In the early days of beta blockers clinicians found that if you had a patient in heart failure and you gave them a beta blocker... well, undoubtedly, some... one or two patients died, but it was bad news, as though you needed your beta receptors in the heart to protect you against heart failure. And so physicians taught for years: never give a beta blocker to patients with heart failure. Then a... a physician in Gothenburg in Sweden – I don't know why Sweden keeps coming up but there it is, it's a very exciting place scientifically – had patients with what's called dilated cardiomyopathies in which one of the problems is high heart rates, and he felt, 'If only I could reduce the heart rate, I feel they'd be more comfortable', and the only way he knew to do that was with a beta blocker. So, he started experimenting giving a little dose and for the first 24 hours it didn't look good, but then he had the courage to keep going, and after a couple of days they began to get a little bit better, and so he kept going and then he would increase the dose, get worse, then get better, and grad... and he titrated them, and he was bringing patients out of heart failure with a beta blocker. So that was '75 that was published.

By 2000, 15 years later, we had now got four huge studies done. By huge I mean about 5000 patients in each, with four different marketed beta blockers. One was metoprolol – AstraZeneca/ICI compound – which is classified... oh, I have to... I'm missing out a big piece. When I was at ICI we had alpha receptors and we had beta receptors. In the meantime we found there was many types of alpha receptors and many types of beta receptors. In fact, three are recognised, and they're called beta-1, beta-2, and beta-3. And, back in the early days, after I had left ICI, they went on to make selective beta 1 receptor antagonist, still marketed as atenolol. And so, there was a number of selective beta-1 antagonists but just, of which metoprolol – which they acquired by taking over a Swedish company – was one. So, AstraZeneca metoprolol. Then there was another compound called bisoprolol which was classified as a beta-1 antagonist. Then another company in the States had been marketing carvedilol as a non-selective and it blocked both beta-1 and beta-2, but it did some other things, but beta-1 and beta-2; carvedilol. And then the fourth one was bucindolol classified as non-selective. So two selective for beta-1 and two non-selective. In each case a pattern was found of titration. You start with small dose and gradually build them up; first 24 hours they get worse and then they get better, and you can... so now Finn Waagstein who was the man who started all this in 1975 – Gothenburg – he says, 'What we have in common in these four drugs are beta 1 receptor block, so it's the beta 1 receptor blockade which is doing the business'. Now, pharmacologists, clinical pharmacologists I'm afraid, and clinicians, talk about beta-1 selectivity as though it was a quality, when in fact it's a quantity. And in the case of metoprolol the quantity is surprising small. Now, when we are comparing... potencies, you take a dose response curve and one system, and a dose response in the other, and you compare the... the 50% points; you compare it horizontally. But therapeutically what you do is you titrate up towards the top of those response curves, and when you get up there the difference between the two tops narrows, so down at the 50% point metoprolol is four full selective. Up at the top it's not selective at all. And so I showed them data that all of these drugs are producing significant beta-2 receptor blockade.

Now, why am I excited by that? Because... when I started I was interested in heart rate, and it so happened, as we now know, that the pacemaker of the heart has only got beta-1 receptors, whereas the ventricles have got beta-1 and beta-2. Now, whenever a beta receptor ag... agonist acts on the beta receptor it switches on the production of what are called G-proteins, and specifically beta-1 generates what's called GS-proteins – S for stimulation – and the GS-proteins switch on phosphorylating enzymes, and one of these phosphorylating enzymes phosphorylates the receptor and inactivates it. So you stimulate it; chain goes; inactivation; then it's recycled. The beta-2 is the same. It couples to GS. But once it has been phosphorylated and inactivated for GS coupling, it now couples to another G-protein called GI. So, here we now have the production of GI-proteins once the receptor is phosphorylated. Now, GI-proteins – I is for inhibition – does just that, inhibits the contractions but we also know it does an awful lot of other things downstream to what are called tyrosine kinase enzymes.