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Working in the dream world of Imperial Chemical Industries


Developing the idea of a beta receptor antagonist
James Black Scientist
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George Smith had been invalided out of the war – the navy – and gone to Baltimore to... and he was learning to be a heart surgeon. And the technique in those days of treating angina was to try and increase the blood supply, because in angina the circulation is compromised through block... blockage... was to bring in blood vessels from outside the heart. And they did this by bringing the omentum, a vascular tissue in the... through the diaphragm, and he would scarify the surface of the epicardium, stitch this thing on it and... and, well, Smith showed that, in fact, the extra blood flow which was going to the heart was really quite small. So, he thought: well, if such a small increase in blood supply is effective, maybe a small increase in the delivery of oxygen would be just as effective. So, he pioneered the technique of high pressure, or hyperbaric oxygen, and showed that the ventricular fibrillation which the cardiac... the arrhythmia which develops when a coronary artery occludes... that you could prevent that if you exposed these animals to two atmospheres pressure of oxygen. So that's where I got into the act, because I knew enough physics to know that oxygen isn't really very soluble in water and, in any case, as you know, the haemoglobin – the oxygen carrying protein – is fully saturated at a fifth of an atmosphere of oxygen, so two atmospheres of oxygen was only increasing in the amount of dissolved oxygen, and it's not very soluble, so I could figure out that the increase in oxygen that he was giving was not very much.

So then there's a whole series of things happen. My father had what turned out to be his fatal heart attack following a minor car accident, and... and he got his heart attack that night, and that made me think about stress, because it was... it was often... these heart attacks were often occurring on Friday nights and so on. An element of stress was quite commonly taught as being involved in this. And so, you know, I knew enough physiology by now to know that the stress effect on the heart is sympathetic to increased heart rate. And so, the question then was: if such a small increase in the supply of oxygen is effective, how about an equally small decrease in demand? So, the main thing which is stimulating the demand is heart rate, so why can't we just reduce the heart rate? Well, drugs called anti-adrenaline drugs had been known since the 1930s, and they were known that they would produce blood pressure, but only if you stood up, and you fainted. If you lie down it did nothing, but if you stood up, your blood pressure would fall, and it was known that when you were standing up and your blood pressure was like that, your heart rate was beating like blazes. So it was really known, but not really commented on, that apparently this heart rate effect wasn't being taken out by anti-adrenaline drugs. And so I just thought: well, that's.... I put it away out of my mind, actually. Anti-adrenaline drugs weren't going to do the trick. Then, by accident I came across a... a chapter in a book I'd bought because I thought I should learn some pharmacology, and this was Pharmacology in Medicine, it was called, and there was chapters in it by a chap called Ahlquist – Raymond Ahlquist – and he was able to write in this book the work which he had had great difficulty getting published. And this was about trying to understand the pharmacology of... not adrenaline but a compound very close to adrenaline. This was isoprenaline, and this was a drug which was made and tested and brought into medicine in 1940, and it was brought in to dilate the bronchi, and so it was known to be a bronchodilator, and it was known also that it stimulated the heart, to make it go faster. And, the prevailing ideas about how adrenaline worked on tissues were very ambiguous at that time. People didn't talk about receptors... the only people who talked about receptors were pharmacologists with a mathematical bent because if they wanted to describe the relationship between dose and response, to write down, to make it into an algebraic sort of equation to see what it looked like, they had to have the concentration of drug interacting with something else and they called them receptors, but it was a pure idea though no one knew the existence of these things. But Ahlquist took this idea of receptors and said, 'Maybe what we have with adrenaline are two kinds of receptors', and he called them alpha receptors and beta receptors, and what the heart had were beta receptors, and the bronchi were beta receptors, whereas blood vessels, which constrict when you stand up, are alpha receptors. And so he concluded that the anti-adrenaline drugs of the day were alpha receptor blockers; that's why you fainted when you stood up, and your heart rate wasn't blocked. So when I read this it seemed obvious that what I wanted was a beta receptor antagonist.

The late Scottish pharmacologist Sir James W Black (1924-2010) revolutionised medical treatment of hypertension and angina with his invention of propranolol, the first ever beta blocker. This and his synthesis of cimetidine, used for the treatment of peptic ulcers, earned him the Nobel Prize in Physiology or Medicine in 1988.

Listeners: William Duncan

After graduating with a BSc Bill Duncan went on to gain a PhD from Edinburgh University in 1956. He joined the Pharmaceuticals Division of ICI where he contributed to the development of a number of drugs. In 1958, he started a collaboration with Jim Black working on beta blockers and left ICI with him in 1963 to join the Research Institute of Smith Kline & French as Head of Biochemistry. He collaborated closely with Black on the H2 antagonist programme and this work continued when, in 1968, Duncan was appointed the Director of the Research Institute. In 1979, he moved back to ICI as Deputy Chairman (Technical), a post he occupied until 1986 when he became Chairman and CEO of Coopers Animal Health. He ‘retired’ in 1989 but his retirement was short-lived and he held a number of directorships in venture capital backed companies. One of his part-time activities was membership of the Bioscience Advisory Board of Johnson and Johnson who asked him to become Chairman of the Pharmaceutical Research Institute of Johnson and Johnson in New Jersey. For personal reasons he returned to the UK in 1999, but was retained by Johnson and Johnson until 2006 in a number of senior position in R&D working from the UK. From 1999 to 2007 he was a non-executive director of the James Black Foundation. He is now fully retired.

Tags: Baltimore, 1930s, 1940, Pharmacology in Medicine, George Smith, Raymond Ahlquist

Duration: 6 minutes, 53 seconds

Date story recorded: August 2006

Date story went live: 02 June 2008