Raymond P. Ahlquist

DEVELOPMENT OF THE CONCEPT OF ALPHA AND BETA ADRENOTROPIC RECEPTORS

The adrenotropic (adrenergic) receptor is defined as that specialized part of the effector cell through which the adrenergic neurotransmitters and related compounds act to evoke a characteristic response of the effector cell. The receptor belongs to the effector since after denervation the receptor remains; and some effector cells have receptors with no apparent associated adrenergic nerve. The alpha and beta adrenotropic receptor conceptlV2 was the byproduct of a research effort to find a drug that would relax the myometrium when this structure was contracted by vasopressin; it had been determined that the human, nonpregnant uterus was contracted vigorously by vasopressin, and that this could be one of the causes of dysmenorrhea. Five different catecholamines were obtained and these were tested as myometrial antispasmodics using standard pharmacologic procedures both in uitro (rabbits and rats) and in viuo (dogs). The ileum was also used as a test organ. From these studies two unexpected sets of results were obtained: 1. The responses of the ileum were very uniform and not species-dependent; the gut was relaxed by all compounds, and the relaxing effect was not apparently related to effects on blood pressure or heart rate. 2. The effects on the myometrium were species-dependent and dosedependent, and could be varied by pretreatment with adrenergic blocking agents. As a result of these initial observations, a more thorough comparative study of these catecholamines was undertaken. The compounds tested are shown in FIGURE 1. Compound I , arterenol (norepinephrine, noradrenaline) was used as the racemic mixture. The levorotatory compound levarterenol was not available a t that date. Compound 11, epinephrine, was used both in the form of the synthetic racemic mixture, and in the form of the official levorotatory substance. The latter was either the natural product or the synthetic. Compound 111, methylarterenol (oxynorephedrine), and compound IV, methylepinephrine (oxyephedrine) were obtained labeled as derivatives of ephedrine. I t was not known which of the several optical forms were present. These compounds have two asymmetric carbon atoms. Compound V, isoproterenol, was used as the racemic mixture. This was a new drug a t the time of these studies. Equimolar doses of these catecholamines were compared on a number of

Present state of alpha- and beta-adrenergic drugs I. The adrenergic receptor.

The cardiovascular alpha adrenergic receptors evoke vasoconstriction, the cardiovascular beta receptors evoke vasodilation and cardiac stimulation. All blood vessels have both alpha and beta receptors. In some areas, for example skin and kidney, the alpha receptors predominate. In some vascular beds, for example the nutrient vessels in skeletal muscle, beta receptors predominate. In other beds, such as coronary, visceral, and connective tissue both receptors are active. The cardiovascular effects of adrenergic agonists depend on which receptor they act on. Phenylephrine is specific for alpha receptors. Isoproterenol is specific for beta receptors. Epinephrine and norepinephrine act on both. The real value of knowing the receptor specificity of each agonist is that side effects can more easily be predicted. For example, adrenergic cardiac stimulants are antiasthmatics. Therefore, adrenergic antiasthmatics can produce excessive cardiac stimulation. For the future, agonists that are not only receptor-specific but also tissue-specific will be developed. The first of these in the United States is terbutaline. The rest of the world has in addition a similar drug, salbutamol. No one knows if this drug will be approved for use by American physicians.

Alterations of plasma free fatty acids and glucose during labor

Abstract Comparisons were made between the maternal blood sugar and FFA levels during the first stage of labor and at delivery. In all patients studied of various parities both blood sugar and FFA levels are higher at delivery than during the first stage of labor. The increments of rise of blood sugar and FFA concentrations are not correlated with the length of labor between the labor sample collection and delivery, the degree of cervical dilatation at the time of labor sample collection, or the length of fast prior to labor sample collection. It appears that the rise in blood sugar and FFA occurs late in labor, possibly exclusively during the second stage of labor, and may possibly be related to catecholamine release during this period.

Present state of alpha and beta adrenergic drugs. II. The adrenergic blocking agents.

There are selective blocking agents (antagonists) for alpha receptors and beta receptors. These blocking agents prevent the response to injected agonists and neurogenically released norepinephrine. The principal cardiovascular response to alpha blockade is postural hypotension with reflexly induced cardiac stimulation. If neurogenic vasoconstriction is present, this will be removed. The principal cardiovascular response to beta blockade is bradycardia. If fast arrhythmias are present, these will be slowed. Beta blockade tends to increase peripheral resistance. Unless circulation is previously impaired this vasoconstrictive effect is insignificant.

