Desensitization of the P2-purinoceptors on the rat colon muscularis mucosae.

1. Adenosine 5'-triphosphate (ATP) and adenosine have been shown to contract the rat colon muscularis mucosae, and the receptors at which they act have been classified as P2Y and A1 respectively. Uridine 5'-triphosphate (UTP) also contracts this tissue, and desensitization was used to investigate the receptors by which it acts, in the light of recent suggestions that specific pyrimidinoceptors may exist for UTP, or that nucleotide receptors may exist which are responsive to both ATP and UTP but not to some ATP analogues such as 2-methylthioadenosine 5'-triphosphate (2-MeSATP). 2. ATP, UTP and adenosine each contracted the rat colon muscularis mucosae in a concentration-dependent manner over the concentration range 0.3-300 microM, although maximal responses to ATP and UTP were not obtained. ATP was approximately 4 times as potent as UTP and approximately equipotent with adenosine although the maximal response to adenosine appeared to be less than that to ATP or UTP. 3. Desensitization of the tissue with ATP (200 microM) given immediately before each concentration of the agonists reduced subsequent contractions induced by ATP itself and also by UTP, but did not reduce contractions induced by adenosine. Desensitization of the tissues with UTP (200 microM) also reduced contractions induced by ATP and UTP but not by adenosine, whereas desensitization with adenosine (200 microM) reduced contractions induced by adenosine itself but not by ATP or UTP. 4. Desensitization of the tissue with 2-MeSATP (200 microM), which is a more potent agonist than ATP at P2Y-purinoceptors, greatly reduced the responses to ATP and to UTP, but had no effect on responses induced by adenosine. Attempts to desensitize the tissue with adenosine 5'-(alpha,beta-methylene)triphosphonate(AMPCPP), which is a more potent agonist than ATP at P2X-purinoceptors but is less potent atP2y-purinoceptors, were unsuccessful.5. These results show that cross desensitization to ATP and UTP occurred and was specific for these agonists rather than being due to a general decrease in the ability of the muscle to contract. This implies that ATP and UTP act at the same receptor, which does not support the existence of specificpyrimidinoceptors but which could be taken as evidence for the existence of a nucleotide receptor on this tissue. However, the ability of 2-MeSATP, which is inactive at the proposed nucleotide receptors,also selectively to desensitize this receptor indicates instead that ATP and UTP are both acting at a purinoceptor of the P2Y type in this tissue.