Converting enzyme inhibition and the kidney

We review information on the renal response to converting enzyme inhibition, and attempt to evaluate the evidence that a reduction in angiotensin II formation is responsible for the renal response. There is little response to converting enzyme inhibitors in animals or man when the renin-angiotensin system is suppressed by a literal sodium intake. With restriction of sodium intake, an increase in renal blood flow occurs; because a quantitatively similar response occurs to the angiotensin II analogs it is likely that the response reflects reversal of the local action of angiotensin II. In other settings it is not yet clear whether the renal response to converting enzyme inhibitor reflects only a reduction in angiotensin II formation or an additional action such as potentiation of the local actions of bradykinin or enhanced prostaglandin formation. Because these agents induce a potentiated increase in renal blood flow in the patient with essential hypertension, and with it an increase in glomerular filtration rate and sodium excretion in some patients, despite a fall in arterial pressure these questions have considerable importance.     

Potential benefits of aliskiren beyond blood pressure reduction

There is now clear evidence that reducing blood pressure (BP) with a broad range of agents, including angiotensin converting enzyme inhibitors and angiotensin receptor blockers, improves cardiovascular and renal outcomes. There is also evidence suggesting that these drugs have beneficial effects that are independent of BP lowering. Aliskiren is a direct renin inhibitor that interrupts the renin-angiotensin-aldosterone system (RAAS) at its rate-limiting step. Unlike angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, aliskiren produces a sustained reduction in plasma renin activity and reduces plasma levels of angiotensin II and aldosterone. Preclinical data and clinical trials in high-risk patients using surrogate markers increasingly suggest that aliskiren can reduce the progression of end-organ damage beyond that afforded by BP control. With its unique mechanism of action, combining aliskiren with another RAAS-blocking agent that has a different mechanism of action may provide more comprehensive blockade of the RAAS, potentially conferring additional clinical benefits. Evaluation of these end-organ effects in humans is underway in clinical trials designed to assess the effects of aliskiren alone and in combination with other antihypertensive agents on cardiovascular and renal outcomes.     

Renal and endocrine responses to a renin inhibitor, enalkiren, in normal humans

Interpretation of renin-angiotensin blockade with angiotensin converting enzyme inhibitors is potentially confounded by their multiple effects. We used a selective renin inhibitor (enalkiren, A-64662) to explore the renal and endocrine effects of angiotensin II in healthy men. Each received 90-minute enalkiren infusions at 2-day intervals, on a low (10 mmol, 16 subjects) and high (200 mmol, 12 subjects) salt diet. Plasma renin activity, immunoreactive plasma angiotensin II and aldosterone concentrations, inulin, and p-aminohippurate clearance were measured by standard methods. Plasma renin activity fell at 0.1 micrograms/kg, but the threshold for biologic effect was 256 micrograms/kg, where plasma immunoreactive angiotensin II and aldosterone concentration fell, and renal plasma flow rose (p less than 0.01). The maximal renal vascular response (+152 +/- 23 ml/min/1.73 m2) occurred at 512 micrograms/kg (p less than 0.01). Diastolic and mean blood pressure fell modestly but significantly (p less than 0.05). Responses were limited on a high salt diet. We confirm that conventional plasma renin activity measurement is misleading in humans receiving a renin inhibitor. The renal vascular response to renin inhibition in this study appeared to substantially exceed reported responses to angiotensin converting enzyme inhibition, perhaps reflecting a crucial and relatively inaccessible intrarenal locus.     

Why are angiotensin converting enzyme inhibitors underutilised in the treatment of heart failure by general practitioners?

Treatment with angiotensin converting enzyme inhibitors confers significant morbidity and mortality benefits in patients with heart failure, yet previous studies have repeatedly shown that these drugs are underutilised in general practice. To investigate why this is the case, we conducted an anonymous questionnaire survey of 515 general practitioners in the Nottingham Health District. The response rate was 60.2%. We found that although 39.3% of respondents underestimated the poor prognosis associated with heart failure, 98% were aware of the prognostic benefits conferred by angiotensin converting enzyme inhibitors. However, 46.3% of respondents expressed concern about the potential adverse effects associated with angiotensin converting enzyme inhibitors, the main fears being hypotension and renal impairment. General practitioners who were concerned about adverse effects were significantly less likely to have initiated an angiotensin converting enzyme inhibitor for heart failure than those who were not (P<0.01). Further research is needed to identify which patients can safely be commenced on angiotensin converting enzyme inhibitors in general practice. In the meantime, general practitioners should be encouraged to refer patients whenever they are concerned about initiating angiotensin converting enzyme inhibitors in the community.     

