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John L. Reid, D.M., F.R.C.P., F.R.S.E. Dr. Reid is Chairman of the Department of Medicine and Regius Professor of Medicine and Therapeutics at the University of Glasgow, Scotland. He graduated in Physiology and Medicine from the University of Oxford and undertook postgraduate clinical training in Medicine and Clinical Pharmacology at the Royal Postgraduate Medical School in London and the National Institutes of Health, Bethesda, Maryland. He has been Head of Clinical Pharmacology and Therapeutics at the University of Glasgow since 1978. He is the author of numerous scholarly articles in both basic vascular pharmacology and in clinical hypertension, with emphasis recently on the role of ACE inhibitors and angiotensin II receptor blockers. |
Introduction of Dr. John Reid
Dr. Weber: Without any further ado, I am going to start the program. Our first speaker is Professor John Reid, who is the Head of the Department of Medicine and Therapeutics at the Western Infirmary in Glasgow. John will soon be our host at the International Society of Hypertension meetings in Glasgow. He is certainly internationally one of the most renown and accomplished investigators in the field of hypertension and cardiovascular medicine. John, it is a real pleasure and honor to welcome you to start off our proceedings today and to discuss angiotensin II as a target for treatment.
AII: A Target for Intervention
Dr. John Reid
28.8 modem
14.4 modemReal Audio recording of Dr. Reid's Presentation
Introductory remarks: Invitation to attend the International Society of Hypertension meetings in Glasgow, June, 1996
Thank you very much, Michael. It is a great pleasure to take part in this symposium at the American Society of Hypertension meeting. I am just concerned that I might overrun my time, so I am going to start the way I'm going to finish--by extending a very warm welcome to all of you to the 16th meeting of the International Society of Hypertension, which takes place next month in Glasgow. The preliminary program and full information is in your briefcase if you have not already registered. We have, we believe, a very exciting program. U.S. as well as U.K. CME is available to physicians attending the meeting. We also believe we will have around 5,000 to 6,000 clinicians and scientists interested in hypertension. You will be very welcome to join us. I will come back to that at the end, but I guess I better get on with the business of today's symposium and address the title that I was asked to: Angiotensin II, a Target for Treatment.
Angiotensin II is the key effector of the renin-angiotensin system
This is an introduction, really, to the symposium today. I followed the chairman's brief reasonably closely, rather more closely than I usually do. I am going to say a few general words justifying angiotensin II as a possible target for treatment then go on to discuss some of our own data in this field and finally introduce the new therapeutic approaches that can permit us to modify angiotensin II function in cardiovascular disease. Angiotensin II, as shown here in this simplified diagram, is shown as the key factor in terms of effecting the consequences of the renin angiotensin aldosterone system. Clearly there are a number of points at which the renin angiotensin system can influence physiology and potentially pathology.
Angiotensin II is more than a classic hormone, having autocrine and paracrine effects
I think it is also to important just to introduce right at the beginning the concept that I think is now widely accepted that the renin angiotensin system doesn't only contribute in its established, classical, hormonal circulating way but also in a wide range of tissues--heart, kidney, brain, adrenal, blood vessels--it is likely to play local autocrine or paracrine roles, and you'll hear much more of that later on. So we are not simply dealing with the classical, circulating hormonal system. As far as physiological effects are concerned, again if we are going to look on angiotensin II as a target for treatment, we've got to realize that this is a normal hormone, a normal body constituent, which has important physiological homeostatic functions. Modifications of these functions may have consequences in terms of normalcy of function in individuals if one is pursuing such a treatment strategy. We'll hear later today in more detail about AII's physiological effects on the kidney, its well established endocrine effects, its hemodynamic effects and other effects modulating central and peripheral neural functions.
