Although the angiotensin receptor antagonist (ARB) shares the angiotensin-II-blocking activity with the angiotensin-converting enzyme inhibitor (ACE-I), pharmacological mechanisms of action of these agents differ. We evaluated the temporal profiles of action of ACE-I and ARB on urinary protein excretion and nitrate/nitrate (NOx) excretion in hypertensive (140 and/or 90 mmHg) patients with chronic renal disease (serum creatinine<265 (range, 44–265) μmol/l or creatinine clearance>30 (range, 30–121) ml/min). Patients with mild (<1 g/day; range, 0.4–1.0) and moderate proteinuria (>1 g/day; range, 1.1–6.9) were randomly assigned to ACE-I- and ARB-treated groups, and were treated with ACE-I (trandolapril or perindopril) or ARB(losartan or candesartan) for 48 weeks. In all groups, treatment with ACE-I or ARB decreased blood pressure to the same level, but had no effect on creatinine clearance. In patients with mild proteinuria, neither ACE-I nor ARB altered urinary protein excretion. In patients with moderate proteinuria, ACE-I caused 44±6% reduction in proteinuria (from 2.7±0.5 to 1.5±0.4 g/day, n=14) at 12 weeks, and this beneficial effect persisted throughout the protocol (48 weeks, 1.2±0.2 g/day). In contrast, ARB did not produce a significant decrease in proteinuria at 12 weeks (23±8%, n=13), but a 41±6% reduction in proteinuria was observed at 48 weeks. Similarly, although early (12 weeks) increases in urinary NOx excretion were observed with ACE-I (from 257±70 to 1111±160 μmol/day) and ARB (from 280±82 to 723±86 μmol/day), the ARB-induced increase in NOx excretion was smaller than that by ACE-I (P<0.05). In conclusion, although both ACE-I and ARB reduce blood pressure similarly, the effect of these agents on proteinuria differs in chronic renal disease with moderate proteinuria. Relatively early onset of the proteinuria-reducing effect was observed with ACE-I, which paralleled the increase in urinary NOx excretion. Conversely, ARB decreased proteinuria and increased urinary NOx excretion gradually. These time course-dependent changes in proteinuria and urinary NOx may reflect the pharmacological property of ACE-I and ARB, with regard to the action on bradykinin.
Several lines of experimental studies have demonstrated that the renin–angiotensin (ANG) system constitutes a pivotal determinant of renal injury, and the blockade of the renin–ANG system has been shown to retard the progression of renal disease.1,2 Recently, two types of pharmacological tools, ie, ANG-converting enzyme inhibitors (ACE-I) and ANG receptor antagonists (ARB), are in clinical use, and several large-scale clinical trials have demonstrated the beneficial effect of these agents on renal disease.3,4,5,6 As expected from the haemodynamic action on blood pressure and renal arterioles, both agents reduce glomerular capillary pressure, which subsequently would exert a favourable effect on the progression of renal disease, in concert with the inhibitory action on the direct glomerular injury induced by ANG II. It is of note that these agents possess different action on the kinin metabolism. Thus, ACE-I-induced kinin accumulation by simultaneous inhibition of kininase II would be anticipated to affect several aspects of renal function. The augmented action of intrarenal bradykinin would modify the renal vasodilator action,7,8 as well as systemic blood pressure,9 probably through the release of nitric oxide (NO). In contrast to the earlier expectation that ARB produced less bradykinin, Siragy et al.10 demonstrated that ARB stimulated bradykinin and NO production, which are most consistently mediated by ANG type 2 receptor (AT2) stimulation possibly through the elevated ANG II level. Thus, although the pharmacological actions of ACE-I and ARB markedly differ, it remains undetermined whether renal actions of these agents vary in the long-term treatment of hypertension.
A growing body of evidence has accrued that ANG II is generated through multiple pathways.11 Traditionally, the conversion of ANG I to ANG II is mediated predominantly by angiotensin-converting enzyme (ACE), and this formulation is supported by a well-established observation that ACE-I potently reduces blood pressure in a variety of disease in which renin–ANG is stimulated. In contrast, several studies have been reported indicating an increased number of cells containing chymase-like enzyme that is capable of producing ANG-II in various renal diseases including immunoglobulin A (IgA) nephropathy12 and renal artery stenosis.13 Thus, in the setting of increased activity of the non-ACE-mediated ANG II formation, ARB theoretically could be more effective than ACE-I in blocking the ANG II action. It has not been determined, therefore, whether ACE-I or ARB is more potent in retarding the development of renal disease.