Rationale for Combining a Direct Renin Inhibitor with other Renin- Angiotensin System Blockers. Focus on Aliskiren and Combinations

Inhibition of the renin-angiotensin system has been a highly successful therapeutic approach for the prevention of hypertension-related end organ damage. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers lower blood pressure and reduce morbidity and mortality in patients with cardiovascular and kidney disease. However, progression to end-stage disease remains common in these patient populations. A compensatory increase in plasma renin activity occurs with the use of either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, thus causing increased levels of angiotensin II, which may limit the therapeutic effectiveness of these agents. The direct renin inhibitor, aliskiren, suppresses the renin-angiotensin system by inhibiting its first and rate-limiting step. This early inhibition reduces the production of all downstream components of the system. In this review, recent clinically relevant advances in the understanding of renin-angiotensin system biology are explored as a rationale for combining aliskiren with other blockers of the renin-angiotensin system. These combinations more fully inhibit the renin-angiotensin system, with the goal of providing additional therapeutic benefits in diseases associated with chronic activation of the renin-angiotensin system.     

Estimating renin participation in hypertension: superiority of converting enzyme inhibitor over saralasin.

This study was designed to examine more closely the differences in blood pressure responses in hypertensive patients to two agents which block the renin-angiotensin system. Accordingly, 39 seated patients received under the same conditions both saralasin, an octapeptide competitive antagonist of angiotensin II, and the nonapeptide converting enzyme inhibitor, SQ20881, which blocks the generation of angiotensin II from angiotensin I. A second component of the study involved administration of these agents in 10 addtional studies in anephric subjects. Although both agents produced maximal responses in blood pressure that correlated well with each other (p less than 0.001) and with the pretreatment plasma renin levels (p less than 0.001), analysis of the results by renin subgroups revealed significant differences. Thus, both drugs lowered the diastolic pressures of patients with high renin levels, but but converting enzyme inhibitor produced changes of greater amplitude (p less than 0.05). In contrast, saralasin was consistently pressor in both patients with low renin levels and anephric patients in whom converting enzyme blockade preduced no significant changes in blood pressure. Another impressive disparity in the responses to the two agents occurred in the group with normal renin levels in whom saralasin produced either neutral or pressor responses (mean change was +2.0 +/- 1.5 standard error of the mean (SEM) per cent control diastolic pressure) whereas the converting enzyme inhibitor consistently induced depressor responses (mean change was -10.2 +/- 1.2 per cent, p less than 0.001). Altogether, the results suggest that converting enzyme inhibitor tests for angiotensin II-dependent blood pressure with more sensitivity than the partial agonist saralasin. Moreover, it is unlikely that the differences between the responses to the two agents were due to bradykinin accumulation, since depressor responses to converting enzyme inhibitor were not observed in the patients with low renin levels and the anephric patients.     

Regulation of aldosterone secretion by the renin-angiotensin system during sodium restriction in rats.

The role of angiotensin II as mediator of the aldosterone response to short periods of sodium restriction was studied in rats by administration of a converting enzyme inhibitor to block formation of the octapeptide throughout the duration of decreased sodium intake. In control animals, short-term sodium restriction caused increased levels of adrenal receptors for angiotensin II, with enhancement of early and late steps in aldosterone biosynthesis and elevation of plasma aldosterone concentration. Each of these changes induced by sodium deficiency was abolished during blockade of angiotensin II formation by continuous infusion of the converting enzyme inhibitor, SQ 14,225. The absolute dependence of adrenal glomerulosa cell responses on angiotensin II formation indicates that the renin-angiotensin system is the primary regulator of aldosterone secretion during physiological fluctuations in sodium intake.     

