Contractile effects of uridine 5′‐triphosphate in the rat duodenum

Abstract

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-7-S), guanosine 5'-triphosphate (GTP) and uridine 5'-diphosphate (UDP) each relaxed the duodenum, with an agonist potency order of ATP = ADP>ATP-7-S>>GTP>>UTP = UDP, consistent with the presence of a P2Y purinoceptor mediating relaxation. 3 ATP-i-S, UTP and UDP each contracted the duodenum with an agonist potency order of ATP-y-S > UTP> UDP, although maximal responses to these agonists were not obtained at a concentration of 267 JAM (ATP-i-S) and 300 pM (UTP and UDP). No contractions were observed with any of the other agonists at concentrations up to 300 JM. 4 Indomethacin (25 JM) did not inhibit the contractions induced by UTP, indicating that they were not mediated via production of prostaglandins. 5 Suramin (100 JAM and 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-j-S, shifting the concentration-response curve to the right, and completely abolished contractions induced by ATP-y-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 (0.1IJM). 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.

Inhibitory action of PPADS on relaxant responses to adenine nucleotides or electrical field stimulation in guinea‐pig taenia coli and rat duodenum

“…However, the rat duodenum is unlikely to possess a relaxationmediating nucleotide receptor because UTP is much less potent than ATP (Johnson & Hourani, 1994 (10-100 gM; pA2= 5.02) in rat duodenum (Ziyal et al, 1994). Inhibition by PPADS (100 gM) of 2-methylthio ATP degradation by ecto-nucleotidases might explain this phenomenon.…”

“…In this case, however, a non-linear Schild plot would have been expected. In addition, no contractions were observed with 2-methylthio ATP (up to 300 gM) in rat duodenum (Johnson & Hourani, 1994 (Gross et al, 1994).…”

Pharmacological characterization of uracil nucleotide-preferring P2Y receptors modulating intestinal motility: a study on mouse ileum

“…Previous studies suggested that pyrimidines may also modulate gastrointestinal motility. UTP has been reported to induce muscular contractile responses in the rat proximal stomach [10], duodenum [11], rat colon muscularis mucosae [12], whilst a relaxant response has been shown in a rat distal colon due to activation of neuronal P2Y 2 receptors and nitric oxide release [13]. UTP relaxant responses have been shown also in a mouse distal colon [14].…”

“…Indeed, P2Y receptors can be subdivided into (1) adenine nucleotide-preferring receptors mainly responding to ADP and ATP; (2) uracil nucleotide-preferring receptors; (3) receptors of mixed selectivity; and (4) receptors responding to the sugar nucleotides UDP-glucose and UDP-galactose [1]. In particular, ADP is the most potent physiological agonist at humans and rodents P2Y 1 , P2Y 12 , and P2Y 13 receptors, whilst ATP is the agonist at the human P2Y 11 receptor (although this receptor may be activated by UTP). UTP is an agonist for P2Y 2 and P2Y 4 receptors, whilst UDP is agonist for P2Y 6 receptors.…”

“…So far, seven mammalian P2X-receptor subtypes (P2X [1][2][3][4][5][6][7] ) and eight mammalian P2Y-receptors subtypes (P2Y 1,2,4,6,11,12,13,14 ) have been cloned and recognized. P2X receptors are ligand-gated ion channels activated by ATP.…”