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. 1994 Nov;113(3):1015–1021. doi: 10.1111/j.1476-5381.1994.tb17094.x

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

U Windscheif 1, V Ralevic 1, H G Bäumert 1, E Mutschler 1, G Lambrecht 1, G Burnstock 1
PMCID: PMC1510409  PMID: 7858843

Abstract

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.

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Selected References

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  1. Burnstock G., Kennedy C. Is there a basis for distinguishing two types of P2-purinoceptor? Gen Pharmacol. 1985;16(5):433–440. doi: 10.1016/0306-3623(85)90001-1. [DOI] [PubMed] [Google Scholar]
  2. Burnstock G. Sympathetic purinergic transmission in small blood vessels. Trends Pharmacol Sci. 1988 Apr;9(4):116–117. doi: 10.1016/0165-6147(88)90185-x. [DOI] [PubMed] [Google Scholar]
  3. Burnstock G., Warland J. J. P2-purinoceptors of two subtypes in the rabbit mesenteric artery: reactive blue 2 selectively inhibits responses mediated via the P2y-but not the P2x-purinoceptor. Br J Pharmacol. 1987 Feb;90(2):383–391. doi: 10.1111/j.1476-5381.1987.tb08968.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dunn P. M., Blakeley A. G. Suramin: a reversible P2-purinoceptor antagonist in the mouse vas deferens. Br J Pharmacol. 1988 Feb;93(2):243–245. doi: 10.1111/j.1476-5381.1988.tb11427.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gordon J. L. Extracellular ATP: effects, sources and fate. Biochem J. 1986 Jan 15;233(2):309–319. doi: 10.1042/bj2330309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Grimm U., Fuder H., Moser U., Bümert H. G., Mutschler E., Lambrecht G. Characterization of the prejunctional muscarinic receptors mediating inhibition of evoked release of endogenous noradrenaline in rabbit isolated vas deferens. Naunyn Schmiedebergs Arch Pharmacol. 1994 Jan;349(1):1–10. doi: 10.1007/BF00178199. [DOI] [PubMed] [Google Scholar]
  7. Han C., Li J., Minneman K. P. Subtypes of alpha 1-adrenoceptors in rat blood vessels. Eur J Pharmacol. 1990 Nov 6;190(1-2):97–104. doi: 10.1016/0014-2999(90)94116-f. [DOI] [PubMed] [Google Scholar]
  8. Hendriks M. G., Pfaffendorf M., Van Zwieten P. A. Characterization of the muscarinic receptor subtype mediating vasodilation in the rat perfused mesenteric vascular bed preparation. J Auton Pharmacol. 1992 Dec;12(6):411–420. doi: 10.1111/j.1474-8673.1992.tb00389.x. [DOI] [PubMed] [Google Scholar]
  9. Hogaboom G. K., O'Donnell J. P., Fedan J. S. Purinergic receptors: photoaffinity analog of adenosine triphosphate is a specific adenosine triphosphate antagonist. Science. 1980 Jun 13;208(4449):1273–1276. doi: 10.1126/science.6103581. [DOI] [PubMed] [Google Scholar]
  10. Hoyle C. H., Edwards G. A. Activation of P1- and P2Y-purinoceptors by ADP-ribose in the guinea-pig taenia coli, but not of P2X-purinoceptors in the vas deferens. Br J Pharmacol. 1992 Oct;107(2):367–374. doi: 10.1111/j.1476-5381.1992.tb12753.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hoyle C. H., Knight G. E., Burnstock G. Suramin antagonizes responses to P2-purinoceptor agonists and purinergic nerve stimulation in the guinea-pig urinary bladder and taenia coli. Br J Pharmacol. 1990 Mar;99(3):617–621. doi: 10.1111/j.1476-5381.1990.tb12979.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jackson E. K. Role of adenosine in noradrenergic neurotransmission in spontaneously hypertensive rats. Am J Physiol. 1987 Oct;253(4 Pt 2):H909–H918. doi: 10.1152/ajpheart.1987.253.4.H909. [DOI] [PubMed] [Google Scholar]
  13. Lambrecht G., Friebe T., Grimm U., Windscheif U., Bungardt E., Hildebrandt C., Bäumert H. G., Spatz-Kümbel G., Mutschler E. PPADS, a novel functionally selective antagonist of P2 purinoceptor-mediated responses. Eur J Pharmacol. 1992 Jul 7;217(2-3):217–219. doi: 10.1016/0014-2999(92)90877-7. [DOI] [PubMed] [Google Scholar]
  14. McLaren G. J., Lambrecht G., Mutschler E., Bäumert H. G., Sneddon P., Kennedy C. Investigation of the actions of PPADS, a novel P2x-purinoceptor antagonist, in the guinea-pig isolated vas deferens. Br J Pharmacol. 1994 Mar;111(3):913–917. doi: 10.1111/j.1476-5381.1994.tb14825.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. O'Connor S. E., Dainty I. A., Leff P. Further subclassification of ATP receptors based on agonist studies. Trends Pharmacol Sci. 1991 Apr;12(4):137–141. doi: 10.1016/0165-6147(91)90530-6. [DOI] [PubMed] [Google Scholar]
