DESENSITIZATION OF THE P(2)-PURINOCEPTORS ON THE RAT COLON MUSCULARISMUCOSAE

1 Adenosine 5'-triphosphate (ATP) and adenosine have been shown to con tract the rat colon muscularis mucosae, and the receptors at which the y act have been classified as P2y and A1 respectively. Uridine 5'-trip hosphate (UTP) also contracts this tissue, and desensitization was use d to investigate the receptors by which it acts, in the light of recen t suggestions that specific pyrimidinoceptors may exist for UTP, or th at nucleotide receptors may exist which are responsive to both ATP and UTP but not to some ATP analogues such as 2-methylthioadenosine 5'-tr iphosphate (2-MeSATP). 2 ATP, UTP and adenosine each contracted the ra t colon muscularis mucosae in a concentration-dependent manner over th e concentration range 0.3-300 mum, although maximal responses to ATP a nd UTP were not obtained. ATP was approximately 4 times as potent as U TP and approximately equipotent with adenosine although the maximal re sponse to adenosine appeared to be less than that to ATP or UTP. 3 Des ensitization of the tissue with ATP (200 mum) given immediately before each concentration of the agonists reduced subsequent contractions in duced by ATP itself and also by UTP, but did not reduce contractions i nduced by adenosine. Desensitization of the tissues with UTP (200 mum) also reduced contractions induced by ATP and UTP but not by adenosine , whereas desensitization with adenosine (200 mum) reduced contraction s induced by adenosine itself but not by ATP or UTP. 4 Desensitization of the tissue with 2-MeSATP (200 mum), which is a more potent agonist than ATP at P2Y-purinoceptors, greatly reduced the responses to ATP a nd to UTP, but had no effect on responses induced by adenosine. Attemp ts to desensitize the tissue with adenosine 5'-(alpha,beta-methylene)t riphosphonate (AMPCPP), which is a more potent agonist than ATP at P2X -purinoceptors but is less potent at P2Y-purinoceptors, were unsuccess ful. 5 These results show that cross desensitization to ATP and UTP oc curred and was specific for these agonists rather than being due to a general decrease in the ability of the muscle to contract. This implie s that ATP and UTP act at the same receptor, which does not support th e existence of specific pyrimidinoceptors but which could be taken as evidence for the existence of a nucleotide receptor on this tissue. Ho wever, the ability of 2-MeSATP, which is inactive at the proposed nucl eotide receptors, also selectively to desensitize this receptor indica tes instead that ATP and UTP are both acting at a purinoceptor of the P2Y type in this tissue.