Alpha- and beta-adrenergic receptors: Ahlquist's landmark hypothesis of a single mediator with two receptors

David B. Bylund
2007 American Journal of Physiology. Endocrinology and Metabolism  
This essay looks at the historical significance of an APS classic paper that is freely available online: Ahlquist RP. A study of adrenotropic receptors. Am J Physiol 153: 586 -600, 1948 ( FOR THOSE INTERESTED in the areas of autonomic physiology and adrenergic pharmacology, there is perhaps no paper more important than Raymond Ahlquist's ( Fig. 1 ) seminal contribution in the American Journal of Physiology in 1948 (3). This paper
more » ... is paper established two fundamental concepts: first, that a single sympathetic mediator could produce both excitatory and inhibitory responses; and second, that adrenergic receptors were of two different types based on rank order potency of activation by agonists. To appreciate the importance of this remarkable paper, three pieces of background information are helpful. First, around 1900 John Jacob Abel successfully isolated epinephrine in relatively pure form (2). Starting in the 1920s, W. B. Cannon attempted to identify the chemical transmitter of the sympathetic nervous system (which he called sympathin), and in 1933 he mistakenly concluded that there were two sympathins, sympathin E (excitatory) and sympathin I (inhibitory) (7). This was due, in part, to the fact that he was using a natural preparation, adrenalin, which at that time was a variable mixture of epinephrine and (up to 35%) norepinephrine. Second, Dale's classical work (8) on the influence of ergot alkaloid antagonists on the effects of epinephrine and sympathetic nerve stimulation suggested two distinct types of receptors for epinephrine. One type, through which epinephrine produced excitatory responses, was "paralyzed" (blocked) by ergot alkaloids, whereas the other type, through which epinephrine mediated inhibitory responses, was not paralyzed by ergots. Third, in 1948, Ahlquist defined the "adrenotropic" (now know as adrenergic) receptors as "those hypothetical structures . . .affected by epinephrine" (3). Ahlquist further noted that "the adrenotropic receptors have been considered to be of two classes, those whose action results in excitation and those whose action results in inhibition of the effector cells," and these in turn were assumed to be activated by sympathin E and sympathin I, respectively. Against this backdrop Ahlquist chose to investigate the actions of six closely related catecholamines on multiple func-tions in multiple species (dogs, cats, rats, and rabbits). The drugs used were arterenol (norepinephrine), cobefrine (␣methylnorepinephrine), epinephrine (both racemic and levo), methyl-epi (␣-methylepinephrine), and N-isopropylarterenol (isoproterenol). Responses were investigated in both intact animals and isolated tissue preparations, including contraction and relaxation of various vascular and uterine smooth muscles, dilation of the pupil, and stimulation of myocardial contraction. He found, for example, that "the relative order of activity of these amines as myocardial stimulants. . .[was the] same as that found for their vasodilator actions. This indicates that the myocardial receptor is related to the vasodilator receptor rather than to the vasoconstrictor receptor." In fact, with perhaps one exception, the rank orders of catecholamine potency for all tissues and functions fell into one of two distinct patterns. Based on these observations, Ahlquist insightfully concluded that these adrenotropic effects, regardless of being excitatory or inhibitory, were mediated by two distinct receptors; "tentatively the first kind of receptor has been called the alpha adrenotropic receptor and the second kind the beta receptor." Ahlquist's critical new concept was that receptor types/ subtypes should be defined by their pharmacological characteristics, i.e., the rank order of drug potencies, rather than by
doi:10.1152/ajpendo.00664.2007 pmid:17957033 fatcat:nr3t6yhskzb7xgqie33gflx6tu