Pathologic role of the angiotensin system
In addition to the physiological effects though, I think we have to consider the possibility of pathological effects of angiotensin II. And here in the most general terms, I would suggest that we are primarily considering sodium retention and associated hypertension and also the independent effects of angiotensin II in encouraging cardiac and vascular hypertrophy, which may also have pathological consequences. It is perhaps a little more speculative to talk about the pathological role of the angiotensin system in a number of conditions, but I think there is sufficient evidence to allow us to at least raise this as a hypothesis. There is no doubt that in malignant hypertension, renovascular hypertension, and indeed in congestive heart failure one could speculate on a role for the renin angiotensin system, although there must be some question, at least in some of these circumstances, as to whether the angiotensin's system role is primary or secondary. It is quite possible it may be both. And I think it is also important to recognize that in selecting angiotensin II as the target for treatment, we might be at a risk of excluding other angiotensin peptides or indeed other parts of the pathway from renin through to aldosterone from being a pathogenetic factor in disease states. I think, however, the evidence supports a role for angiotensin II as being the principle mediator of the effects of the renin angiotensin system with additional effects from aldosterone, both by the kidney and other mechanisms.
Evidence the high plasma levels of angiotensin II can be associated with adverse effects
I think if we explore this hypothesis a little further, we have to consider whether the renin angiotensin system, primarily through angiotensin II, is a risk factor. This is certainly not new. The concept that angiotensin II may be vasculotoxic has a long pedigree, much of the work having been done here in New York.
I will just discuss some of the data which is persuasive if not totally convincing suggesting that the renin angiotensin system through angiotensin II may be an independent risk factor for stroke, myocardial infarction, or sudden death. But I think one also has to be aware of the possibility that at least some of these associations may be a secondary factor related to disease or drug-induced activation of the renin angiotensin system and not a primary independent risk factor.
As I mentioned before, the areas where there may be a potential role for angiotensin II in pathology include malignant hypertension, renovascular hypertension, and heart failure. And clearly in these conditions there is a well-established association between the level of activation of the renin angiotensin system and adverse outcome. That is particularly true in terms of heart failure and is also true in terms of hypertension. Some of the first observations were made from John Laragh's group [1]. In this paper published in 1972 with Hans Brunner as the first author, many of you will remember very controversial findings where hypertensive patients characterized for their renin status--low, normal and high--were shown to have a range of associated adverse cardiovascular complications. The patients with high renin appeared to be those who had the worst cardiovascular outcome. This 1972 paper played a large part in promoting the renin profiling and classifying of patients according to renin status because of this claimed association to outcome. I think it is fair to say that even in the early 1970s there were a number of other observational studies which didn't support such a clear relationship. I think there must be concerns about the relatively small numbers involved here and particularly the absence of any events in the low renin group. But having said that, the follow-up work [2], again from the New York group (Michael Alderman was the first author of this paper in 1991) did appear in a rather more epidemiologically rigorous population to support this link between activation of renin angiotensin system and adverse outcome, here referring to the incidence of myocardial infarction adjusted for age, sex, and race. And if you can't see that at the back, let me show you that here for smoking, for cholesterol, and for blood glucose if the patients were classified according to low, normal, or high renin profile and then for the absence or presence of smoking, raised cholesterol or not raised cholesterol, raised glucose or not raised glucose, the subjects with the high renin appeared to have an excess number of events for 1000 patient years. I think that one can see that this appears to be the case after age, sex, and race adjustment, and indeed appears to be the case even when you take account of the other risk factors. And this is persuasive evidence that the level of activation of the renin angiotensin system is playing a part in determining outcome in our patients.
Angiotensin, noradrenaline, and mortality risk in heart failure
As far as heart failure is concerned, the early studies clearly showed the association between activation of the sympathetic nervous system and outcome. This is from Jay Cohn's group where plasma noradrenalin in the lowest group was associated with a much higher probability of survival in heart failure compared to the highest tertile of plasma noradrenalin. The studies at this time...and, of course, plasma-renin activity was the principle assessment of the renin angiotensin system, showed that in addition to sympathetic activation there was usually parallel activation of the renin angiotensin system as part of the neurohormonal activation associated with severe heart failure [3]. And I think as you are aware, the success in terms of outcome of ACE inhibitors in heart failure suggests strongly that modification of angiotensin mechanisms has a beneficial outlook in heart failure patients and also thereby suggests that angiotensin II was playing a pathological role.
