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. 1992 Jun 15;89(12):5562–5566. doi: 10.1073/pnas.89.12.5562

A1 adenosine-receptor antagonists activate chloride efflux from cystic fibrosis cells.

O Eidelman 1, C Guay-Broder 1, P J van Galen 1, K A Jacobson 1, C Fox 1, R J Turner 1, Z I Cabantchik 1, H B Pollard 1
PMCID: PMC49332  PMID: 1376923

Abstract

A1 adenosine-receptor-antagonist drugs such as 8-cyclopentyl-1,3-dipropylxanthine (CPX) and xanthine amine congener (XAC) are found to activate the efflux of 36Cl- from CFPAC cells. These cells are a pancreatic adenocarcinoma cell line derived from a cystic fibrosis (CF) patient homozygous for the common mutation, deletion of Phe-508. The active concentrations for these compounds are in the low nanomolar range, consistent with action on A1 adenosine receptors. In addition, drug action can be blocked by exogenous agonists such as 2-chloroadenosine and also can be antagonized by removal of endogenous agonists by treatment with adenosine deaminase. Cells lacking the CF genotype and phenotype, such as HT-29 and T84 colon carcinoma cell lines, appear to be resistant to activation of chloride efflux by either drug. CFPAC cells transfected with the CF transmembrane regulator gene, CFTR, are also resistant to activation by CPX. We conclude that, since these antagonists are of relatively low toxicity and appear to act somewhat selectively, they might be considered as promising therapeutic candidates for CF.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alzheimer C., Sutor B., ten Bruggencate G. Transient and selective blockade of adenosine A1-receptors by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) causes sustained epileptiform activity in hippocampal CA3 neurons of guinea pigs. Neurosci Lett. 1989 Apr 24;99(1-2):107–112. doi: 10.1016/0304-3940(89)90273-5. [DOI] [PubMed] [Google Scholar]
  2. Arispe N., Rojas E., Hartman J., Sorscher E. J., Pollard H. B. Intrinsic anion channel activity of the recombinant first nucleotide binding fold domain of the cystic fibrosis transmembrane regulator protein. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1539–1543. doi: 10.1073/pnas.89.5.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barrett K. E., Huott P. A., Shah S. S., Dharmsathaphorn K., Wasserman S. I. Differing effects of apical and basolateral adenosine on colonic epithelial cell line T84. Am J Physiol. 1989 Jan;256(1 Pt 1):C197–C203. doi: 10.1152/ajpcell.1989.256.1.C197. [DOI] [PubMed] [Google Scholar]
  4. Cartwright C. A., McRoberts J. A., Mandel K. G., Dharmsathaphorn K. Synergistic action of cyclic adenosine monophosphate- and calcium-mediated chloride secretion in a colonic epithelial cell line. J Clin Invest. 1985 Nov;76(5):1837–1842. doi: 10.1172/JCI112176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Collis M. G., Shaw G., Keddie J. R. Diuretic and saliuretic effects of 1,3-dipropyl-8-cyclopentylxanthine, a selective A1-adenosine receptor antagonist. J Pharm Pharmacol. 1991 Feb;43(2):138–139. doi: 10.1111/j.2042-7158.1991.tb06651.x. [DOI] [PubMed] [Google Scholar]
  6. Dalemans W., Barbry P., Champigny G., Jallat S., Dott K., Dreyer D., Crystal R. G., Pavirani A., Lecocq J. P., Lazdunski M. Altered chloride ion channel kinetics associated with the delta F508 cystic fibrosis mutation. Nature. 1991 Dec 19;354(6354):526–528. doi: 10.1038/354526a0. [DOI] [PubMed] [Google Scholar]
  7. Dharmsathaphorn K., Pandol S. J. Mechanism of chloride secretion induced by carbachol in a colonic epithelial cell line. J Clin Invest. 1986 Feb;77(2):348–354. doi: 10.1172/JCI112311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dobbins J. W., Laurenson J. P., Forrest J. N., Jr Adenosine and adenosine analogues stimulate adenosine cyclic 3', 5'-monophosphate-dependent chloride secretion in the mammalian ileum. J Clin Invest. 1984 Sep;74(3):929–935. doi: 10.1172/JCI111511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Drumm M. L., Pope H. A., Cliff W. H., Rommens J. M., Marvin S. A., Tsui L. C., Collins F. S., Frizzell R. A., Wilson J. M. Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer. Cell. 1990 Sep 21;62(6):1227–1233. doi: 10.1016/0092-8674(90)90398-x. [DOI] [PubMed] [Google Scholar]
