Contractile effects of uridine 5'-triphosphate in the rat duodenum

1. Previous studies have shown that the rat duodenum relaxes to adenosine and adenosine 5'-triphosphate (ATP) via P1 and P2Y purinoceptors respectively, but in preliminary studies uridine 5'-triphosphate (UTP) was found to contract this tissue. The non-selective P2 antagonist suramin and a number of nucleotides were therefore used to investigate this response further. 2. ATP, UTP, adenosine 5'-diphosphate (ADP), adenosine 5'-O-(3-thiotriphosphate) (ATP-gamma-S), guanosine 5'-triphosphate (GTP) and uridine 5'-diphosphate (UDP) each relaxed the duodenum, with an agonist potency order of ATP = ADP > ATP-gamma-S >> GTP >> UTP = UDP, consistent with the presence of a P2Y purinoceptor mediating relaxation. 3. ATP-gamma-S, UTP and UDP each contracted the duodenum with an agonist potency order of ATP-gamma-S > UTP > UDP, although maximal responses to these agonists were not obtained at a concentration of 267 microM (ATP-gamma-S) and 300 microM (UTP and UDP). No contractions were observed with any of the other agonists at concentrations up to 300 microM. 4. Indomethacin (25 microM) did not inhibit the contractions induced by UTP, indicating that they were not mediated via production of prostaglandins. 5. Suramin (100 microM and 1 mM) inhibited relaxations induced by ATP, shifting the concentration-response curve to the right, with the maximal response to ATP being decreased by the higher concentration of suramin (1 mM). Suramin (1 mM) inhibited relaxations induced by ATP-gamma-S, shifting the concentration-response curve to the right, and completely abolished contractions induced by ATP-gamma-S. In contrast, suramin (100 JAM and 1 mM) had no effect on contractions induced by UTP.Contractions induced by UTP were, however, less sustained in the presence of suramin, which also affected the basal tone of some tissues when precontracted with carbachol (0.1 microM). In the presence of suramin (I mM), no contractions to ATP were observed.6. These results confirm that in the rat duodenum there is a P2Y purinoceptor that mediates relaxation in response to a number of purine nucleotides, and at which the pyrimidine nucleotides UTP and UDP are almost inactive. There are also receptors at which UTP and ATP-y-S act to cause contraction.Suramin discriminates between the contractile effects of these two agonists, which may indicate the presence of a suramin-insensitive pyrimidinoceptor as well as a suramin-sensitive receptor for ATP-y-S.An alternative explanation is that the differential effects of suramin are via its actions as an antagonist in addition to its action as an ectonucleotidase inhibitor.