Antagonist dissociation constants and relative agonist efficacies for compounds interacting with beta-1 and beta-2 adrenergic receptors in the rat jugular vein
Cohen, M.L.; Ruffolo, R.R.; Wiley, K.S.
Journal of Pharmacology and Experimental Therapeutics 215(2): 325-331
1980
ISSN/ISBN: 0022-3565 PMID: 6108357 Document Number: 168221
The rat jugular vein provides a model system for the determination of both Kd and relative agonist efficacies for compounds interacting with .beta.-1 and .beta.-2 adrenergic receptors. Kd for .beta.-1 and .beta.-2 adrenergic receptor antagonists were calculated by determining the inhibition of concentration-response curves to norepinephrine and isoproterenol, respectively. Data obtained in the jugular vein for propranolol, practolol, metoprolol and dichloroisoproterenol closely agreed with Kd reported for the compounds based on data generated in both atria and trachea and data obtained from binding studies and adenylate cyclase inhibition. Use of the jugular vein compared to use of multiple tissues ensures constant conditions of uniform innervation, receptor population and drug disposition parameters for determination of .beta.-1 and .beta.-2 Kd. Agonist activity can be evaluated and compared providing an advantage relative to receptor binding studies. By this technique, the .beta. adrenergic receptor antagonists, penbutolol and carazolol, showed greater affinity for .beta.-1 and .beta.-2 adrenergic receptors (12- and 16-fold, respectively) than propranolol, and carazolol selectively interacted with .beta.-2 adrenergic receptors. For the selective .beta.-2 receptor agonists (isoproterenol, salbutamol, metaproterenol and protokylol), 50% relaxation occurred with 1-3% receptor occupation, but for the selective .beta.-1 adrenergic agonists (norepinephrine, nylidrin and prepalterol), 40-100% receptor occupation was necessary for 50% relaxation. A clear separation of .beta. adrenergic receptor agonists occurred in the jugular vein with selective .beta.-2 receptor agonists having higher relative efficiencies than selective .beta.-1 adrenergic receptor agonists in this system. The use of this tissue may provide a rapid and efficient method for assigning .beta. adrenergic subtype specificity for agonists and antagonists and permits quantitative determination of antagonist Kd for .beta.-1 and .beta.-2 receptors.