In the present study, we evaluated the renal protective action of 48-week treatment with ACE-I and ARB in patients with nondiabetic chronic renal disease. Furthermore, whether the effect of these agents on urinary excretion of NO metabolites differs was examined.
A total of 52 outpatients with hypertension (>140 and/or 90 mmHg) and proteinuria (>0.3 g/24 h) who visited Ashikaga Red Cross Hospital during the period from 1998 to 1999 were enrolled in this study. These patients had been diagnosed as chronic renal disease (IgA nephropathy, n=8; membranous nephropathy, n=5; focal segmental glomerulosclerosis, n=1; and proliferative glomerulonephritis; n=38). Serum creatinine level <265 μmol/l or creatinine clearance >30 ml/min/1.72 m2 was confirmed before the entry into this protocol. Diabetic nephropathy, polycystic kidney disease, and chronic pyelonephritis were excluded from this study. The patients had been educated on dietary therapy including low protein (0.8 g/kg/day) and low sodium intake (7 g/day) at least 3 months before the enrolment of this study. The study was approved by the institutional ethical committe, and informed consent had been obtained from all patients.
At entry, the patients were randomly assigned to ACE-I- and ARB-treated groups. In the ACE-I-treated group, either perindopril (2 mg/day) or trandolapril (1 mg/day) was started, and the doses were titrated to achieve systemic blood pressure to <135/85 mmHg. In the ARB-treated group, 25 mg losartan or 4 mg candesartan cilexetil were initially prescribed, and the doses were adjusted according to the level of the blood pressure or renal haemodynamics. In each group, the patients were further divided into two subgroups according to the level of proteinuria; patients with mild proteinuria<1.0 g/day were assigned to ACE-I-L and ARB-L groups, and those with moderate proteinuria >1.0 g/day were allocated to ACE-I-H and ARB-H groups.
Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured twice after the 5-min sedentary position on every visit. A 24 h creatinine clearance was used for evaluation of renal function and was evaluated during control and treatment periods (12, 24, and 48 weeks). Laboratory examination, including blood chemistry (serum potassium and creatinine) and daily urinary excretion of protein, was assessed at 12,24, and 48 weeks. Urinary protein was measured by the central laboratory (Laboratory Division, Ashikaga Red Cross Hospital), with the use of a standard method (pyrogallol red molybdate method; Micro TP-Test, Walko, Tokyo), and daily urinary protein excretion was determined by collecting 24-h urine.
Daily excretions of urinary metabolites of NO (ie, nitrate and nitrite) were assessed with the method of Griess reaction,8,14 and the sum of these values (NOx) was estimated as a marker of urinary excretion of NO. The intra-assay coefficient of variation for NOx was <6%.
Results are expressed as mean±s.e.m. Statistical analysis was performed with two-way analysis of variance with repeated measures, followed by Fisher's post hoc test. P values <0.05 were considered statistically significant.
Effects of ACE-I and ARB on systemic and renal function
The baseline profiles in each group are shown in Table 1. There was no difference in age, SBP, DBP, serum creatinine, creatinine clearance, or serum potassium among these groups. Urinary protein excretion did not differ between ACE-I-L and ABR-Lgroups, or ACE-I-H and ARB-H groups.
Figure 1 illustrates the changes in SBP and DBP in patients with mild (left) and moderate proteinuria (right). In the ACE-I-L group (n=13), SBP and DBP decreased at 12 weeks (from 148±3/86±5 to 135±3/76±4 mmHg, P<0.05), and remained decreased at 24 weeks (132±4/80±3 mmHg, P<0.05) and 48 weeks (131±4/74±4 mmHg, P<0.05). In the ARB-L group (n=13), similar reductions in SBP and DBP were observed at 12 weeks (from 154±4/86±3 to 137±3/71±2 mmHg,P<0.05), and these reductions persisted throughout the protocol.