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Combination: Theory and Practice

Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are commonly used to treat hypertension and/or a range of progressive end-organ diseases. The success of each of these drug classes in disease-state management is without dispute, and has led to speculation that given together the observed response would improve upon that observed with a member of each drug class individually given. Few studies are available, however, which carefully address the effect(s) of the combination of an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker. Review of available studies would seem not to strongly support combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker as preferred therapy in the broad base of general hypertensive patients with or without end-organ disease. Additional clarifying studies are needed to determine if specific patient subsets exist that might benefit from such combination therapy.     

Angiotensin converting enzyme inhibitors in renal diseases

Chronic diffuse renal diseases, involvement of the kidney in systemic and metabolic disorders are characterized by steady progression of renal pathology with loss of functional nephrons, lowering of renal functions and gradual development of chronic and eventually terminal renal failure. Basic mechanism of progression of chronic renal failure is activation of local renin-angiotensin system with intrarenal formation of a potent vasoconstrictor and growth factor - angiotensin II. Potentially nephroprotective effect can be achieved by pharmacological block of angiotensin II by angiotensin converting enzyme inhibitors. It has been shown in some prospective studies (AIPRI, REIN, ACEi-1 Trial, MICRO-HOPE) that the use of these drugs is associated with slowing of progression of renal pathology irrespective of its etiology and delayed development of terminal renal failure in patients with preexisting chronic renal insufficiency. Data available indicate that angiotensin converting enzyme inhibitors should be first line agents in the treatment of patients with chronic diffuse renal diseases of various etiology and diabetic nephropathy.     

Vascular angiotensin receptors and their role in blood pressure control.

The renin angiotensin system has an important role in regulating arterial blood pressure in homeostasis and disease. A reciprocal relationship exists between sodium balance and the circulating levels of renin and angiotensin II. The vascular responsiveness to angiotensin II, the major vasconstrictor component of the renal pressor system, can be impaired by numerous factors including sodium depletion or a reduction in effective plasma volume. In situations in which the renin-angiotensin system is activated, a negative relationship between the angiotensin II pressor response and the circulating angiotensin II level is observed. This effect seems to involve a change of the angiotensin II receptor interaction in the vascular smooth muscle. The prevention of angiotensin II generation by the inhibition of converting enzyme causes an immediate increase in the pressor response to angiotensin; after bilateral nephrectomy, it takes much longer to develop. In addition, the depressor response to angiotensin antagnoists and converting enzyme inhibitor is preserved after bilateral nephrectomy for much longer periods than can be accounted for by the disappearance of circulating renin. These observations support the view that the decrease in vascular response to angiotensin II during sodium deprivation or when body fluid volumes are reduced is the result of prior occupancy of the receptor sites by endogenous hormone generated both in the plasma and locally within blood vessel walls. Therefore, a change in the number or affinity of receptors consequent to a change in sodium balance or as a modulating function of the renin-angiotensin system need not be postulated to explain changes in angiotensin vascular responsiveness.     

Differential renal function during angiotensin converting enzyme inhibition in renovascular hypertension

Renal function was measured sequentially in 32 patients with proven renovascular hypertension who were treated with the oral angiotensin converting enzyme inhibitor captopril. Renal function was assessed by serial measurement of serum creatinine. Six patients showed acute rises in serum creatinine concentration compatible with acute renal failure. Acute renal failure was confined to those patients with stenosis to a solitary kidney (transplant or native, occurring in 3 of 8 patients) or bilateral renal artery stenosis (occurring in 3 of 13 patients). No rise in serum creatinine concentration was observed in 11 patients with unilateral renal artery stenosis during long-term angiotensin converting enzyme inhibitor therapy. Acute renal failure during angiotensin converting enzyme inhibitor therapy was not related to the degree of blood pressure fall or the plasma angiotensin II level. Eleven patients with renovascular hypertension were followed prospectively with estimation of renal function by 99mTc-diethylenetriaminepentaacetic acid (DTPA) clearance (determined by computer analysis of scintillation camera renography). In six patients with unilateral renal artery stenosis, total 99mTc-DTPA clearance and serum creatinine level remained constant following angiotensin converting enzyme inhibitor therapy, while in five patients with bilateral renal artery stenosis 99mTc-DTPA clearance fell from 40 +/- 9 to 27 +/- 5 ml/min (p less than 0.05). Split renal function studies revealed that 99mTc-DTPA clearance fell in most kidneys with stenosed arteries during angiotensin converting enzyme inhibition, including the stenosed kidney from patients with unilateral renal artery stenosis (16 stenosed kidneys studied; change in Tc-DTPA clearance, -7.5 +/- 2.7 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysis

