Purinoceptors mediating relaxation and spasm in the rat gastric fundus

1 The relaxant and spasmogenic effects of purines and analogues were studied in longitudinal strips of rat gastric fundus to characterize the purinoceptors involved. Classification was studied by use of agonist potency orders and of antagonists in circumstances where the influence of confounding factors was reduced. In general tone was raised by carbachol (0.1 μ m ). 2 Adenosine produced relaxation and was potentiated by nitrobenzylthioinosine (NBTI, 0.3 and 30 μ m ), an adenosine‐uptake inhibitor. 8‐Sulphophenyl‐theophylline (8‐SPT, 30 μ m ), a selective P 1 ‐purinoceptor antagonist, antagonized adenosine and 5′‐N‐ethylcarboxamidoadenosine (NECA), a selective agonist at P 1 ‐purinoceptors. 3 At resting tone, adenosine 5′‐triphosphate (ATP) induced a small, phasic relaxation followed by a maintained spasm. When tone was raised by carbachol, ATP induced a larger relaxation followed by a smaller spasm. NBTI did not potentiate ATP, nor did 8‐SPT antagonize ATP, suggesting that ATP does not act directly or indirectly at P 1 ‐purinoceptors. 4 With raised tone, and in the presence of indomethacin (10 μ m ) and 8‐SPT (30 μ m ), 2‐methylthio ATP (2‐MeSATP) and ATP produced relaxations followed by spasms while α,β‐methylene ATP (α,β‐MeATP) induced only relaxation; all responses were concentration‐dependent. The compounds had similar slopes and maxima for relaxation and spasm. The rank orders of potency were 2‐MeSATP ≫ α,β‐MeATP > ATP for relaxation and 2‐MeSATP ≫ ATP for spasm. 5 With raised tone, and in the presence of indomethacin and 8‐SPT, desensitization to α,β‐MeATP (100 μ m ) completely and only slightly suppressed responses to ATP and 2‐MeSATP, respectively, as relaxants but had no effect on relaxant responses to adenosine. The magnitude of the spasms to ATP and 2‐MeSATP was considerably increased by desensitization with α,β‐MeATP but the spasm to KCl was not affected. 6 With raised tone, and in the presence of indomethacin and 8‐SPT, reactive blue 2 (10 μ m ) non‐selectively antagonized ATP, 2‐MeATP, α,β‐MeATP, adenosine and isoprenaline as relaxants. Reactive blue 2 prevented the spasms to ATP and 2‐MeSATP but not spasm to KCl. 7 With raised tone, and in the presence of indomethacin, suramin (100 μ m ) antagonized ATP, but not adenosine, as relaxants and antagonized ATP, but not KCl, as spasmogens. 8 It is proposed that adenosine is susceptible to nucleoside‐specific uptake and acts predominantly via a P 1 ‐purinoceptor and also by a non‐P 1 ‐purinoceptor mechanism. ATP‐ and α,β‐MeATP‐induced relaxations probably occur via a P 2X ‐purinoceptor. The anomalous nature of the 2‐MeSATP‐induced relaxation suggests it acts both via a P 2X ‐purinoceptor and an additional mechanism. A P 2Y ‐purinoceptor is most likely to be involved in the spasms to ATP and 2‐MeSATP. Therefore, the functional nature of the responses mediated by P 2X ‐ and P 2Y ‐purinoceptors, relaxation and spasm respectively, are opposite to those seen in most smooth muscles.