The pharmacology of beta-adrenergic blocking agents.

T HE endogenously released neurotransmitter substance, norepinephrine, or an injected sympathomimetic amine, ultimately exerts its actions on an organ system by combining with an area of the effector cell termed the adrenergic “receptor site.” That drugs and neural chemical mediators react with specific receptors in living tissues was suggested by Langley”” in 1905, who suggested that effector cells contain both excitatory (motor) and inhibitory “receptor substances.” The response of a tissule to epinephrine was dependent upon the relative proportions of excitatory and inhibitory receptors present. This hypothesis received support in 1906 from the studies of Dale’” on the adrenergic blocking activity of the ergot alkaloids, in which it was demonstrated that the excitatory actions of epinephrine, with the exception of its cardiostimulatory actions, were antagonized or even reversed by ergot. However, ergot was without effect on the inhibitory actions of epinephrine. It remained for Ahlquist” in 1948 to define clearly the dual adrenergic receptor hypothesis. Ahlquist’s concept was based on the premise that two types of adrenergic receptors could be demonstrated by differing rank orders of potency within a single series of closely related agonists on a variety of different adrenergically controlled functions. A total of six sympathomimetic amines were studied for their ability to produce vasoconstriction, uterine muscle stimulation, contraction of the nictitating membrane, pupillary dilatation, and inhibition of gastrointestinal smooth musclc~. A consistent order of potency emerged among the six sympathomimetic amines, in which norepinephrine was the most potent and isoproterenol the least potent of the amines studied. This order of potency was found to be reversed when the same agonists were tested for their ability to produce vasodilatation, inhibition of the uterus, and cardiac stimulation. On the basis of these results, Ahlquist’ postulated the existence of two distinct types of adrenergic receptors, in agreement with the earlier observations of Dale”” and proposed the terms SaZ$~a and beta adrenergic receptors only because “excitatory” and “inhibitory” did not describe them properly. “Alpha” was applied to those adrenergic receptors most responsive to norepinephrine and least responsive to isoprotercnol ( Isuprel ), and “beta” was applied to those receptors most responsive to isoproterenol and least responsive to norepinephrinr. The classification of receptors in different organs is summarized in Table 1.