Effects of adenosine 5′-triphosphate, uridine 5′-triphosphate, adenosine 5′-tetraphosphate and diadenosine polyphosphates in guinea-pig taenia caeci and rat colon muscularis mucosae

The functional effects of adenosine 5'-triphosphate (ATP), uridine 5'-triphosphate (UTP), adenosine 5'-tetraphosphate (AP(4)) and the diadenosine polyphosphates P-1,P-3-diadenosine triphosphate (Ap(3)A), P-1,P-4-diadenosine tetraphosphate (Ap(4)A) and P-1,P-5-diadenosine pentaphosphate (Ap(5)A) were studied in two isolated smooth muscle preparations thought to contain P-2Y (P2Y(1)) receptors, the guinea-pig taenia caeci (which relaxes to ATP) and the rat colon muscularis mucosae (which contracts to ATP). In addition, the breakdown of these compounds by the rat colon muscularis mucosae was investigated by high pressure liquid chromatography. In the guinea-pig taenia caeci all the purine nucleotides caused relaxation with a potency order of Ap(3)A=Ap(4)A> ATP>AP(4)A=Ap(5)A, and these relaxations were antagonised by suramin with apparent pA(2) values in the region of 5, consistent with activation of a P2Y(1) receptor. In the rat colon muscularis mucosae the nucleotides caused contraction with a potency order of Ap(3)A = Ap(4)A>ATP=AP(4) =Ap(5)A >UTP. However, while suramin (100 mu M) inhibited responses to ATP and UTP at all concentrations of agonist, it only inhibited contractions induced by the higher concentrations of AP(4), Ap(3)A and Ap(4)A and had little effect on contractions induced by Ap(5)A. A higher concentration of suramin (1 mM) enhanced contractions induced by ATP bur greatly inhibited those induced by UTP and had no effect on responses to the other agonists. The A(1) adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 nM) had no effect on responses to ATP or UTP but inhibited responses to Ap(3)A, Ap(4)A, Ap(5)A and AP(4). A combination of suramin (1 mM) and DPCPX (10 nM) almost abolished responses to all the agonists. ATP and UTP were rapidly degraded by the rat colon muscularis mucosae while AP(4), Ap(3)A, Ap(4)A and Ap(5)A were degraded more slowly, and the major product detected after breakdown of the purine nucleotides was inosine rather than adenosine. The breakdown of all the nucleotides was inhibited by suramin (1 mM), although this inhibition did not achieve statistical significance in the case of ATP. These results show that while the diadenosine polyphosphates appear to act as P2 agonists in the taenia caeci, in the rat colon muscularis mucosae their major action is via adenosine A(1) receptors rather than via P2 receptors. In addition, although they are more stable than ATP or UTP, their action in this tissue is clearly affected by their degradation which complicates the effects of suramin.