Tetraethylammonium, Ganglionic Blocking Agents, and the Development of Antihypertensive Therapy

TETRAETHYLAMMONIUM, GANGLIONIC BLOCKING AGENTS, AND THE DEVELOPMENT OF ANTIHYPERTENSIVE THERAPY GEORGE H. ACHESON, M.D.* In December 1971 I received an inquiry from Bob Dripps asking how it came to be that the work Gordon Moe and I published on tetraethylammonium had not been done until we did it in the mid-forties. Dripps, head of the Department of Anesthesiology at the University of Pennsylvania, was in San Francisco working withJulius Comroe, head of the Cardiovascular Research Institute at the medical school there. They were "tracing the hypertensives" as a part of "a study of the origins of major advances in clinical medicine". The work with tetraethylammonium that Dripps referred to appeared in three papers [1-3] from the Department of Pharmacology of the Harvard Medical School, published in the Journal of Pharmacology and Experimental Therapeutics in 1945 and 1946, by me, Gordon K. Moe, and Sergio Aranha Pereira, a Rockefeller Fellow from Säo Paulo, Brazil. We reported experiments and presented arguments that tetraethylammonium ion had a selective action at autonomic ganglia to block the transmission of impulses in the preganglionic axons across the ganglionic synapse to the postganglionic cells. We gave to tetraethylammonium and other substances with similar properties a descriptive name, "ganglionic blocking agents." It seems worthwhile to try to answer Dripps's question. I shall take what looks like a backward approach. First, I will describe what happened after our three papers were published (what kind of a splash our reports made), why one might think ofour work being related to "major advances in clinical medicine," and why Dripps should have asked this question. Then I will recall what led to our work and how it was made public. And, finally, I will try to answer Dripps's question: How did it come to be that the work was not done long before we did it?—for, ?Present address: 25 Quissett Avenue, Woods Hole, Massachusetts 02543. Professor emeritus of pharmacology. University of Cincinnati College of Medicine. I thank Saul Benison, professor of the history of medicine, for his encouragement and criticism. 136 I George H. Acheson · Ganglionic Blocking Agents indeed, the ideas that we dealt with were already in the literature decades before we did our work. I. What Splash Resultedfrom Our Work? Our reports gave rise to a wave of research on tetraethylammonium salts and related compounds. The decennial index of Chemical Abstracts (1946) lists only five papers on biological work with tetraethylammonium in the 10 years before our publications; but, when Moe and Freyburger reviewed ganglionic blocking agents in 1950 [4], they cited over 200 papers having to do with this topic. Our work soon hit the textbooks, and our new term for an old concept, "ganglionic block," became standard in the classification of drugs that act on the autonomic nervous system. For a while, tetraethylammonium ion was a standard test substance, to be used when one wished to test whether or not the system one was studying was influenced by ganglionated autonomic nerves. In addition, everybody was trying tetraethylammonium on his or her favorite biological system. More important was the fact that clinicians began trying tetraethylammonium in their favorite diseases. It was tried in all kinds of vascular disease and in many other disorders. For example, it was studied as a drug to antagonize itching, to relieve herpes zoster, to treat peptic ulcer, and to relieve pain. The most striking effect of tetraethylammonium ion we had dealt with was a fall of blood pressure, and the application of this compound to hypertension was of great interest . In 1946, Robert Wilkins reviewed the treatment of hypertension [5]. His review is in some waysjust what one would expect to find in a similar review in 1974, but drugs did not have much ofa role in the treatment of hypertension in 1946. Vasoconstrictor influences were by then regarded as the important point of attack; anything that lowered the blood pressure might be useful. Emphasis was placed on reassurance ofthe patient, who was pictured as worried about having hypertension. Patients were to be encouraged to lead normal lives. It was recognized that one could lower the blood pressure in some patients by bed rest or by dehydration...