Gradual reactivation of vascular angiotensin I to angiotensin II conversion during chronic ACE inhibitor therapy in patients with diabetes mellitus

We have clearly shown that during chronic lisinopril therapy in patients with diabetes, gradual reactivation of the vascular conversion of AI to AII occurs. Our other main finding was the dissociation between plasma RAAS and vascular tissue RAAS, shown by the fact that only the latter reactivated in this study.

Our study has two major strengths. First, we performed an in vivo study in humans. Hence there are no concerns about species differences as there would be with animal studies, nor are there any concerns that the experimental model itself introduced artefacts, as might happen with ex vivo studies or in vitro studies. Second, we performed a longitudinal study of the same individuals. Often longitudinal phenomena are studied by using a cross-sectional approach, where many different individuals at different stages of their disease are each studied once. Such a cross-sectional approach is an imperfect, if not flawed way to study longitudinal phenomena, because it introduces inter-individual variation, which may over time swamp subtle yet important intra-individual changes.

An intriguing question for the future is whether the ACE genotype has any influence on whether an individual reactivates his or her vascular RAAS system or not. Our study was not powered to answer this question, because a genotype study with three genotypes in only 30 individuals would be absurdly small and could lead to erroneous conclusions. However, the raw data for this study do not suggest that there were major inter-individual differences in the amount of reactivation seen. Nevertheless, this is an issue that needs to be studied more closely in the future, rather than being addressed by this study, which was too small.

Another intriguing question is whether the reactivation seen by us would also occur at higher lisinopril doses. We deliberately chose a dose of lisinopril that is regarded by the BNF as being at the top of the usual recommended maintenance dose. So whatever we found would be directly relevant to everyday clinical practice for the majority of patients. Another unknown is whether other ACE inhibitors, which are more tissue-bound, would demonstrate the same effect. However, again we decided to use the commonest ACE inhibitor in use in the UK, thus making our study relevant to the majority of UK patients.

One obvious unanswered question is the nature of the mechanism, whereby AI to AII conversion reactivates during chronic ACE inhibitor therapy. It could be due to reactivation of vascular ACE itself or to other non-ACE enzymes such as chymase. In CHF, there is evidence that both probably contribute [8, 9, 10]. Two studies in CHF suggest that vascular ACE itself contributes, because in those studies increases of the ACE inhibitor dose re-established some further suppression of vascular tissue AI to AII conversion. On the other hand, one other study in CHF demonstrates that vascular tissue AII can indeed be generated by non-ACE pathways during chronic ACE inhibitor therapy [8, 9, 10]. To date, there are no data on this mechanistic question in non-CHF patients. Recent new insights in angiotensin research do not offer any simple alternative explanations for our finding [12]. For example, AI accumulates during ACE inhibitor therapy and some of that becomes the vasodilator, angiotensin (1–7), but there is no apparent reason why less AI should become angiotensin (1–7) during chronic ACE inhibitor therapy, unless more AI is channelled into AII instead, which is what we are proposing anyway.

A question that follows from the above is why vascular ACE might reactivate (if it does) during chronic ACE inhibitor therapy. Again there are two possibilities. First, in tissue culture captopril was found to induce ACE in human endothelial cells [13]. This is akin to the phenomenon of upregulation of receptors when they are exposed constantly to an antagonist drug. The second possibility is that progressive atherosclerosis in the vasculature induces ACE activity [14, 15, 16]. However, overt atherosclerosis is not prominent in brachial arteries, although there may be enough progressive vascular/endothelial dysfunction to induce local ACE activity. Further work would be required to clarify these issues more precisely.

Our study shows a dissociation between the plasma RAAS components and vascular tissue RAAS in that only the latter reactivated over time. In fact, this mirrors exactly what we found in our previous study in CHF, emphasising again the dissociation between plasma and tissue components of the RAAS [9]. The reasons for this dissociation are not at all clear, since plasma AII is now thought to be derived to some extent from the tissues, from vascular ACE and from kidney-derived renin.

Do our data have any clinical implications? If a similar phenomenon occurs in renal tissue, then our results could provide a mechanistic rationale to explain why a combined ACE inhibitor and ARB therapy performs better in diabetic microalbuminuria [17, 18]. Second, and more speculatively, is the possibility that the gradual reactivation of vascular tissue AI to AII conversion during chronic ACE inhibitor therapy could detract from the cardioprotective benefits achieved when ACE inhibitors are used chronically, as in HOPE study type diabetic patients. Partial support for this possibility comes from the CHF patients enrolled in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity Added Trial [19], where adding candesartan to an ACE inhibitor produced further reductions in cardiovascular deaths and CHF hospitalisations. However, this support is only partial because other studies such as the Valsartan in Acute Myocardial Infarction Trial (VALIANT) did not make the same findings, possibly because the ACE inhibitor dose was halved when it was combined with an ARB in VALIANT [20]. This was done for safety reasons, but it does limit the ability of the VALIANT trial to inform us about the clinical consequences of adding an ARB to an ACE inhibitor. Nevertheless, it should be noted that in the VALIANT trial the ARB-alone arm did no better than the ACE inhibitor-alone arm, even though it could be expected to do so if ACE reactivation really does detract from the ACE inhibitor-alone benefit. Moreover, the kind of information seen in CHF studies cannot automatically be extrapolated to other non-CHF disease states. In fact, large ongoing studies are currently addressing whether or not an ARB produces added benefit in HOPE study type patients without heart failure.

One limitation of our study is that we did not study a nondiabetic, non-CHF control group in order to see if AI to AII conversion reactivation only occurs in diabetic and CHF patients. In fact, there is no reason to believe that this phenomenon should be limited to these two patient subgroups, but future work would be required to examine this.

In conclusion, we have clearly shown for the first time that vascular AI to AII conversion does gradually increase over time in vivo in humans with type 2 diabetes mellitus. Further studies are required to elucidate the precise mechanism of this gradual reactivation and whether overcoming this phenomenon will enhance the clinical benefits of chronic ACE inhibitor therapy in HOPE study type patients with diabetes mellitus. Possible ways to overcome this phenomenon are either to increase the ACE inhibitor dose to above current target doses or to add an ARB to ACE inhibitor therapy.