No abstract

THE introduction o£ the beta-adrensrgic receptor blocking ageaC, dichloroisoproterenol (DCI), by Powell and Slater l provided the coat coapelling evidence in support of the dwl adrensrgic receptor hypothesis of Ahlquist 2 .Numerous other beta -receptor antagonists have since been introduced, including pronethalol 3 and propranolol 4' S . The competitive equilibrium nature of the adrenargic blockade produced by these agents suggests that that while they probablq possess affinity for the bate-adrenergic receptor site, they are without "intrinsic activity" as beta-receptor stimulants or agonists 6 . Ariens has suggested that the side-chain alcoholic hgdrozyl group is one of the major determinants of affinity between beta-sympathominetics lThe racemic mi.zture of propranolol will be referred to as propranolol, or as dl-propranolol . The dextrorotatory and levorotatory isomers will be referred to as d-propranolol and 1-propranolol, or as daztto-propranolol and levo-propranoloZ, respectively .

Propranolol (Inderal), a new, potent, non-carcinogenic beta adrenergic receptor antagonist has been shown to possess antiarrhythmic activity when tested against experimentally induced cardiac arrhythmias. The potent beta adrenergic receptor inhibition produced by propranolol leads to a prevention of those cardiac arrhythmias resulting from a combination of a sensitizing agent and a sympathomimetic amine. Methylchloroform–adrenaline and U-0882–isoproterenol arrhythmias were prevented by previous administration of propranolol at a dose sufficient to produce beta adrenergic receptor blockade.Propranolol has been shown to be capable of reversing ventricular tachycardia associated with ouabain intoxication in the anesthetized dog. The agent exerts an effect upon the ouabain-induced ventricular automatic focus and abolishes the activity of the abnormal pacemaker. The mechanism, although unknown, is not believed to be associated with the ability of propranolol to produce beta adrenergic receptor blockade.

Beta-Adrenergic Blocking Agents By BENEDICT R. LUCCHESI AND LEIGHTON S. WWIWTI A. DEVELOPMENT OF THE CONCEPT OF ADRENERCK HECXITORS 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.