VASOCONSTRICTOR AND VASODILATOR RESPONSES TO VARIOUS AGONISTS IN THE RAT PERFUSED MESENTERIC ARTERIAL BED - SELECTIVE-INHIBITION BY PPADS OF CONTRACTIONS MEDIATED VIA P-2X-PURINOCEPTORS

1 The effect of pyridoxalphosphate-6-azophenyl-2',4'-disulpohonic acid (PPADS) on vasoconstrictor and/or vasodilator responses to various agonists and electrical held stimulation was investigated in the rat mesenteric arterial bed at basal tone and at tone raised by methoxamine (15-50 mu M). 2 At basal tone, nucleotides produced vasoconstriction with the following rank order of potency: alpha,beta-methylene ATP>> 2-methylthio ATP greater than or equal to ATP = UTP. PPADS (0.3-10 mu M) concentration-dependently antagonized alpha,beta-methylene ATP-, 2-methylthio ATP- and ATP-induced responses. UTP-, noradrenaline- and nerve-mediated (4-32 Hz) increases in perfusion pressure remained unaffected by 10 mu M PPADS. 3 In raised tone preparations, nucleotides produced vasodilations, their rank order of potency being 2-methylthio ATP > ATP > UTP. Responses to 2-methylthio ATP were slightly antagonized, whereas ATP- and UTP-induced responses remained unaffected by 10 mu M PPADS. In addition, acetylcholine- and adenosine-elicited relaxations were not influenced by 10 mu M PPADS. 4 The present results confirm the previously described selective P-2x antagonism by PPADS, this compound being ineffective at muscarinic M(3)- and adenosine P-1-receptors as well as at alpha(1)-adrenoceptors. There was some inhibition of P-2y-purinoceptors but at a much higher concentration than required for inhibition of P-2x-purinoceptors. 5 In addition, this study provides evidence for the ineffectiveness of PPADS at both vasoconstriction- and vasodilatation-mediating P-2u-purinoceptors.