JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kenakin, T. P.
Right arrow Articles by Beek, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kenakin, T. P.
Right arrow Articles by Beek, D.

Measurement of antagonist affinity for purine receptors of drugs producing concomitant phosphodiesterase blockade: the use of pharmacologic resultant analysis

TP Kenakin and D Beek

Department of Molecular Pharmacology, Glaxo Research Laboratories, Glaxo Inc., Research Triangle Park, North Carolina.

It was observed experimentally that both theophylline and isobutylmethylxanthine (IBMX) produced surmountable antagonism of the agonist effects of 2-chloroadenosine on purine receptors in rat vas deferens and guinea pig atria. In the case of IBMX, there was a statistically significant difference between the Schild regressions in the two tissues, ostensibly indicating a possible purine receptor heterogeneity with respect to the binding of this antagonist. However, the analysis was complicated by the fact that both theophylline and IBMX produced positive inotropic responses in guinea pig atria (presumably by inhibition of cardiac phosphodiesterase), making the calculation of dose ratios subjective and ambiguous. To determine whether the phosphodiesterase blocking property of theophylline and IBMX was interfering with the observation of purine receptor antagonism in guinea pig atria, a new technique described as pharmacologic resultant analysis was utilized to measure the purine receptor blocking properties of theophylline and IBMX in guinea pig atria in the presence of phosphodiesterase blockade. Based on the principle of additive dose ratios for two antagonists competing for one receptor, pharmacologic resultant analysis measures the effects of a test antagonist (in this case theophylline or IBMX) on the competitive blockade of a reference antagonist; for these studies, the reference antagonist was 8- sulfophenyltheophylline. Under these circumstances, the direct effects of the test antagonist (positive inotropy) are expressed throughout the experiment and cancel with the normal null methods used for measurement of competitive antagonism. Using this technique, it was found that the potencies of both theophylline and IBMX on the purine receptors in rat vas deferens and guinea pig atria were identical. The use of this method in the delineation of multiple drug activities is discussed.

Volume 243, Issue 2, pp. 482-486, 11/01/1987
Copyright © 1987 by American Society for Pharmacology and Experimental Therapeutics






Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1987 by the American Society for Pharmacology and Experimental Therapeutics.