Pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) as a tool for differentiation of P2Y2-receptor-mediated vasorelaxation in guinea pig aorta.
The action of the putative P2Y1-receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) was studied in guinea pig aorta for potential use in the differentiation between P2Y1 and P2Y2 purine receptors. Concentration-effect curves to 2-methylthioadenosine triphosphate (2MeSATP) and uridine triphosphate (UTP), agonists at P2Y1- and P2Y2-receptor sites, respectively, and the common agonist adenosine triphosphate (ATP) were constructed in guinea pig aortic ring preparations with the tone raised by 5 microM of noradrenaline. A ranked order of agonist potency of 2MeSATP > ATP > UTP resulted from the construction of concentration response curves to vasorelaxation of the agonists. Deendothelialization virtually abolished vasorelaxation to UTP but made no significant difference to 2MeSATP-induced responses. PPADS exhibited noncompetitive inhibition at P2Y1-receptor sites by reducing the maximal response to 2MeSATP, although a trend towards a right shift of the concentration-effect curves was observed. In total contrast, PPADS enhanced P2Y2-mediated vasorelaxation to UTP by shifting the concentration-effect curves to the left and increasing maximal responses. Thus, PPADS is a noncompetitive antagonist at P2Y1 receptors but enhances responses, at least to UTP, at P2Y2 receptors in guinea pig aorta via a hitherto unknown mechanism. Thus, PPADS is a potentially useful substance that may be used for differentiation between P2Y1 and P2Y2 receptors in the guinea pig aorta.
Payne
S J
SJ
Liver Sciences Unit, Academic Department of Surgery, GKT School of Medicine, St. Thomas' Hospital, London.
Brown
C A
CA
Benjamin
I S
IS
Alexander
B
B
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D013873:Thionucleotides / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D058919:Purinergic P2 Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D013873:Thionucleotides; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D000255:Adenosine Triphosphate; D014544:Uridine Triphosphate; C008501:2-methylthio-ATP