Analytical pharmacology draws heavily on the concept of equilibrium of agonist and silent antagonist concentrations competing at a specific receptor site. This condition breaks down in nerve transmission when transmitter release is inhibited by prejunctional a2-adrenoceptors activated by an agonist such as @entity1338 . We have developed a method that allows the agonist dissociation constant KA of @entity1338 to be determined in a robust isolated right atrial assay of @entity19 , @entity35 and @entity840 . By applying low numbers of field pulses 1-4 to prevent autoinhibitory feedback, @entity1338 shifted the nerve pulse stimulation-tachycardia curves to the right. These peak responses to field pulses were equated to responses to exogenous @entity1063 and the pKA determined by global fitting and display in the Clark plot. The pKA for @entity1338 ranged from 8.95 in the @entity19 , 7.8 in @entity35 and 8.3 in @entity840 . The @entity1169 @entity3242 was 8.87 in @entity19 and 8.91 in @entity35 atria, reading very similarly to those values from b-adrenoceptor agonist assays under equilibrium conditions. In mesenteric resistance arteries mounted in a myograph for electrical field stimulation, @entity1338 again inhibited contractions to field pulses in @entity19 arteries with a pKA of 7.12, but was inactive in @entity35 arteries due to competing autoinhibitory feedback from nerve-released @entity1063 . In both species, @entity3159 inhibited the field pulses with a @entity3242 of 9.08 in @entity35 and 9.03 in @entity19 arteries. We conclude that @entity3242 for antagonists and pKA for the prejunctional inhibitors of nerve transmission can be determined with this novel analytical approach.

Novel technique to determine the pKA of XXXX at prejunctional a2-adrenoceptors in cardiac and vascular sympathetic transmission.

@entity1169 :: ('MESH:D011433', 'Chemical') :: ['propranolol'] @entity35 :: ('10116', 'Species') :: ['rat'] @entity19 :: ('10090', 'Species') :: ['mouse'] @entity3159 :: ('MESH:D011224', 'Chemical') :: ['prazosin'] @entity840 :: ('10141', 'Species') :: ['guinea pig'] @entity3242 :: ('11652(Tax:10090)', 'Gene') :: ['pKB'] @entity1338 :: ('MESH:D003000', 'Chemical') :: ['clonidine'] @entity1063 :: ('MESH:D009638', 'Chemical') :: ['noradrenaline']
@entity1338 :: (MESH:D003000,Chemical) :: ['clonidine']