ADRENERGIC RECEPTORS IN INTESTINAL SMOOTH MUSCLE

In his original description of the adrenergic receptive mechanism, Ahlquist (1948) designated the adrenergic receptor which subserves inhibition of intestinal smooth muscle as an alpha type. This conclusion was based primarily on the observation that epinephrine, norepinephrine (arterenol), and isoproterenol produced an intestinal inhibitory response in isolated, intact intestinal smooth muscle. The order of potency was such tha t epinephrine was more potent than norepinephrine, which was in turn more potent than isoproterenol. The development of dichloroisoproterenol (DCI), an agent tha t selectively blocks beta adrenergic receptors, provided a valuable tool for the investigation of adrenergic receptive mechanisms (Powell & Slater, 1958; Moran & Perkins, 1958). This present paper summarizes results that were obtained by the use of selective alpha (Dibozane) and beta (dichloroisoproterenol) adrenergic receptor blocking agents resulting in the concept of a dual receptive mechanism for intestinal smooth muscle (Ahlquist & Levy, 1959; Levy, 1959).

Placental transfer of epinephrine: I. Maternal-fetal metabolic alterations of glucose and nonesterified fatty acids

Abstract 1. Fifty-five normal obstetric patients in labor were divided into two study groups (44 control patients and 11 experimental patients who received an infusion of epinephrine at delivery). All patients conformed to rigid selection criteria. 2. Maternal and fetal glucose and NEFA levels were compared at delivery. In addition these measurements were carried out in maternal blood prior to the epinephrine infusion. 3. Following maternal epinephrine infusion, maternal glucose and NEFA levels are elevated; however, only fetal glucose is elevated. 4. The elevation of fetal glucose is thought to be due to two factors: (a) transfer of glucose from maternal to fetal blood and (b) transfer of epinephrine from maternal to fetal blood with stimulation of fetal hepatic glycogenolysis. 5. Failure to find increased fetal NEFA is explained as follows: (a) maternal NEFA does not readily cross the placenta into the fetal circulation and (b) fetal adipose tissue is resistant to the lipolytic action of epinephrine. 6. The process of labor and delivery results in a significant rise in maternal glucose and NEFA which is probably due to maternal endogenous catecholamine secretion.

Present state of alpha and beta adrenergic drugs III. Beta blocking agents

The beta blocking agents are valuable drugs in cardiology. They are effective in any fast arrhythmia. Together with nitroglycerin, beta blockers are drugs of first choice in angina. As antihypertensives, they have advantages that should make them drugs of first choice. For migraine the beta blockers are equal to any other type of drug. With more study their place in treating anxiety will be clarified. And without question other uses will be found. It is difficult for this author to understand the attitude of the FDA to this class of drugs. To limit the American physician to only one drug in this large group of drugs is unheard of. Although it can be argued that propranolol is the best one, there are obvious cases where another drug would be better. For example, propranolol induces nightmares in a few patients. There is evidence to show that timolol does this less frequently. FDA delay in approval of propranolol for essential hypertension is totally incomprehensible. Other approved drugs are less effective and much more toxic. Propranolol, and the other beta blockers, are safe and effective. The adverse beta effects are easily controlled or avoided. The other adverse effects are no more frequent than with any other class of drugs, and all are reversible. It is to be hoped that science and common sense will prevail over bureaucratic indecision.

Adrenergic Beta-Blocking Agents

It has been ten years since a beta-adrenergic receptor (beta-adrenoceptor) blocking agent was introduced into clinical medicine. Pronethalol first, then propranolol was used successfully to treat angina pectoris [1]. Other effective uses for propranolol were quickly found: hypertension [2], cardiac arrhythmias [3], hyperkinetic circulatory syndrome, obstructive cardiomyopathy, thyrotoxicosis, migraine, anxiety and essential tremor. More beta-blockers were discovered and developed. At this writing only propranolol is approved by the Federal Food and Drug Administration (FDA) for use in the United States, and then only for arrhythmias, obstructive cardiomyopathy and angina. In the rest of the world eight or nine others are in common use.

PROPRANOLOL IN HYPERTENSION

The recent recognition by the FDA of essential hypertension as an indication for propranolol has made available to the physician in the United States a significant, unique antihypertcnsive drug. Propranolol, the prototype beta-adrenergic receptor blocking agent, is effective for about 90 per cent of patients with hypertension; in about 60 per cent of patients, propranolol can be considered the drug of first and only choice. Propranolol blocks all adrenergic beta receptors. The beta receptors of the heart produce sinus tachycardia, increased force of ventricular contraction, and an increased rate of impulse conduction. Beta receptors in some smooth muscles produce vasodilation and relax the bronchi, intestine, and uterus. Blockade of beta receptors produces cardiac sympathectomy, some increase in peripheral resistance, and an antibronchodilator effect. If patients are selected properly and carefully, propranolol is a safe drug. Propranolol should not be administered to patients with heart block, untreated congestive failure of the circulation, obstructive airway disease, or impaired peripheral circulation. In any patient, the first dose of propranolol may be regarded as the oniy hazardous dose. This dose represents an unknown degree of beta blockade in the face of an unknown amount of sympa-