OBJECTIVES: To compare the effects of angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors on the risk of myocardial infarction, stroke, cardiovascular mortality and total mortality. METHODS: We conducted a meta-analysis of randomized comparative trials between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors. Inclusion criteria were publication in peer-reviewed journals indexed in Medline, randomized comparison of angiotensin II receptor blockers vs. angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers + angiotensin-converting enzyme inhibitors vs. angiotensin-converting enzyme inhibitors, report of major complications including myocardial infarction, stroke, cardiovascular mortality or all-cause mortality; average follow-up of at least 1 year in at least 200 patients. RESULTS: Six trials fulfilled the inclusion criteria, for a total of 49 924 patients. In the pooled estimate, there were no significant differences between angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors on the risk of myocardial infarction (odds ratio 1.01; 95% confidence interval 0.95-1.07; P = 0.75), cardiovascular mortality (odds ratio 1.03; 95% confidence interval 0.98-1.08; P = 0.23) and total mortality (odds ratio 1.03; 95% confidence interval 0.97-1.10; P = 0.20). This was the case also when the analysis involved only the comparison between angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Overall, the risk of stroke was slightly lower with angiotensin II receptor blockers than angiotensin-converting enzyme inhibitors (odds ratio 0.92; 95% confidence interval 0.85-0.99; P = 0.037), the direct angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers comparison showing a nonsignificant trend in a similar direction. Statistical heterogeneity among trials was not significant, with a low to null inconsistency statistic, for stroke (P = 0.67), myocardial infarction (P = 0.86), cardiovascular mortality (P = 0.14) and total mortality (P = 0.12). CONCLUSION: This overview suggests that angiotensin II receptor blockers are as effective as angiotensin-converting enzyme inhibitors on the risk of myocardial infarction, cardiovascular mortality and total mortality. Angiotensin II receptor blockers may be slightly more protective than angiotensin-converting enzyme inhibitors on the risk of stroke.     

Update on therapy for heart failure

The success of angiotensin-converting enzyme (ACE) inhibitors in reducing morbidity and mortality in patients with heart failure has led to investigations of other inhibitors of the renin-angiotensin-aldosterone system. Although ACE inhibitors remain first-line drugs in the treatment of heart failure and left ventricular dysfunction, clinical evidence suggests that a newer class of agents--angiotensin II receptor blockers--may provide additional benefit by blocking the adverse effects of angiotensin II more completely. An improved adverse-effect profile also makes angiotensin II receptor blockers appropriate in patients who cannot tolerate ACE inhibitors. Clinical trials have demonstrated the beneficial effects of angiotensin II receptor blockers on the combined endpoints of morbidity and mortality in patients with heart failure. Aldosterone antagonism with spironolactone has additive benefits in patients receiving an ACE inhibitor. The most recent treatment guidelines for heart failure recommend the use of angiotensin II receptor blockers and spironolactone in selected patients.     

Acute renal insufficiency after flurbiprofen treatment in a patient treated with angiotensin converting enzyme inhibitor

We report a case of acute renal insufficiency in a 77 year-old patient who took flurbiprofen as antiplatelet therapy. This is an important observation because it illustrates the potential risk of acute renal insufficiency, when using flurbiprofen before invasive medical examination or surgery in patients receiving long-term treatment with angiotensin converting enzyme inhibitors or angiotensin II inhibitors. This risk is probably underestimated in usual clinical practice.     