In patients with moderate proteinuria, ACE-I markedly decreased SBP (from 152±4 to 134±4 mmHg, P<0.01, n=14) and DBP (from 90±3 to 78±3 mmHg, P<0.01) at weeks (Figure 1, right). SBP was further decreased at 24 weeks (120±3 mmHg, P<0.01) and at 48 weeks (124±3 mmHg, P<0.01). Baseline blood pressures in the ARB-H group (150±3/89±3 mmHg, n=12) were nearly identical with those seen in the ACE-I-treated group. A 12-week treatment with ARB also caused significant reductions in SBP (137±4 mmHg, P<0.05) and DBP (79±3 mmHg, P<0.05), and these reductions were sustained throughout the study. There was no difference in blood pressure or changes in blood pressure between these treatment groups at any periods.
In the groups with mild proteinuria, neither ACE-I nor ARB had any effect on creatinine clearance throughout the study protocol (Figure 2). Similarly, these agents did not alter creatinine clearance in patients with moderate proteinuria. Serum potassium levels were unaltered throughout the protocol in any of the groups (data not shown).
The effect of ACE-I and ARB on urinary protein excretion was summarised in Figure 3. In mild proteinuric groups (Figure 3, left), daily urinary protein excretion did not alter significantly in either ACE-I- or ARB-treated patients. In groups with moderate proteinuria (right), however, ACE-I reduced proteinuria by 44±6% (from 2.7±0.5 to 1.5±0.4 g/day, P<0.05, n=14) at 12 weeks, and the reduction in proteinuria attained 54±7% at 48 weeks (1.2±0.2 g/day). In contrast, the administration of ARB caused a 23±8% decrement in proteinuria at 12 weeks (P<0.05 vs ACE-I-H), which did not attain statistical significance (from 2.7±0.4 to 2.0±0.4 g/day, P>0.2, n=12); a significant decrease was observed at 48 weeks (to 1.6±0.3 g/day, P<0.05), that is, 41±6% decrease in proteinuria, a value not different from that in ACE-I-H groups (P>0.5).
Link between NO and urinary protein excretion in patients with moderate proteinuria
We further examined the effect of ACE-I and ARB on urinary NOx excretion in patients with moderate proteinuria (Figure 4). In the ACE-I-H group, urinary NOx excretion was markedly increased at 12 weeks (from 257±70 to 1111±160 μmol/day, P<0.01, n=13), and this increase persisted throughout the study. In the ARB-H group, the increase in urinary NOx excretion was also observed at 12 weeks (from 280±82 to 723±86 μmol/day, P<0.01, n=12). Of note is a finding that the level of urinary NOx excretion attained with ARB was significantly lower than that with ACE-I (P<0.05), and 24 weeks were required to obtain the same level of urinary NOx excretion (1035±266 μmol/day).
To elucidate the possible link between nitric oxide and the proteinuria-reducing effect of the ANG blockade observed at 12 weeks, the changes in proteinuria were plotted as a function of urinary NOx excretion in Figure 5. There was no relation between the changes in proteinuria and the changes in NOx excretion in either ACE-I- or ARB-treated groups. When the results obtained in these groups were combined, however, a significant, albeit weak, inverse correlation was noted between the changes in proteinuria and those in urinary NOx excretion (r=−0.35, P<0.05).
Since the recognition of ACE-I as a renal protective agent,1,2,3,4 the inhibition of ANG II activity has been anticipated to serve to prevent renal injury. Indeed, a couple of recent large-scale trials also demonstrate that ARB exerts salutary action in diabetic nephropathy.5,6 Although these two classes of agents act mainly through the inhibition of ANG II activity, it is well known that there exists an obvious difference in the pharmacological property with regard to the bradykinin metabolism and the subsequent NO activity between these agents. This formulation, however, is reorganised by recent studies demonstrating that ARB, which selectively blocks AT1 receptors, also enhances NO activity in experimental animals,10,15 probably through AT2 receptor activation [Carey et al,16 see below]. Thus, it remains undetermined whether ACE-I or ARB is more potent in protecting the development of renal injury in human renal disease.
In the present study, we have found that patients with mild proteinuria (<1 g/day) manifest modest or no changes in urinary protein excretion, although nearly the same reductions in blood pressure are observed as those in patients with moderate proteinuria (proteinuria >1 g/day). In contrast, in patients with moderate proteinuria, both ACE-I and ARB not only reduce blood pressure, but also decrease proteinuria. These observations are consistent with previous reports by Maschio et al,4 demonstrating relatively preferential renal protection in patients with massive urinary protein excretion. Furthermore, the time course of the decreases in proteinuria differs in ACE-I and ARB in patients with moderate proteinuria; relatively earlier (ie, at 12 weeks) reductions in proteinuria were observed with ACE-Ithan those with ARB (Figure 3). In contrast, all of these agents reduced proteinuria to nearly the same degree in the long-term treatment. Since the changes in blood pressure were identical in these two groups, the divergent temporal profiles of proteinuria are most likely attributable to the renal action per se of these agents.
