a further reduction of adenosine relaxation in the presence of DPCPX, but not in the presence of MRS 1754. 4 From these results we conclude that, in the murine proximal colon, adenosine induces inhibitory effects via TTX-insensitive activation of A1 receptor. In the distal colon, adenosine activates both A1 and A2B receptors, the latter located on enteric inhibitory neurons releasing NO.