Possible mechanisms for adverse effects of angiotensin II
Now this point I want to just suggest to you --that if we are going to discuss angiotensin II as a risk factor, as a vascular toxic factor, in some patient groups, we have to consider the mechanisms. It would probably take a whole morning. Certainly we could devote a whole symposium to discussing these possible mechanisms, including the possibility that they are all secondary to the pressor responses to angiotensin II. That remains possible but seems unlikely when one considers that component of blood pressure that can be modified by withdrawal of angiotensin II in many patients. But this could be a contributing factor to either the early or late, acute or slow pressor response to angiotensin II. Certainly there are quite a number of occasions, which I will allude to later, in models of hypertension, particularly the SHR and SHRSP, whereby lowering blood pressure, by interfering with angiotensin II, one can to a great extent reverse vascular structural changes and risk... not in all occasions but in some occasions. I think the other possibility is mineralocorticoid effects either through renal effects on sodium retention or through some of the more interesting recent observations on vascular and cardiac structure induced by mineralocorticoids. Interactions with the central and peripheral autonomic nervous system represent another alternative where, by facilitating sympathetic nervous function, the renin angiotensin system may augment pressor and vascular toxic effects.
Finally the one which I am going to spend a few moments talking about and which I think will develop very much more fully by Dr. Dzau and Dr. Unger later -- the effects of angiotensin II on growth, hypertrophy, hyperplasia, remodeling, cell cycle kinetics and other local functional changes.
Work in progress in our group with stroke prone spontaneously hypertensive rats: functional studies
I will just at this stage briefly digress to discuss some work in progress in our group, collaborative work with Anna Dominiczak and Ian McGrath. We are looking at the stroke prone spontaneously hypertensive rat (SHRSP), and we have published studies showing that in the SHRSP there are well characterized abnormalities of cell growth in aortic smooth muscle. This includes in the SHRSP a high proportion of cells with increased DNA content [4]. This polyploidy has been reversible by blocking angiotensin II effects either with ACE inhibitors or with angiotensin receptor antagonists. As an extension of this work, we have been looking in the same animals at function and structure in the basilar artery, particularly looking for factors which may influence the sensitivity to stroke disease in the stroke-prone SHR. This is an interesting but not all together an odd finding in the basilar artery of the SHR rat and DKY controls. Functional studies using micromyography show that the maximum contractile force with potassium chloride is substantially reduced in the SHRSP animals. I could show you the same data for serotonin responses--reduction, not in the sensitivity but actually in the maximum response to serotonin.
Now what is interesting is that after 10-week treatment with losartan, there is almost a complete recovery of function. This is another example of the near-complete recovery of function in the SHRSP with reduction in blood pressure. The regimen we used, and this was published in Hypertension a few months ago, with regard to the results in aortic smooth muscle cells... nearly normalized blood pressure with losartan.
Structural studies in SHRSP rats
We coupled these studies with studies of structure using in vivo confocal microscopy to determine the structure of vascular smooth muscle in the basilar artery. We were looking particularly at the geometric arrangement of the vascular smooth muscle cells in the basilar artery and correlating this with the function responses that I've just referred to. This is a series of confocal sections through the basilar artery of WKY animals showing at different depths: 1, 7, 12, and 19 micrometers, this sheet-like organization, which was characteristic of the WKY controls. A relatively novel finding was that in the basilar arteries of the SHRSP, there were a number of areas of disorganized foci where cells were not lying in the same plane as we would expect, either longitudinally or secularly. And this is an example of some of these disorganized foci. These are associated with branching points, and they may be associated with aging. But these were age-matched animals and we were careful to insure that we were covering an extent of basilar artery to allow us to draw some conclusions about these. We also went on to quantify the disorganized foci by looking at the portion of cells which showed a deviation from 90 degrees to the expected axis of the cells in three layers of the basilar artery. I just show you this because in contrast to the findings which I showed you with KCl and which I mentioned with serotonin, treatment of animals with an angiotensin receptor antagonist, losartan, did not reverse these structural changes. They persisted after blood pressure reduction and after functional recovery. In WKY rats, 10 or 12 percent of cells showed this deviation compared to nearly 30 percent in the SHRSP. That was consistent through these three layers of basilar artery. There was not a restoration of structure in parallel with functional restoration after treatment with losartan.
