Journal of Human Hypertension (2002) 16, S59–S63 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh AT1-receptor blockade and the kidney: importance of non-ACE pathways in health and disease NK Hollenberg Brigham and Women’s Hospital and Harvard Medical School, Departments of Radiology and Medicine, Boston, Massachusetts, USA Large-scale trials with angiotensin converting enzyme is increased in diabetic patients, and comparison of the (ACE) inhibitors and angiotensin II type 1 (AT1)-receptor renal vascular responses to captopril and candesartan blockers have clearly shown that blockade of the renin- shows a strong correlation between the effects of ACE angiotensin system reduces the deterioration in renal inhibition and AT1-receptor blockade, indicating that the function associated with diabetes. AT1-receptor block- deleterious effects of renin-angiotensin system acti- ers represent a more rational approach to blockade of vation in diabetes are mediated largely through angio- this system than ACE inhibitors, due to the presence of tensin II. The presence of multiple risk factors, such as non-ACE pathways of angiotensin II formation. Studies genetic predisposition, hyperglycaemia, obesity and in healthy volunteers maintained on a low-salt diet indi- tissue damage, places diabetic patients at high risk of cate that such pathways account for approximately 30– disease related to activation of the renin-angiotensin 40% of total angiotensin II formation, and this figure system. Effective and early blockade of this system is increases to 60–70% in individuals maintained on a therefore an important aspect of management. high-salt diet (resembling the situation in most human Journal of Human Hypertension (2002) 16, S59–S63. populations). Activation of the renin-angiotensin system doi:10.1038/sj.jhh.1001441 Keywords: angiotensin II; angiotensin converting enzyme; candesartan; captopril; diabetes; renin-angiotensin system Introduction vention in diabetic patients with microalbuminuria, and of using adequate doses to achieve effective The demonstration that treatment with angiotensin receptor blockade, and raise the question of how converting enzyme (ACE) inhibitors significantly 1 blockade of the renin-angiotensin system can achi- reduces the progression of diabetic nephropathy eve such substantial risk reductions in an essentially focused attention on the role of the renin- metabolic disease. angiotensin system in the kidney, and led to the widespread use of ACE inhibitor therapy in patients Therapeutic targets for blockade of the at risk of nephropathy. Moreover, recent large out- renin-angiotensin system come studies with angiotensin II type 1 (AT1)-recep- tor blockers have shown that these agents reduce the Blockade of the renin-angiotensin system was first deterioration in renal function, and delay the onset achieved with ACE inhibitors, which were of end-stage renal failure, in diabetic patients.2–4 In developed in the 1970s after the chance finding that the Irbesartan Diabetic Nephropathy Trial (IDNT)2 a component of pit viper venom had a powerful and the Reduction of Endpoints in NIDDM with the hypotensive effect. Arguably, however, a pharma- Angiotensin II Antagonist Losartan (RENAAL)3 cologist aiming to block the renin-angiotensin target study, treatment with an AT1-receptor blocker would not have selected ACE as a therapeutic target. reduced the incidence of end points by approxi- Renin is the rate-limiting step in the pathway lead- mately 20%. By contrast, in the Irbesartan in ing to angiotensin II formation (Figure 1), and thus patients with type 2 diabetes and Microalbuminuria would represent a rational target for intervention; (IRMA II) study,4 the onset of overt nephropathy was however, the development of suitable candidate reduced by 39% in patients receiving irbesartan, 150 compounds has proved difficult because of prob- mg, and by 70% in those receiving 300 mg. Such lems with synthesis and bioavailability.5 Moreover, findings highlight the importance of early inter- angiotensin II is produced by a number of pathways that do not involve ACE, such as chymase, trypsin and cathepsin G (Figure 1). Blockade of the AT1- Correspondence: Professor NK Hollenberg, Brigham and receptor thus represents a more rational therapeutic Women’s Hospital, 75 Francis St, Boston, MA 02115, USA target than ACE inhibition. AT1-receptor blockade in the kidney NK Hollenberg S60 Figure 1 The renin-angiotensin system. Non-ACE pathways of angiotensin II formation Non-ACE pathways in the kidney Evidence for the contribution of non-ACE pathways The relative contributions of ACE and non-ACE to angiotensin II formation in the human pathways of angiotensin II formation in the human cardiovascular system comes from a study in which kidney have been investigated in experiments in angiotensin II was measured in plasma and myocar- healthy volunteers fed a low-salt diet.11 If the dial tissue from normal and failing hearts obtained increase in renal plasma flow that occurs during at transplantation.6 In