Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1996 May;118(2):369–377. doi: 10.1111/j.1476-5381.1996.tb15412.x

Pharmacokinetic-haemodynamic relationships of 2-chloroadenosine at adenosine A1 and A2a receptors in vivo.

R A Mathoôt 1, W Soudijn 1, D D Breimer 1, A P Ijzerman 1, M Danhof 1
PMCID: PMC1909643  PMID: 8735640

Abstract

1. The purpose of the present study was to develop an experimental strategy for the quantification of the cardiovascular effects of non-selective adenosine receptor ligands at the adenosine A1 and A2a receptor in vivo. 2-Chloroadenosine (CADO) was used as a model compound. 2. Three groups of normotensive conscious rats received an short intravenous infusion of 1.4 mg kg-1 CADO during constant infusions of the A1-selective antagonist, 8-cyclopentyltheophylline (CPT; 20 micrograms min-1 kg-1), the A2a-selective antagonist, 8-(3-chlorostyryl) caffeine (CSC; 32 micrograms min-1 kg-1) or the vehicle. The heart rate (HR) and mean arterial blood pressure (MAP) were recorded continuously during the experiment and serial arterial blood samples were taken for analysis of drug concentrations. The ratio MAP/HR was also calculated, which may reflect changes in total peripheral resistance on the assumption that no changes in stroke volume occur. 3. During the infusion of CPT, CADO produced a reduction in both blood pressure and MAP/HR by activation of the A2a receptor. The concentration-effect relationships were described according to the sigmoidal Emax model, yielding potencies based on free drug concentrations (EC50,u) of 61 and 68 ng ml-1 (202 and 225 nM) for the reduction of blood pressure and MAP/HR, respectively. During the infusion of CSC, an EC50,u value of 41 ng ml-1 (136 nM) was observed for the A1 receptor-mediated reduction in heart rate. The in vivo potencies correlated with reported receptor affinities (Ki(A1) = 300 nM and Ki(A2a) = 80 nM). The maximal reductions in MAP/HR and heart rate were comparable to those of full agonists, with the Emax values of -12 +/- 1 x 10(-2) mmHg b.p.m.-1 and -205 b.p.m. respectively. 4. It is concluded that this integrated pharmacokinetic-pharmacodynamic approach can be used to obtain quantitative information on the potency and intrinsic activity of new non-selective adenosine receptor agonists at different receptor subtypes in vivo.

