When he ran, then, the trial, not on equal doses, but on equal effects, then 16 out of the 17 patients with angina he looked at, were able to do much more exercise than beforehand.

[Q] That seemed quite an important principle that came out of Prichard's work.

Absolutely.

[Q] Titrating to an effect.

Absolutely, and we're still not doing it and we can't afford to go on the way we're doing it. Anyway, that's... we can maybe talk about that later. So, then we came with propranolol. By this time, of course, Brian had learned what he had to do so, again, he titrated his patients and... but on that first trial he found that, during the titration, when he was getting them all... the pulse rate at 60, that... and... and during the study, the... the blood pressure had come slowly down. So, when we started with propranolol he went straightaway to look at patients with high blood pressure, because up till then the only way to treat high blood pressure was to interfere with the sympathetic nervous system to blood vessels which gave you postural hypotension; that is, your blood pressure fell when you stood up, but not when you were lying flat. So he found that – again, titrated 17 out of 18 patients, I think it was, with hypertension – the blood pressure came slowly down over six weeks, and... the problem was you would've thought... and...and this was now not dependent on posture, and I have a slide somewhere showing how you can take... I think it was bethanechol... I can't remember... bethanidine, which was a sympathetic neuron blocking drug, posture dependent, and then gradually as you replace the bethanidine with propranolol, you got the fall in blood pressure whether you were standing or falling. And this was the major discovery about beta blockers which was surprising. It had not really been predicted by anybody.

Now, here's the thing: this was 1964. Brian published that when he'd finished, and two things: the medical profession didn't believe it because the dose range between the smallest dose and the highest dose was about tenfold, and so he... it was thought to be almost like toxicology, and this wasn't serious medicine. And so he was met with scepticism; that was the first thing. The second thing is: that's 1964, so we're now talking about 40-odd years, and it's well established that when you put onto beta blocker, any beta blocker, whatever other properties it has, the blood pressure comes down quickly on the first 24-36 hours, and then over months it gradually, slowly, slowly, slowly falls. And there is no agreement among pharmacologists or physicians what's happening. All we know is that when you stop the blood pressure doesn't immediately go back. Also, the biggest clinical trial ever done in this country was done with propranolol. This was something like 18,000 patients were recruited through... through general practitioners, and they were treated with either propranolol or a diuretic or a placebo for 5 years. And these were people with mild high blood pressure, and the drill was that if, during this 5 years, their blood pressure deteriorated, then they would be taken out of the trial and treated properly. And so what they had at the end of five years was that something like one in five of the placebo group had to be withdrawn because the blood pressure had gone out of range, whereas hardly any of the treated group did that happen. So, you're not only... you were preventing deterioration. Now, the conclusion of the trial was that you might stop 1 in 850 people getting a stroke, and so it's probably not worthwhile treating patients with mild hypertension, whereas the conclusion which they should have taken, I think, was the earlier you detect high blood pressure the better, treat it vigorously, and who knows; you might get a cure. But this is a policy which is still not in practice. So, not only is there no agreement about the basis of this chronic effect, but there's no agreement about the policy to use in treating. Right. So, that's beta blockers.