plasma, conversion of blockade of the renin-angiotensin system were angiotensin I to angiotensin II can be completely solely attributable to blockade of angiotensin II pro- blocked by ACE inhibitors; by contrast, in myocar- duced via ACE, then renin inhibitors, ACE inhibi- dial membrane preparations, ACE inhibitors have tors, and AT1-receptor blockers should produce only a limited effect on angiotensin II formation similar results. By contrast, if the renal vascular whereas serine protease inhibitors reduce angioten- response is partly due to a reduced breakdown of sin formation by approximately 80%. Similar results vasodilator kinins such as bradykinin following were obtained in studies with human gastroepiploic ACE inhibition, the effect of ACE inhibitors would artery preparations, in which chymase inhibitors be expected to be greater than that of renin inhibi- reduced the contractile response to angiotensin II, tors or AT1-receptor blockers. formed locally following addition of angiotensin I, In one study, participants received 90-min to a greater extent than ACE inhibitors, and the two infusions of the renin inhibitor enalkiren, 256 ␮g/kg inhibitors in combination produced almost com- or 512 ␮g/kg, at 2-day intervals.12 The lower dose plete abolition of the response.7 In these was at the top of the dose-response curve for inhi- experiments, approximately 30–40% of angiotensin bition of angiotensin II formation. The increase in II formation was attributable to ACE, and the renal plasma flow following administration of enal- remainder to non-ACE pathways. There are, how- kiren was substantially greater than that seen in pre- ever, marked species differences; in humans and vious studies with ACE inhibitors, and was dose- other primates, angiotensin I is the sole substrate for dependent; a greater response was achieved with the chymase and angiotensin II is the sole product, higher dose, even though plasma angiotensin II con- whereas in rodents and rabbits this enzyme is prim- centrations were not further reduced (Figure 2). This arily responsible for degradation of angiotensin II, suggests that the response to the renin inhibitor was rather than formation. For this reason, studies with attributable to inhibition of non-ACE pathways animal models have often been misleading. An within the kidney. example of this is provided by early studies in rats, This study was repeated using different renin which showed that ACE inhibitors were strong inhibitors and three ACE inhibitors, each at the top inhibitors of neointima formation after vascular of their dose-response ranges.13 The combined data injury.8,9 However, large clinical trials, notably the from these studies showed that the renal vascular MERCATOR Study,10 failed to show significant response to renin inhibition was markedly greater beneficial effects of ACE inhibitors on restenosis than the response to ACE inhibition (approximately rates after percutaneous transluminal coronary 140 mL/min/1.73 m2 vs 90–100 mL/min/1.73 m2). In angioplasty. It is now widely accepted that this dis- further studies, the AT1-receptor blockers crepancy between animal studies and clinical trial candesartan, irbesartan and eprosartan were found outcome is largely due to the presence of non-ACE to produce comparable increases in renal plasma pathways of angiotensin II formation in humans. flow to renin inhibitors.11,14,15 Together, these data Journal of Human Hypertension AT1-receptor blockade in the kidney NK Hollenberg S61 Figure 2 Changes in plasma angiotensin II and aldosterone concentrations, and renal plasma flow, following administration of the renin inhibitor enalkiren in healthy volunteers maintained on a low-salt diet.12 Reprinted with permission from Cordero P et al. Renal and endocrine responses to a renin inhibitor, enalkiren, in normal humans. Hypertension 1991; 17: 510–516. diet, the responses to both agents were attenuated (Figure 3). In this situation, however, the response to candesartan was even more markedly greater than the response to captopril (97 ± 20 mL/min/1.73 m2 vs 30 ± 15 mL/min/1.73 m2, respectively, P Ͻ 0.01; Figure 3), since the response to captopril was dimin- ished to a greater extent than the response to candes- artan. This suggests that the high-salt diet had less effect on non-ACE pathways of angiotensin II forma- tion than on ACE; in this situation, non-ACE path- ways accounted for approximately 60–70% of renal angiotensin II formation, compared with 30–40% in volunteers maintained on low-salt diets. This find- ing may be clinically relevant since the daily salt Figure 3 Increase in renal plasma flow following treatment with intake of most people is closer to that in the high- candesartan cilexetil, 16 mg, or captopril, 25 mg, in healthy vol- salt diet used in this study than to the low salt-diet. unteers maintained on low-salt or high-salt diets.16 Reproduced Since non-ACE pathways appear to make a greater with permission from Hollenberg NK et al. Salt intake and non- ACE pathways for intrarenal angiotensin II generation in man.