Vasoconstrictor and vasodilator responses to various agonists in the rat perfused mesenteric arterial bed: selective inhibition by PPADS of contractions mediated via P2x-purinoceptors.

1. The effect of pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on vasoconstrictor and/or vasodilator responses to various agonists and electrical field stimulation was investigated in the rat mesenteric arterial bed at basal tone and at tone raised by methoxamine (15-50 microM). 2. At basal tone, nucleotides produced vasoconstriction with the following rank order of potency: alpha,beta-methylene ATP >> 2-methylthio ATP > or = ATP = UTP. PPADS (0.3-10 microM) 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 microM 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 microM PPADS. In addition, acetylcholine- and adenosine-elicited relaxations were not influenced by 10 microM PPADS. 4. The present results confirm the previously described selective P2x antagonism by PPADS, this compound being ineffective at muscarinic M3- and adenosine P1-receptors as well as at alpha 1-adrenoceptors. There was some inhibition of P2y-purinoceptors but at a much higher concentration than required for inhibition of P2x-purinoceptors. 5. In addition, this study provides evidence for the ineffectiveness of PPADS at both vasoconstriction- and vasodilatation-mediating P2u-purinoceptors.