  16. O'Connor S. E. Recent developments in the classification and functional significance of receptors for ATP and UTP, evidence for nucleotide receptors. Life Sci. 1992;50(22):1657–1664. doi: 10.1016/0024-3205(92)90420-t. [DOI] [PubMed] [Google Scholar]
  17. O'Connor S. E., Wood B. E., Leff P. Characterization of P2x-receptors in rabbit isolated ear artery. Br J Pharmacol. 1990 Nov;101(3):640–644. doi: 10.1111/j.1476-5381.1990.tb14133.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pipili E. A study on the postjunctional excitatory alpha-adrenoreceptor subtypes in the mesenteric arterial bed of the rat. J Auton Pharmacol. 1986 Jun;6(2):125–132. doi: 10.1111/j.1474-8673.1986.tb00639.x. [DOI] [PubMed] [Google Scholar]
  19. Ralevic V., Burnstock G. Actions mediated by P2-purinoceptor subtypes in the isolated perfused mesenteric bed of the rat. Br J Pharmacol. 1988 Oct;95(2):637–645. doi: 10.1111/j.1476-5381.1988.tb11686.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ralevic V., Burnstock G. Effects of purines and pyrimidines on the rat mesenteric arterial bed. Circ Res. 1991 Dec;69(6):1583–1590. doi: 10.1161/01.res.69.6.1583. [DOI] [PubMed] [Google Scholar]
  21. Ralevic V., Burnstock G. Postjunctional synergism of noradrenaline and adenosine 5'-triphosphate in the mesenteric arterial bed of the rat. Eur J Pharmacol. 1990 Jan 17;175(3):291–299. doi: 10.1016/0014-2999(90)90567-p. [DOI] [PubMed] [Google Scholar]
  22. Ralevic V., Burnstock G. Roles of P2-purinoceptors in the cardiovascular system. Circulation. 1991 Jul;84(1):1–14. doi: 10.1161/01.cir.84.1.1. [DOI] [PubMed] [Google Scholar]
  23. Ralevic V., Milner P., Kirkpatrick K. A., Burnstock G. Flow-induced release of adenosine 5'-triphosphate from endothelial cells of the rat mesenteric arterial bed. Experientia. 1992 Jan 15;48(1):31–34. doi: 10.1007/BF01923600. [DOI] [PubMed] [Google Scholar]
  24. Ramme D., Regenold J. T., Starke K., Busse R., Illes P. Identification of the neuroeffector transmitter in jejunal branches of the rabbit mesenteric artery. Naunyn Schmiedebergs Arch Pharmacol. 1987 Sep;336(3):267–273. doi: 10.1007/BF00172677. [DOI] [PubMed] [Google Scholar]
  25. Seifert R., Schultz G. Involvement of pyrimidinoceptors in the regulation of cell functions by uridine and by uracil nucleotides. Trends Pharmacol Sci. 1989 Sep;10(9):365–369. doi: 10.1016/0165-6147(89)90009-6. [DOI] [PubMed] [Google Scholar]
  26. Sjöblom-Widfeldt N., Gustafsson H., Nilsson H. Transmitter characteristics of small mesenteric arteries from the rat. Acta Physiol Scand. 1990 Feb;138(2):203–212. doi: 10.1111/j.1748-1716.1990.tb08834.x. [DOI] [PubMed] [Google Scholar]
  27. Sjöblom-Widfeldt N. Neuro-muscular transmission in blood vessels: phasic and tonic components. An in-vitro study of mesenteric arteries of the rat. Acta Physiol Scand Suppl. 1990;587:1–52. [PubMed] [Google Scholar]
  28. Starke K., von Kügelgen I., Bulloch J. M., Illes P. Nucleotides as cotransmitters in vascular sympathetic neuroeffector transmission. Blood Vessels. 1991;28(1-3):19–26. doi: 10.1159/000158839. [DOI] [PubMed] [Google Scholar]
  29. Yamamoto R., Cline W. H., Jr, Takasaki K. Reassessment of the blocking activity of prazosin at low and high concentrations on sympathetic neurotransmission in the isolated mesenteric vasculature of rats. J Auton Pharmacol. 1988 Dec;8(4):303–309. doi: 10.1111/j.1474-8673.1988.tb00573.x. [DOI] [PubMed] [Google Scholar]
  30. Yamamoto R., Takasaki K., Nickols G. A. Purinergic vasoconstrictor component revealed by moderate cooling in the isolated mesenteric vasculature of Sprague-Dawley rats. J Pharmacol Exp Ther. 1992 Sep;262(3):1133–1138. [PubMed] [Google Scholar]
  31. Ziganshin A. U., Hoyle C. H., Bo X., Lambrecht G., Mutschler E., Bäumert H. G., Burnstock G. PPADS selectively antagonizes P2X-purinoceptor-mediated responses in the rabbit urinary bladder. Br J Pharmacol. 1993 Dec;110(4):1491–1495. doi: 10.1111/j.1476-5381.1993.tb13990.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ziganshin A. U., Hoyle C. H., Lambrecht G., Mutschler E., Bümert H. G., Burnstock G. Selective antagonism by PPADS at P2X-purinoceptors in rabbit isolated blood vessels. Br J Pharmacol. 1994 Mar;111(3):923–929. doi: 10.1111/j.1476-5381.1994.tb14827.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. von Kügelgen I., Häussinger D., Starke K. Evidence for a vasoconstriction-mediating receptor for UTP, distinct from the P2 purinoceptor, in rabbit ear artery. Naunyn Schmiedebergs Arch Pharmacol. 1987 Nov;336(5):556–560. doi: 10.1007/BF00169313. [DOI] [PubMed] [Google Scholar]

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