Evidence that the ATP‐induced increase in vasomotion of guinea‐pig mesenteric lymphatics involves an endothelium‐dependent release of thromboxane A 2

Experiments were made to investigate mechanisms by which adenosine 5′‐trisphosphate (ATP) enhanced vasomotion in mesenteric lymphatic vessels isolated from young guinea‐pigs. ATP (10 −8 –10 −3   M ) caused a concentration‐dependent increase of perfusion‐induced vasomotion with the endothelium mediating a fundamental role at low ATP concentrations (10 −8 –10 −6   M ). The response to 10 −6   M ATP showed tachyphylaxis when applied at intervals of 10 min but not at intervals of 20 or 30 min. Suramin (10 −4   M ) or reactive blue 2 (3×10 −5   M ) but not PPADS (3×10 −5   M ) abolished the excitatory response to 10 −6   M ATP confirming an involvement of P 2 purinoceptors. The excitatory response to 10 −6   M ATP was abolished by treatment with either pertussis toxin (100 ng ml −1 ), antiflammin‐1 (10 −9 M ), indomethacin (3×10 −6   M ) or SQ29548 (3×10 −7   M ), inhibitors of specific G proteins, phospholipase A 2 , cyclo‐oxygenase and thromboxane A 2 receptors respectively. ATP simultaneously induced a suramin‐sensitive inhibitory response, which was normally masked by the excitatory response. ATP‐induced inhibition was mediated by endothelium‐derived nitric oxide (EDNO) as the response was abolished by N G ‐nitro‐ L ‐arginine ( L ‐NOARG; 10 −4   M ), an inhibitor of nitric oxide synthase. We conclude that ATP modulates lymphatic vasomotion by endothelium‐dependent and endothelium‐independent mechanisms. One of these is a dominant excitation caused through endothelial P 2 purinoceptors which because of an involvement of a pertussis toxin sensitive G‐protein may be of the P 2Y receptor subtype. Their stimulation increases synthesis of phospholipase A 2 and production of thromboxane A 2 , an arachidonic acid metabolite which acts as an endothelium‐derived excitatory factor.British Journal of Pharmacology (1999) 127 , 1597–1602; doi: 10.1038/sj.bjp.0702710