The opposing effects of chronic angiotensin-converting enzyme blockade by captopril on the responses to exogenous angiotensin II and vasopressin vs. norepinephrine in rats

To study the influence of acute and chronic angiotensin-converting enzyme blockade on the pressor response to exogenous angiotensin II, vasopressin and norepinephrine, we gave normal female Wistar rats 100 mg of captopril or 1 ml of 5% glucose twice daily by gavage for 2 weeks. On the 15th day, rats were anesthetized with pentobarbital, and dose-response curves to angiotensin II, lysine-vasopressin, and norepinephrine were obtained before and after intraperitoneal injection of 100 mg/kg of captopril or 1 ml of 5% glucose. Acute as well as chronic converting enzyme blockade enhanced the pressor response to exogenous angiotensin II. Similarly, sensitivity to exogenous vasopressin was increased by both acute and chronic converting enzyme inhibition. In contrast, chronic converting enzyme blockade significantly blunted the response to exogenous norepinephrine, whereas acute blockade tended to accentuate its pressor effect. These results suggest that chronic angiotensin-converting enzyme blockade may partly inhibit sympathetic activity which, in turn, might contribute to the antihypertensive efficacy of this therapeutic approach. These results also point to an important physiological interaction between the two pressor hormones, angiotensin II and vasopressin.     

Estimation of angiotensin II receptor activity in chronic congestive heart failure

The renin-angiotensin system has been shown to participate in the pathophysiology of chronic heart failure in many patients. However, the immediate assessment of this contribution in individual patients may sometimes be difficult. As a pharmacologic estimate of angiotensin II receptor activity, we infused the angiotensin II analogue, saralasin, in 20 patients with severe chronic congestive heart failure (CHF). The infusion resulted in blood pressure responses ranging from an agonist pressor response (increased systemic resistance) in patients with low intrinsic renin-angiotensin system activity, to an antagonist depressor response (decreased systemic resistance) in patients with marked activation of the renin-angiotensin system. The ability of the saralasin response to pharmacologically estimate angiotensin II receptor activity in CHF was further revealed by two physiologic maneuvers that decrease endogenous circulating angiotensin II and angiotensin II receptor occupancy. Both converting enzyme inhibition with captopril and sodium repletion, factors known to decrease endogenous angiotensin II activity, provoked agonist responses to saralasin infusion. Furthermore, saralasin was able to reverse the orthostatic hypotension precipitated by converting enzyme inhibition of angiotensin-dependent vascular tone. In summary, saralasin provided a means to estimate angiotensin receptor activity and may therefore serve as a probe of angiotensin-mediated vasoconstriction in the pathophysiology of chronic CHF.     

Development and design of specific inhibitors of angiotensin-converting enzyme

Captopril is a remarkably effective new antihypertensive drug designed and developed as a potent and specific inhibitor of angiotensin-converting enzyme, a zinc metallopeptidase that participates in the synthesis of a hypertensive peptide, angiotensin II, and in the degradation of a hypotensive peptide, bradykinin. Earlier studies with a snake venom peptide (teprotride or SQ 20881) that could be administered only by injection demonstrated that specific inhibitors of angiotensin-converting enzyme could be highly effective as antihypertensive drugs, and helped to clarify the specificity and mechanism of action of the enzyme. A hypothetical model of the active center of angiotensin-converting enzyme based on its presumed analogy to the well characterized zinc metallopeptidase carboxypeptidase A was used to guide logical sequential improvements of a weakly active prototype inhibitor that led eventually to the highly optimized structure of captopril. The hypothetical working model of the active site of angiotensin-converting enzyme used to develop captopril continues to provide a firm basis for development of new types of specific inhibitors of this biologically important enzyme.     

Angiotensin-converting enzyme inhibitors

J Clin Hypertens (Greenwich). 2011;13:667–675. ©2011 Wiley Periodicals, Inc.Key Points and Recommendations

