Members of the various series of adrenergic blocking agents differ widely in the blockade they produce and even more widely in the nature of their side-effects. However, a general pattern of activity emerges if the components of specific adrenergic blockade are extricated from complicating side-effects, often a difficult process because of the limited nature of many reports.
The data listed in table II summarize the pharmacological properties of the more important series of adrenergic blocking agents. This tabulation is certainly not definitive and some exceptions to almost every statement in the table have been reported. Aberrant results in the field of adrenergic blockade have been frequently attributed to species differences or to qualitative differences in the activities of a few members of a series. Such differences may exist (e.g., absence of significant adrenergic vasodilatation in the rabbit); but in explaining conificting results they should be invoked only as a last resort. Whenever wellcontrolled experiments with a group of related agents have been carried out in parallel on several species, many apparent exceptions have disappeared. Side-effects, use of an inadequate dose range or factors of experimental technic frequently may be the basis for apparent exceptions, and must be rigorously ruled out before observations which conflict with a general pattern of activity can be accepted.
The contraction of smooth muscle and the secretion of exocrine glands in response to adrenergic stimuli are inhibited by all adrenergic blocking agents and blockade of these responses has been tacitly accepted as the basis for defining adrenergic blocking activity. The most thoroughly studied manifestations of this action are inhibition of the pressor response to injected epinephrine and inhibition of the epinephrine-induced contraction of various smooth muscle structures in vitro. However, the elimination of such responses does not constitute proof of specific adrenergic blockade; many substances in adequate dosage are capable of destroying the ability of smooth muscle to contract. Reversal of the pressor response, as distinct from its depression, is more adequate evidence of specific blockade because such reversal indicates that the vascular system is still capable of physiological responses. In experiments on smooth muscle in vitro, reactions to several activating agents must be studied in parallel in order to establish the specificity of alterations in the response to epinephrine.
All specific adrenergic blocking agents inhibit responses to circulating mediator more readily than those to adrenergic nerve stimulation. Some agents show a much greater differential than others in their activity against these two types of stimuli, but all gradations occur and the difference is therefore unreliable as a basis for classifying blocking agents. Inhibition of vasomotor reflexes cannot be considered as proof of "sympatholytic" activity. The ergot alkaloids inhibit vasomotor reflexes more readily than responses to injected epinephrine, but the mechanism involved is depression of the brain stem rather than inhibition of responses to sympathetic nerve activity.
Specific blockade of adrenergic "inhibitory" responses does not appear to have been conclusively established for any blocking agent. Epinephrine-induced relaxation of certain organs is inhibited by a number of compounds. However, the interpretation of this effect is complicated by the presence of intramural parasympathetic ganglia in many organs which respond to adrenergic stimuli by relaxation, the known parasympathomimetic and direct musculotropic actions of many adrenergic blocking agents, and the ganglionic effects of epinephrine. In sharp contrast to the uniformity of blockade of excitatory responses, antagonism of inhibitory responses varies widely with different species, organs, blocking agents and experimental conditions. Two general observations regarding the inhibition of adrenergic relaxation of smooth muscle weigh against the conclusion that this is an expression of specific adrenergic blockade. (A). The responses of organs most subject to complicating reactions, (e.g., intestine) are most frequently reported to be inhibited. In contrast, relaxation of the non-pregnant cat uterus by epinephrine is relatively uniform and dependable; responses of this organ are much less frequently reported to be inhibited and only partial blockade is usually observed. Finally, blockade of adrenergic inhibition of the vascular musculature has never been clearly demonstrated. Vascular smooth muscle represents the most reliable object upon which to test blockade of adrenergic inhibitory responses because of the absence of ganglia, the absence of constrictor responses to cholinergic stimuli, etc. (B) Blockade of adrenergic inhibitory responses is reported most frequently as a property of those drugs (ergot alkaloids, phenoxyethylamines, benzodioxanes) which possess many important side-effects and least frequently as a property of those agents \g=b\-haloalkylamines, yohimbine) which exhibit the greatest .specificity of action. It must be concluded that blockade of adrenergic inhibitory responses by members of any of the known series of adrenergic blocking agents has not been conclusively established.
It is generally agreed that no adrenergic blocking agent specifically inhibits the chronotropic and inotropic responses of the mammalian heart to adrenergic stimuli. Even those agents which profoundly depress the myocardium have rarely been reported to depress in equal measure its response to epinephrine. In contrast to the responses of the mammalian heart, stimulation of the amphibian heart by epinephrine appears to be subject to inhibition by several agents. This inhibition may be markedly altered by the composition of the perfusion fluid, a fact which may account for a number of contradictory reports which have appeared.
In contrast to their ineffectiveness against the chronotropic and inotropic responses of the mammalian heart to epinephrine, adrenergic blocking agents are quite effective in preventing epinephrine-induced arrhythmias both in the presence and in the absence of sensitizing hydrocarbons. Some agents (β-haloalkylamines, yohimbine, imidazolines) apparently protect by virtue of their adrenergic blocking activity, whereas others (ergot alkaloids, benzodioxanes, phenoxyethylamines) protect by directly depressing the myocardium. Compounds of the latter type are also effective against arrhythmias evoked by nonadrenergic stimuli (electric current, BaC12, etc.) whereas the former are not. Many adrenergic blocking agents inhibit the glycemic response to epinephrine; but other potent agents, notably Dibenamine and Priscol, have little effect on this response. Among agents for which adequate data are available it is obvious that inhibition of the glycemic response is very poorly correlated with the inhibition of excitatory responses of smooth muscle. In addition substances other than adrenergic blocking agents (e.g., posterior pituitary) are able to inhibit the hyperglycemic response to epinephrine. The fact that the antiglycemic action of ergotoxine is additive with that of posterior pituitary suggests that specific adrenergic blockade is not the basis for the observed inhibition.