Although the antiproteinuric action of ACE-I and ARB involves multiple mechanisms, early decreases in proteinuria observed in patients with moderate proteinuria may indicate a differing action of these agents. Thus, in the present study, we have demonstrated that ACE-I causes greater increases in urinary NOx excretion than ARB in the early period (at 12 weeks) of the treatment (Figure 4). Furthermore, at this point the changes in urinary NOx excretion paralleled inversely those of proteinuria (Figure 5). Although the origin of urinary NOx remains a matter of controversy, urinary NOx reflects at least in part the renal production.17,18 In concert, these observations are consistent with the formulation that renal NO contributes importantly to the reduction in proteinuria, and may indicate renal protective action of NO in this circumstance. In addition to the beneficial effect of NO in renal disease, several lines of studies by our laboratory8 and others7 demonstrate implication of the haemodynamic contribution of these agents to renal protection. Thus, although both ACE-I and ARB dilate efferent arterioles, ACE-I is more potent in dilating the efferent arteriole of superficial nephrons when administered acutely in experimental animals.7,8 Moreover, ACE-I (cilazaprilat) enhanced bradykinin and NO activity, which contributed in part to the efferent arteriolar dilation by this agent, whereas E4177, an ARB, had no effect on this activity.8 To the extent that efferent arteriolar dilation favours renal protection, greater dilation of this arteriole could be anticipated to abate glomerular haemodynamic load, and may thus ameliorate proteinuria in a short-term period.
It is of note that the present study suggests that chronic treatment with ARB is capable of augmenting renal NOx excretion (Figure 4). Although the mechanism for the ARB-induced increase in urinary NOx excretion is not clearly determined, it has recently been demonstrated that the action of ARB is mediated in part by bradykinin in systemic vasculature,19,20 cardiac muscles,15 and renal parenchyma.10 Since ARB selectively antagonises AT1 receptors leaving AT2 receptors relatively unblocked, and the chronic ARB administration is expected to elevate plasma ANG II levels,21 it is plausible that bradykinin-induced NO plays a substantial role in mediating renal protective action during treatment with ARB. In concert, the differing actions on glomerular haemodynamics and NO activity may constitute a determinant of proteinuria during the treatment with these agents.
Although the present study demonstrates that both ACE-I and ARB enhance urinary NOx excretion with parallel decreases in proteinuria, the temporal profiles of these parameters differ between ACE-I and ARB. Thus, whereas the long-term (24 and 48 weeks) effect of ARB is comparable to that of ACE-I, ARB exerts a less pronounced increase in urinary NOx excretion and causes only a modest reduction in proteinuria at 12 weeks in patients with moderate proteinuria (Figure 3 and Figure 4). These divergent renal responses to ACE-I and ARB may be attributed to differing mechanisms for renal NO production by these agents. For example, sustained stimulation of AT2 receptors by the ARB-induced ANG II may upregulate the bradykinin production,10,15,19,20 while ACE-I accumulates bradykinin by directly inhibiting its degradating enzyme. Furthermore, in renal disease, where chymase-containing mast cells prevail,22 the non-ACE-dependent ANG II formation may be enhanced within the kidney, but not in systemic vascular beds; in contrast, ARB could disrupt the ANG II activity. Alternatively, the elevated urinary NOx may simply reflect a consequence of renal protection in the long-term treatment.23 Obviously, further studies are required to clarify the mechanism of differing time courses of renal protection by ACE-I and ARB.
In conclusion, the present study shows that both ACE-I and ARB decrease blood pressure and proteinuria in patients with a moderate degree of urinary protein excretion. ACE-I however reduces proteinuria more rapidly than ARB, with a concomitant increase in urinary excretion of NO metabolites. These observations suggest different time profiles of the renal protective action of ACE-I and ARB, although the establishment of this difference requires more extensive investigations. Finally, such distinct time courses of the reduction in proteinuria and the enhancement of NOx excretion imply distinct mechanisms for the renal protective action of these agents.
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