  10. Drumm M. L., Wilkinson D. J., Smit L. S., Worrell R. T., Strong T. V., Frizzell R. A., Dawson D. C., Collins F. S. Chloride conductance expressed by delta F508 and other mutant CFTRs in Xenopus oocytes. Science. 1991 Dec 20;254(5039):1797–1799. doi: 10.1126/science.1722350. [DOI] [PubMed] [Google Scholar]
  11. Jacobson K. A., de la Cruz R., Schulick R., Kiriasis L., Padgett W., Pfleiderer W., Kirk K. L., Neumeyer J. L., Daly J. W. 8-Substituted xanthines as antagonists at A1- and A2-adenosine receptors. Biochem Pharmacol. 1988 Oct 1;37(19):3653–3661. doi: 10.1016/0006-2952(88)90398-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jacobson K. A., van Galen P. J., Williams M. Adenosine receptors: pharmacology, structure-activity relationships, and therapeutic potential. J Med Chem. 1992 Feb 7;35(3):407–422. doi: 10.1021/jm00081a001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ji X. D., Stiles G. L., van Galen P. J., Jacobson K. A. Characterization of human striatal A2-adenosine receptors using radioligand binding and photoaffinity labeling. J Recept Res. 1992;12(2):149–169. doi: 10.3109/10799899209074789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kellett R., Bowmer C. J., Collis M. G., Yates M. S. Amelioration of glycerol-induced acute renal failure in the rat with 8-cyclopentyl-1,3-dipropylxanthine. Br J Pharmacol. 1989 Nov;98(3):1066–1074. doi: 10.1111/j.1476-5381.1989.tb14639.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kelley G. G., Aassar O. S., Forrest J. N., Jr Endogenous adenosine is an autacoid feedback inhibitor of chloride transport in the shark rectal gland. J Clin Invest. 1991 Dec;88(6):1933–1939. doi: 10.1172/JCI115517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kerem B., Rommens J. M., Buchanan J. A., Markiewicz D., Cox T. K., Chakravarti A., Buchwald M., Tsui L. C. Identification of the cystic fibrosis gene: genetic analysis. Science. 1989 Sep 8;245(4922):1073–1080. doi: 10.1126/science.2570460. [DOI] [PubMed] [Google Scholar]
  17. Knowles M. R., Church N. L., Waltner W. E., Yankaskas J. R., Gilligan P., King M., Edwards L. J., Helms R. W., Boucher R. C. A pilot study of aerosolized amiloride for the treatment of lung disease in cystic fibrosis. N Engl J Med. 1990 Apr 26;322(17):1189–1194. doi: 10.1056/NEJM199004263221704. [DOI] [PubMed] [Google Scholar]
  18. Knowles M. R., Clarke L. L., Boucher R. C. Activation by extracellular nucleotides of chloride secretion in the airway epithelia of patients with cystic fibrosis. N Engl J Med. 1991 Aug 22;325(8):533–538. doi: 10.1056/NEJM199108223250802. [DOI] [PubMed] [Google Scholar]
  19. Knowles M. R., Stutts M. J., Spock A., Fischer N., Gatzy J. T., Boucher R. C. Abnormal ion permeation through cystic fibrosis respiratory epithelium. Science. 1983 Sep 9;221(4615):1067–1070. doi: 10.1126/science.6308769. [DOI] [PubMed] [Google Scholar]
  20. Knowles M., Gatzy J., Boucher R. Relative ion permeability of normal and cystic fibrosis nasal epithelium. J Clin Invest. 1983 May;71(5):1410–1417. doi: 10.1172/JCI110894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Li M., McCann J. D., Anderson M. P., Clancy J. P., Liedtke C. M., Nairn A. C., Greengard P., Welsch M. J. Regulation of chloride channels by protein kinase C in normal and cystic fibrosis airway epithelia. Science. 1989 Jun 16;244(4910):1353–1356. doi: 10.1126/science.2472006. [DOI] [PubMed] [Google Scholar]
  22. Montague W., Cook J. R. The role of adenosine 3':5'-cyclic monophosphate in the regulation of insulin release by isolated rat islets of Langerhans. Biochem J. 1971 Mar;122(1):115–120. doi: 10.1042/bj1220115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Quinton P. M., Bijman J. Higher bioelectric potentials due to decreased chloride absorption in the sweat glands of patients with cystic fibrosis. N Engl J Med. 1983 May 19;308(20):1185–1189. doi: 10.1056/NEJM198305193082002. [DOI] [PubMed] [Google Scholar]
