Adrenergic Receptors: A Personal and Practical View

ADRENERGIC RECEPTORS: A PERSONAL AND PRACTICAL VIEW* RAYMOND P. AHLQUlSTf One of the greatest biologic advances was the discovery of the chemical transmission of information in living organisms. Endocrine glands communicate with each other and with other tissues by means of hormones. For example, the anterior pituitary makes, stores, and releases as necessary the hormone ACTH into the blood stream. Cortical cells of the adrenal gland detect the circulating ACTH and respond by releasing the hormone hydrocortisone into the blood stream. Motor nerve ends communicate in a similar manner with the effector cells that they innervate and control. In these chemical information transmission systems, there are three essential parts: (1) the biosynthesis, storage, and release of the transmitter or hormone, (2) the environment into which the transmitter is released in order to get to the effector cells, and (3) the receiving portion of the effector , the receptor that detects the transmitter and initiates some characteristic response. For the autonomic nervous system this process was foreseen by Elliott and Dale at the turn of the century. In the 1920s the chemical substance acetylcholine was shown by the Nobel laureate Otto Loewe to be one of the motor nervous system transmitters. At first, epinephrine was thought to be the adrenergic transmitter; yet it did not quite fit. Euler proposed norepinephrine as the transmitter. Although he also won the Nobel Prize, some of his ideas required modification . The present essay is concerned in general with the adrenergic transmission system, and in particular with the adrenergic receptive mechanism . When I first started teaching pharmacology, the following terms were regarded as almost synonymous: sympathetic, adrenergic, vasoconstriction , pressor, and decongestant. Chemists made new compounds structurally related to epinephrine, and pharmacologists tested them for blood vessel constricting effects. If the drug raised the blood pressure * The twelfth Paul K. Smith Memorial Lecture, Department of Pharmacology, George Washington University School of Medicine, Washington, D.C., December 15, 1972. t Medical College of Georgia, Augusta, Georgia 30902. Perspectives in Biology and Medicine · Autumn 1973 | 119 (pressor response) it was marketed as a decongestant for stuffy noses. But then Konzett in Germany introduced the compound isoproterenol, also known as N-isopropyl-norepinephrine. In the anesthetized dog this catecholamine did not constrict blood vessels, produce a pressor response, or cause decongestion. Instead, it produced vasodilation, a depressor response, and tachycardia. This anomalous behavior was most difficult to explain to medical students. In the course of experiments designed to find myometrial relaxants to treat dysmenorrhea, we compared a number of catecholamines. From this, as has been described elsewhere, we came up with the idea of two receptors [1]· _ Briefly, this concept states that one kind of receptor, a, is associated with contraction of many smooth muscles, such as in the radial portion of the iris, the third eyelid, most blood vessels, the spleen, and the uterus. The ß receptor is associated with relaxation of the smooth muscle of blood vessels, bronchi, and uterus and with stimulation of the heart. Specific drugs can be found that stimulate (agonists) these receptors or antagonize (blocking agents) the receptors. Now we could explain the actions of isoproterenol (a ß agonist). In addition, the actions of the known sympatholytics (now a blocking agents) could be explained. All in all, this was a new concept arrived at by serendipity. In the 1950s the ß blocking agents were found by Powell and Slater [2]. These investigators described the dichloro derivative of isoproterenol. Although they showed that DCI could block certain adrenergic inhibitory actions on smooth muscle, they missed the cardiac effect. Moran and Perkins of Emory showed the blocking action of DCI on the heart and introduced the drug class of ß receptor blocking agents [3]. James Black in England conceived the idea of using a ß blocking agent to treat angina. He introduced pronethalol, then propranolol, [4, 5]. Lands proposed that there might be two ß receptors on the basis of differential responses to a variety of experimental ß agonists [6]. This was the start of a search for ß blocking agents specific for /31 or ß2 receptors. Practalol was the first. This stimulated the search for agonists specific for /31 and /?2. Here are some of the drugs developed out of this idea for...