Comparative assessment of beta-adrenoceptor blocking agents as simple competitive antagonists in isolated heart muscle: similarity of inotropic and chronotropic blocking potencies against isoproterenol.

The pattern of antagonism between isoproterenol and various beta-adrenoceptor blocking agents was explored in spontaneously beating right atria and in driven left atrial strips from kittens and guinea pigs. The onset of beta-adrenoceptor blockade is usually very slow in such preparations; incubation periods of up to an hour may be required for equilibrium conditions. The speed of onset of the blocking action is directly related to the concentration of the antagonist, and therefore, for a given degree of blockade, inversely related to its potency. beta-Adrenoceptor blocking agents were found to interact with isoproterenol in a manner consistent with a simple competitive antagonism provided that (1) the antagonist had little intrinsic stimulant action on the preparation under study, (2) the concentrations of antagonist used had no direct depressant action on the preparation, (3) precautions were taken to assure that the pattern of antagonism was not distorted by loss of agonist into tissue sinks, and (4) dose-response curves were normalized for changes in the baseline frequency or force in successive curves. Corrections for desensitization were necessary only in inotropic dose-response curves. Estimates of the equilibrium dissociation constants (KB) derived from the antagonism of the chronotropic and inotropic effects of isoproterenol were determined for fifteen beta-adrenoceptor blocking agents of widely differing potency. In no case was there a substantial difference between the inotropic and chronotropic values. Published estimates of binding constants for beta-blockers determined on cardiac membrane particles are more variable than those determined on intact tissues, and tend to be slightly (adenylyl cyclase measurements) or considerably (radioligand binding studies) lower than the values obtained in intact tissues. These differences raise the possibility that the properties of the beta-adrenoceptor may sometimes be altered during the isolation and partial purification of membrane fragments.