Angiotensin II receptor antagonists as a potential strategy for treatment
So much for that brief deviation. Let me now in the last couple of minutes, complete the task that the chairman sent me. He asked me if I would at the end go on to introduce the concept of angiotensin receptor antagonists as a potential strategy for treatment having, I hope, justified this to you in terms of possible pathological roles. This is a slightly more complicated diagram of the renin angiotensin system which brings in bradykinin and brings in kinase as another protease. It doesn't bring in angiotensin III and there are a lot of other factors that could come in. It is just to show that there are a number of alternative points. Perhaps the alternative strategies, including blocking the release of the synthetic inhibitor, inhibiting renin, inhibiting ACE, blocking the AT receptor, and strategies to modify the consequences of angiotensin II including diuretics and vasodilators. I think you can see from the last diagram and from the yellow highlighting here that I would see a particular attraction in getting to the heart of the matter and blocking the AT receptor which mediates these events rather than tinkering with things upstream or trying to modify things downstream. But that is a personal opinion. There have been angiotensin receptor antagonists available for over 20 years. There are now a large number in clinical development. This is a far from complete slide of drugs which were in early clinical development. One of them, losartan, is currently available widely throughout the world; others, like valsartan and urbesartan or candesartan, are close to licensing and in advanced clinical development. They show some differences in terms of their profiles, in terms of whether they have pro-drug effects or whether they are surmountable or competitive or insurmountable antagonists.
Losartan and its active metabolite, E3174
At the present time, losartan is available. Losartan, which masquerades under these two code names is codeveloped by DuPont and Merck. It is in fact an active pro-drug which in vivo is rapidly metabolized to the carboxylic acid metabolite E3174. It is likely that E3174 plays a major part in the clinical effects of this drug when given once daily to hypertensive man. So losartan is an orally active competitive antagonist of AT1 receptors. E3174, its carboxylic acid metabolite, which has non-competitive features and is a long-lasting antagonist, possibly is even a more potent antagonist at the AT1 receptor. Looking at the clinical pharmacokinetics, you can see that after the first dose, losartan, shown in grey, is rapidly and consistently absorbed, but also rapidly converted into the metabolite which peaks shortly afterwards; the short half-life and rapid fall-off of losartan, but a much slower fall off of the metabolite, indicates as I suggested that much of the effects in the later period probably are due to the metabolite. After six weeks of dosing, as you would expect with this short half-life, there is no accumulation of parent drug. Accumulation to predicted steady state of E3174 and an inter-dose profile are shown there.
Efficacy of losartan compared with other drugs
I think Mike Weber will come later to discuss the clinical effects of losartan and angiotensin II antagonists in general. I think, just at this very early stage, to say that compared to other agents, first line agents, monotherapy agents, it appears to be comparable, it appears to be suitable for once-daily dosing, and broadly speaking appears to produce comparable effects on blood pressure and other blood pressure with ACE inhibitors. What has not, of course, been demonstrated is whether this strategy is any more successful or indeed as successful as conventional treatment in preventing coronary heart disease and stroke; although the ongoing LIFE study, which examines hypertensive patients with left ventricular hypertrophy and compares in a double-blind manner losartan with atenolol, may provide some answers over the next few years.
