DIFFERENT APPARENT MODES OF INHIBITION OF ALPHA(2A)-ADRENOCEPTOR BY ALPHA(2)-ADRENOCEPTOR ANTAGONISTS

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.