Vas deferens tissue was to go on to prove a major model.

That turned out to be one of the most densely innervated smooth muscles anywhere in the body. There were masses of nerves mingling with the smooth muscle cells. When you stimulate those nerves you get a little signal, a change in membrane potential once again. Unlike the action potential, these are very much smaller signals, which have to sum together to reach the threshold for generating an action potential. So we had a model very much like the skeletal neuromuscular junction – and it turned out to be a model for quite a number of other situations in the body as well.

So there was a summation sequence?

Yes. We looked at the signals we got in the smooth muscle when we stimulated the hypogastric nerve, and we saw the small movements of the membrane, in the same direction as action potential but very much smaller – you could grade them with the strength of stimulation. You had electrodes on the hypogastric nerve and you’d stimulate: at first nothing happened and then you increased the strength. Gradually you would come up to a point where you saw a very small change in membrane potential; with a stronger stimulus it would get bigger and bigger, and then you would get an action potential. So we now had a nice handle on what was going on in neuromuscular transmission in smooth muscle. That was good.

Wondering about neurotransmitters

Eventually you got onto transmitters, didn’t you?

Yes. Perhaps I should explain a bit about the nerves that go to smooth muscle and the other tissues in the body. The skeletal muscles are innervated by nerves whose cell bodies lie in the brain or the spinal cord and send out what we call an axon. That goes out to the skeletal muscle fibre, and at its terminal in the skeletal muscle it releases a substance called acetylcholine, which causes a change in membrane potential similar to but much larger than I described for the vas.

But in the autonomic nervous system – the heart, blood vessels, guts, the whole lot – although the nerve cells send out an axon which releases acetylcholine at its terminal in exactly the same way, that acetylcholine is released onto another nerve cell. It does not go directly to the muscle fibre: instead, there’s a relay in the system, with the synapse. And the cells which are activated by acetylcholine coming out of the preganglionic fibre can release different transmitters. Some of them release acetylcholine when they go out to the periphery; some release noradrenalin; some probably release other substances as well.

So the vas deferens is innervated by sympathetic nerves, and we thought we were looking there at responses to stimulating nerves that worked through the release of noradrenalin. But quite early on in the piece the pharmacology, the way drugs acted on that neurotransmission process, made us wonder whether it really was noradrenalin that was causing the change in membrane potential.

Are you saying that if you blocked noradrenalin, you still got a response?

That’s exactly right. One of the traditional drugs used to block the actions of noradrenalin and adrenalin on smooth muscle was phenoxybenzamine, which actually made those sub-threshold responses, the ones which were not big enough to be an action potential, bigger than in the control. So it was a bit of a puzzle, something new.

At that stage very little was known about neurotransmission and transmitters. I remember studying the standard number of transmitters – acetylcholine and nora but not a big field at all. But all of a sudden you were saying, ‘There’s got to be more.’ You were rewriting the texts.

Yes. I felt for a long time that it could be a question of the noradrenalin acting on a different kind of receptor from any of the receptors that were known to latch on to it. I think most people nowadays believe that it is a different transmitter, and this was Geoff’s baby: a little bit later on, he had the idea that the transmitter might be ATP, adenosine triphosphate.

Why did he come to that conclusion?

As a result of bits and pieces in the literature. There was a suggestion by Sidney Hilton, I think, that ATP might be a vasodilator. Possibly Graham Campbell had the idea – he was another collaborator of Geoff’s and mine, a great reader of literature who had an excellent memory. It’s very hard to attribute an idea like that to an individual, but Geoff certainly persuaded a lot of people that it was the explanation and I think most people nowadays would feel it was well and truly established.

You’re not one who presents it.

Well no, just because you cannot readily mimic the exact changes in membrane properties that are caused by applying ATP to the bath with the changes that occur when ATP comes out of nerves. But it’s an interesting story and I think most people would nowadays agree that ATP is a neurotransmitter.

Focus questions

• What is the autonomic nervous system and what organs does it control?

• How would you describe the difference between a membrane potential and an action potential?