Full text

PDF
369

Selected References

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

  1. Abiru T., Yamaguchi T., Watanabe Y., Kogi K., Aihara K., Matsuda A. The antihypertensive effect of 2-alkynyladenosines and their selective affinity for adenosine A2 receptors. Eur J Pharmacol. 1991 Apr 10;196(1):69–76. doi: 10.1016/0014-2999(91)90410-r. [DOI] [PubMed] [Google Scholar]
  2. Appel S., Mathôt R. A., Langemeijer M. W., IJzerman A. P., Danhof M. Modelling of the pharmacodynamic interaction of an A1 adenosine receptor agonist and antagonist in vivo: N6-cyclopentyladenosine and 8-cyclopentyltheophylline. Br J Pharmacol. 1995 Aug;115(7):1253–1259. doi: 10.1111/j.1476-5381.1995.tb15033.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bruns R. F., Lu G. H., Pugsley T. A. Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes. Mol Pharmacol. 1986 Apr;29(4):331–346. [PubMed] [Google Scholar]
  4. Francheteau P., Steimer J. L., Merdjan H., Guerret M., Dubray C. A mathematical model for dynamics of cardiovascular drug action: application to intravenous dihydropyridines in healthy volunteers. J Pharmacokinet Biopharm. 1993 Oct;21(5):489–514. doi: 10.1007/BF01059111. [DOI] [PubMed] [Google Scholar]
  5. Guyton A. C., Coleman T. G., Granger H. J. Circulation: overall regulation. Annu Rev Physiol. 1972;34:13–46. doi: 10.1146/annurev.ph.34.030172.000305. [DOI] [PubMed] [Google Scholar]
  6. Holford N. H., Sheiner L. B. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet. 1981 Nov-Dec;6(6):429–453. doi: 10.2165/00003088-198106060-00002. [DOI] [PubMed] [Google Scholar]
  7. IJzerman A. P., van der Wenden E. M., von Frijtag Drabbe Künzel J. K., Mathôt R. A., Danhof M., Borea P. A., Varani K. Partial agonism of theophylline-7-riboside on adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol. 1994 Dec;350(6):638–645. doi: 10.1007/BF00169369. [DOI] [PubMed] [Google Scholar]
  8. Jackson E. K., Herzer W. A., Suzuki F. KF17837 is an A2 adenosine receptor antagonist in vivo. J Pharmacol Exp Ther. 1993 Dec;267(3):1304–1310. [PubMed] [Google Scholar]
  9. Jacobson K. A., Gallo-Rodriguez C., Melman N., Fischer B., Maillard M., van Bergen A., van Galen P. J., Karton Y. Structure-activity relationships of 8-styrylxanthines as A2-selective adenosine antagonists. J Med Chem. 1993 May 14;36(10):1333–1342. doi: 10.1021/jm00062a005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Mathôt R. A., Appel S., van Schaick E. A., Soudijn W., IJzerman A. P., Danhof M. High-performance liquid chromatography of the adenosine A1 agonist N6-cyclopentyladenosine and the A1 antagonist 8-cyclopentyltheophylline and its application in a pharmacokinetic study in rats. J Chromatogr. 1993 Oct 22;620(1):113–120. doi: 10.1016/0378-4347(93)80058-c. [DOI] [PubMed] [Google Scholar]
  11. Mathôt R. A., Cleton A., Soudijn W., IJzerman A. P., Danhof M. Pharmacokinetic modelling of the haemodynamic effects of the A2a adenosine receptor agonist CGS 21680C in conscious normotensive rats. Br J Pharmacol. 1995 Feb;114(4):761–768. doi: 10.1111/j.1476-5381.1995.tb13270.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Mathôt R. A., Gubbens-Stibbe J. M., Soudijn W., Jacobson K. A., Ijzerman A. P., Danhof M. Quantification of the in vivo potency of the adenosine A2 receptor antagonist 8-(3-chlorostyryl)caffeine. J Pharmacol Exp Ther. 1995 Oct;275(1):245–253. [PMC free article] [PubMed] [Google Scholar]
  13. Mathôt R. A., Van den Aarsen B. C., Soudijn W., Breimer D. D., Ijzerman A. P., Danhof M. Pharmacokinetic-pharmacodynamic modelling of the cardiovascular effects of R- and S-N6-phenylisopropyladenosine in conscious normotensive rats. J Pharmacol Exp Ther. 1995 Apr;273(1):405–414. [PubMed] [Google Scholar]
  14. Mathôt R. A., Van der Wenden E. M., Soudijn W., IJzerman A. P., Danhof M. Deoxyribose analogues of N6-cyclopentyladenosine (CPA): partial agonists at the adenosine A1 receptor in vivo. Br J Pharmacol. 1995 Oct;116(3):1957–1964. doi: 10.1111/j.1476-5381.1995.tb16398.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mathôt R. A., van Schaick E. A., Langemeijer M. W., Soudijn W., Breimer D. D., Ijzerman A. P., Danhof M. Pharmacokinetic-pharmacodynamic relationship of the cardiovascular effects of adenosine A1 receptor agonist N6-cyclopentyladenosine in the rat. J Pharmacol Exp Ther. 1994 Feb;268(2):616–624. [PubMed] [Google Scholar]
  16. Olsson R. A., Pearson J. D. Cardiovascular purinoceptors. Physiol Rev. 1990 Jul;70(3):761–845. doi: 10.1152/physrev.1990.70.3.761. [DOI] [PubMed] [Google Scholar]
  17. Plagemann P. G., Wohlhueter R. M., Woffendin C. Nucleoside and nucleobase transport in animal cells. Biochim Biophys Acta. 1988 Oct 11;947(3):405–443. doi: 10.1016/0304-4157(88)90002-0. [DOI] [PubMed] [Google Scholar]
  18. Webb R. L., Barclay B. W., Graybill S. C. Cardiovascular effects of adenosine A2 agonists in the conscious spontaneously hypertensive rat: a comparative study of three structurally distinct ligands. J Pharmacol Exp Ther. 1991 Dec;259(3):1203–1212. [PubMed] [Google Scholar]
  19. Webb R. L., McNeal R. B., Jr, Barclay B. W., Yasay G. D. Hemodynamic effects of adenosine agonists in the conscious spontaneously hypertensive rat. J Pharmacol Exp Ther. 1990 Sep;254(3):1090–1099. [PubMed] [Google Scholar]
  20. Yamaoka K., Nakagawa T., Uno T. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm. 1978 Apr;6(2):165–175. doi: 10.1007/BF01117450. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES