Jp. Kukkonen et al., DIFFERENT APPARENT MODES OF INHIBITION OF ALPHA(2A)-ADRENOCEPTOR BY ALPHA(2)-ADRENOCEPTOR ANTAGONISTS, European journal of pharmacology, 335(1), 1997, pp. 99-105
The inhibition of alpha(2A)-adrenoceptor-mediated Ca2+ elevation by al
pha(2)-adrenoceptor antagonists was measured in HEL human erythroleuke
mia cells. The antagonists could be divided in two classes: those that
displayed surmountable inhibition (right-shift of the agonist dose-re
sponse curve), and those that displayed different degrees of insurmoun
table inhibition (depression of the maximum signal and a possible righ
t-shift of the agonist dose-response curve). The degree of surmountabi
lity of the inhibition correlated well with the measured antagonist di
ssociation rates, suggesting that the hypothesis of the antagonist dis
sociation rate governing the mode of inhibition of fast responses, hol
ds true. HEL cells thus provide a useful model system for the investig
ation of physiological consequences of different dissociation rates. A
lso, the dissociation rates of antagonists not available in radiolabel
led form can be predicted from the functional data. The data stresses
the importance of measurement of kinetic parameters of the drug-recept
or interaction in addition to the equilibrium binding constants. (C) 1
997 Elsevier Science B.V.