• • In addition to hypertension, angiotensin‐converting enzyme inhibitors are indicated for treatment of patients at high risk for coronary artery disease, after myocardial infarction, with dilated cardiomypathy, or with chronic kidney disease.
• • The most familiar angiotensin‐converting enzyme subtype, angiotensin‐converting enzyme‐1 (kininase II), cleaves the vasoconstrictor octapeptide angiotensin II from its inactive decapeptide precursor, angiotensin I, while simultaneously inactivating the vasodilator bradykinin.
• • Biochemical pathways within and around the renin‐angiotensin system are highly species‐specific; there is little evidence that “angiotensin‐converting enzyme bypass pathways” have major clinical implications in humans.
• • Dietary sodium loading can diminish or abolish the antihypertensive effect of an angiotensin‐converting enzyme inhibitor, while salt restriction or concomitant diuretic therapy enhances it.
• • Dose‐response curves with angiotensin‐converting enzyme inhibitors are quite flat but their peak effects vary in different individuals.
• • Increased serum creatinine (decreased glomerular filtration rate) during acute or chronic angiotensin‐converting enzyme inhibition identifies individuals likely to experience long‐term renal protective benefits.
• • Angiotensin‐converting enzyme inhibitors are contraindicated in pregnancy due to fetal toxicity.
• • Use of angiotensin‐converting enzymes can be limited by idiosyncratic reactions (cough or angioedema), hyperkalemia (usually in cardiac or renal failure or with combined renin‐angiotensin blockade) or hypotension (usually with severe volume‐depletion or cardiac failure).

Agents that block angiotensin‐converting enzyme (ACE) and the formation of angiotensin II (Ang II) have become mainstays of cardiovascular and renal medicine. Peptide relatives of modern ACE inhibitors were first identified in extracts from Bothrops venom. Further pharmacologic development culminated in the synthesis in the 1970s of the first oral agent, captopril. Development of this breakthrough drug involved some of the most sophisticated physical chemistry of its time: crystallization and 3‐dimensional modeling of the active catalytic site of the ACE molecule, an accomplishment for which its developers received several prestigious awards. ¹ Other ACE inhibitors with more attractive pharmacodynamic effects have since been developed, and most ACE inhibitors, alone and in combination with diuretic or amlodipine, are now available generically. General understanding of the impact of renin‐angiotensin system (RAS) inhibition has been hampered by its biochemical, physiological, and phylogenetic complexity and by the sheer volume of information available. By early 2010, there were more than 24,400 citations under the MESH term “angiotensin‐converting enzyme inhibitors.” The intent of this review is to integrate relevant human basic science and outcome data in order to promote a sophisticated yet practical approach to clinical use of ACE inhibitors. In areas of controversy, original source documentation is cited whenever possible.     

Influence of ramipril diacid on the peripheral vascular effects of angiotensin I

Studies were performed to examine the effect on forearm blood flow of local brachial artery infusions of angiotensin I, angiotensin II and of the converting enzyme inhibitor ramipril diacid (the active metabolite of ramipril). Acute infusions of both angiotensins produced dose-dependent decreases in blood flow (measured by venous occlusion plethysmography). To produce equivalent effects the dose of angiotensin I was 2 to 4 times that of angiotensin II. After ramipril diacid the response to angiotensin II was unchanged, while the dose of angiotensin I required to produce an equipotent response was increased 20-fold. Ramipril diacid given alone produced a small, nonsignificant increase in forearm flow, although the response was significantly related to basal plasma renin. The study confirms the presence of converting enzyme activity within human resistance vessels, and suggests that inhibition of converting enzyme, at sites other than the pulmonary vascular bed, might contribute to the hypotensive action of converting enzyme inhibitors.     

AT(1)-receptor blockade and the kidney: importance of non-ACE pathways in health and disease

Large-scale trials with angiotensin converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT(1))-receptor blockers have clearly shown that blockade of the renin-angiotensin system reduces the deterioration in renal function associated with diabetes. AT(1)-receptor blockers represent a more rational approach to blockade of this system than ACE inhibitors, due to the presence of non-ACE pathways of angiotensin II formation. Studies in healthy volunteers maintained on a low-salt diet indicate that such pathways account for approximately 30-40% of total angiotensin II formation, and this figure increases to 60-70% in individuals maintained on a high-salt diet (resembling the situation in most human populations). Activation of the renin-angiotensin system is increased in diabetic patients, and comparison of the renal vascular responses to captopril and candesartan shows a strong correlation between the effects of ACE inhibition and AT(1)-receptor blockade, indicating that the deleterious effects of renin-angiotensin system activation in diabetes are mediated largely through angiotensin II. The presence of multiple risk factors, such as genetic predisposition, hyperglycaemia, obesity and tissue damage, places diabetic patients at high risk of disease related to activation of the renin-angiotensin system. Effective and early blockade of this system is therefore an important aspect of management.