Concluding remarks
In conclusion, angiotensin II is associated with cardiovascular morbidity and mortality in hypertension heart failure. Interference with the interactions of angiotensin II with its receptor can be achieved by ACE inhibitors or receptor antagonists. Interference with the action of angiotensin II with selective AT1 antagonists is associated with reversal of hemodynamic effects and normalization of most, but not all, the effects on vascular growth and structure. Thank you very much.
References
1. Brunner HR, Laragh JL, Baer L, et al. Essential hypertension: renin and aldosterone, heart attack and stroke. N Engl J Med 286:441-449, 1972.
2. Alderman MH, Madhavan S, Ooi WL, Cohen H, Sealey JE, Laragh JH. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 324:1098, 1991.
3. Francis GS, Cohn JN, Johnson G, Rector TS, Goldman S, Simon A. Plasma norepinephrine, plasma renin activity, and congestive heart failure. Relation to survival and the effects of therapy in V- HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation 87: 6 Suppl, 1993 Jun, V140- 8.
4. Dominiczak AF, Devlin Am, Lee Wk, Anderson NH, Bohr DF, Reid JL. Vascular smooth muscle polyploidy and cardiac hypertrophy in genetic hypertension. Hypertension 27 e Pt 2, 1996 Mar, 752-9.
QUESTIONS AND DISCUSSION Dr. Weber:
We do have time for just a couple of questions after each speaker. I just invite you to use the microphones. Please state your name and where you are from.
Dr. Richard Bukoski (Galveston, TX):
Just a comment about your data regarding force generation in the basilar arteries. We've been doing some work which we will actually present at your meeting next month looking at myosin isoform heavy chain expression. We recently extended our observation from vitamin D to angiotensin, and we find angiotensin is quite effective in stimulating nonmuscle myosin heavy chain formation, which we find correlates quite well with a decrease in force generation. That might be something that you could consider happening there.
Dr. Reid:
That's an excellent idea. This will be presented by Sylvia Aribas in full with due acknowledgement to all the people who have done the work in Glasgow. One of the things that we are aware of is that it may be a matter of the duration of treatment. The functional responses may recover more rapidly than some other structural changes, which may require longer treatment. And that is certainly something we would want to deal with.
Dr. Weber:
John, what about the metabolic actions of drugs such as Losartan? Do you anticipate that we're going to have effects on insulin sensitivity, on lipids and so forth? Similar to the ACE inhibitors? What are your predictions there?
Dr. Reid:
I think the data that I'm aware of and some of the work we've been doing in our own group, John Connell and John Petrie... I think as far as the lipids and glucose levels are concerned, I think at the very least I would have a fairly confident view they are going to be neutral. I think they maybe will have the potential to modify angiotensin II metabolic effects in the same was as I think ACE inhibitors do on some occasions, although not consistently I would have to say. I think as far as other metabolic effects are concerned, the effects on potassium don't appear to be profound. But there will be a potassium-sparing effect which may be more important when used together with a diuretic. And similarly, the modest uricosuric effect of losartan does not appear to be associated with any adverse consequences. But again, it has not been my impression that the magnitude of those changes will be of any big positive clinical benefit.
Dr. Weber: Okay. Just one last thing, John. Explain again... Losartan on the face of it has a relatively short plasma half-life yet a very convincing 24-hour duration of action. I will show some data a little later. What is your speculation there as to how that can happen pharmacologically?
Dr. Reid:
I think it's probably a combination of two pharmacokinetic and pharmacodynamic factors. Firstly, there is no doubt that it forms in man and in some animal species, the rat, but not I think the dog and rabbit--it forms this active metabolite. It is an active drug and it forms an active metabolite. The active metabolite not only has a much longer half-life of about 8 or more hours, but the active metabolite is not a strict competitive reversible antagonist. So the combination of this metabolite having intrinsically longer duration of effect and the fact that it is off set at the receptor site is slow...I think gives this the edge over conventional classical receptor antagonists.
Dr. Weber:
John, thank you so much for getting us off to such a good start.
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