  24. Quinton P. M. Chloride impermeability in cystic fibrosis. Nature. 1983 Feb 3;301(5899):421–422. doi: 10.1038/301421a0. [DOI] [PubMed] [Google Scholar]
  25. Quinton P. M. Cystic fibrosis: a disease in electrolyte transport. FASEB J. 1990 Jul;4(10):2709–2717. doi: 10.1096/fasebj.4.10.2197151. [DOI] [PubMed] [Google Scholar]
  26. Riordan J. R., Rommens J. M., Kerem B., Alon N., Rozmahel R., Grzelczak Z., Zielenski J., Lok S., Plavsic N., Chou J. L. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989 Sep 8;245(4922):1066–1073. doi: 10.1126/science.2475911. [DOI] [PubMed] [Google Scholar]
  27. Rommens J. M., Iannuzzi M. C., Kerem B., Drumm M. L., Melmer G., Dean M., Rozmahel R., Cole J. L., Kennedy D., Hidaka N. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989 Sep 8;245(4922):1059–1065. doi: 10.1126/science.2772657. [DOI] [PubMed] [Google Scholar]
  28. Sato K. Differing luminal potential difference of cystic fibrosis and control sweat secretory coils in vitro. Am J Physiol. 1984 Oct;247(4 Pt 2):R646–R649. doi: 10.1152/ajpregu.1984.247.4.R646. [DOI] [PubMed] [Google Scholar]
  29. Schoumacher R. A., Ram J., Iannuzzi M. C., Bradbury N. A., Wallace R. W., Hon C. T., Kelly D. R., Schmid S. M., Gelder F. B., Rado T. A. A cystic fibrosis pancreatic adenocarcinoma cell line. Proc Natl Acad Sci U S A. 1990 May;87(10):4012–4016. doi: 10.1073/pnas.87.10.4012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Schwiebert E. M., Karlson K. H., Friedman P. A., Dietl P., Spielman W. S., Stanton B. A. Adenosine regulates a chloride channel via protein kinase C and a G protein in a rabbit cortical collecting duct cell line. J Clin Invest. 1992 Mar;89(3):834–841. doi: 10.1172/JCI115662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Snyder S. H., Katims J. J., Annau Z., Bruns R. F., Daly J. W. Adenosine receptors and behavioral actions of methylxanthines. Proc Natl Acad Sci U S A. 1981 May;78(5):3260–3264. doi: 10.1073/pnas.78.5.3260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Trapnell B. C., Zeitlin P. L., Chu C. S., Yoshimura K., Nakamura H., Guggino W. B., Bargon J., Banks T. C., Dalemans W., Pavirani A. Down-regulation of cystic fibrosis gene mRNA transcript levels and induction of the cystic fibrosis chloride secretory phenotype in epithelial cells by phorbol ester. J Biol Chem. 1991 Jun 5;266(16):10319–10323. [PubMed] [Google Scholar]
  33. Welsh M. J. Abnormal regulation of ion channels in cystic fibrosis epithelia. FASEB J. 1990 Jul;4(10):2718–2725. doi: 10.1096/fasebj.4.10.1695593. [DOI] [PubMed] [Google Scholar]
  34. Widdicombe J. H., Welsh M. J., Finkbeiner W. E. Cystic fibrosis decreases the apical membrane chloride permeability of monolayers cultured from cells of tracheal epithelium. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6167–6171. doi: 10.1073/pnas.82.18.6167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Worrell R. T., Butt A. G., Cliff W. H., Frizzell R. A. A volume-sensitive chloride conductance in human colonic cell line T84. Am J Physiol. 1989 Jun;256(6 Pt 1):C1111–C1119. doi: 10.1152/ajpcell.1989.256.6.C1111. [DOI] [PubMed] [Google Scholar]
  36. Zimmerman T. W., Dobbins J. W., Binder H. J. Mechanism of cholinergic regulation of electrolyte transport in rat colon in vitro. Am J Physiol. 1982 Feb;242(2):G116–G123. doi: 10.1152/ajpgi.1982.242.2.G116. [DOI] [PubMed] [Google Scholar]
  37. von der Leyen H., Schmitz W., Scholz H., Scholz J., Lohse M. J., Schwabe U. Effects of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a highly selective adenosine receptor antagonist, on force of contraction in guinea-pig atrial and ventricular cardiac preparations. Naunyn Schmiedebergs Arch Pharmacol. 1989 Aug;340(2):204–209. doi: 10.1007/BF00168970. [DOI] [PubMed] [Google Scholar]

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