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*Institute of Medical Sciences and Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan; Service de Nephrologie, Universite Catholique de Louvain, Brussels, Belgium; and Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan.
Correspondence to: Dr. Toshio Miyata, Molecular and Cellular Nephrology, Institute of Medical Sciences and Department of Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan. Phone: +81-463-93-1936; Fax: +81-463-93-1938;
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Abstract |
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-carboxymethyllysine (CML), during incubation of nonuremic diabetic, nondiabetic uremic, or diabetic uremic plasma or of BSA fortified with arabinose. This effect is shared by all tested AIIR antagonists and ACE inhibitors. On an equimolar basis, they are more efficient than aminoguanidine or pyridoxamine. Unlike the latter two compounds, they do not trap reactive carbonyl precursors for AGE, but impact on the production of reactive carbonyl precursors for AGE by chelating transition metals and inhibiting various oxidative steps, including carbon-centered and hydroxyl radicals, at both the pre- and post-Amadori steps. Their effect is paralleled by a lowered production of reactive carbonyl precursors. Finally, they do not bind pyridoxal, unlike aminoguanidine. Altogether, this study demonstrates for the first time that widely used hypotensive agents, AIIR antagonists and ACE inhibitors, significantly attenuate AGE production. This study provides a new framework for the assessment of families of AGE-lowering compounds according to their mechanisms of action. E-mail: t-miyata@is.icc.u-tokai.ac.jp |
Introduction |
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Aminoguanidine, the first AGE inhibitor discovered in 1986 (14), and (±)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195) (15) are both hydrazine-derivatives. They inhibit in vitro the formation of AGE, pentosidine (16), and N-carboxymethyllysine (CML) (17) from a variety of individual precursors, such as ribose, glucose, and ascorbate, as well as that of advanced lipoxidation end products (ALE), malondialdehyde-lysine and 4-hydroxynonenal-protein adduct (18), from arachidonate (19). They also inhibit pentosidine generation in diabetic and uremic plasma incubated for 4 wk (20).
As expected, both compounds correct several biologic effects that are associated with AGE formation. In murine thymocyte and fibroblasts, they inhibit the phosphorylation of tyrosine residues of a number of intracellular proteins induced by cell surface Schiff base formation (21). Given to diabetic animal models, such as Otsuka-Long-Evans-Tokushima-Fatty (OLETF) or streptozotocin-treated rats, they reduce urinary albumin excretion and improve glomerular morphology (15,22). Oral administration of OPB-9195 to rats after balloon injury of their carotid arteries effectively reduces neointima proliferation in arterial walls (23). Unfortunately, clinical benefits of both compounds given to diabetic patients have been hampered by side effects related to their characteristic trapping of pyridoxal with an attendant vitamin B6 deficiency (24).
We therefore searched for other drugs with tolerance that had been demonstrated in clinical conditions and that might exhibit AGE-inhibiting characteristics. Highly sensitive and specific chemical methodologies for AGE determination were utilized rather than more disputable physicochemical (fluorescence and cross-linkage on electrophoresis) and immunologic assays. We discovered that angiotensin II type 1 receptor (AIIR) antagonists as well as angiotensin-converting enzyme (ACE) inhibitors, unlike a calcium blocker, lowered pentosidine as well as CML formation. We further elucidated the mechanism of their action and propose a comprehensive approach of the various mechanisms implicated in the AGE-lowering effects of presently available drugs.
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Materials and Methods |
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Two types of incubation media containing AGE precursors were used. First, essentially fatty acid-free grade bovine serum albumin (BSA; Sigma, St. Louis, MO) (30 mg) was incubated in the dark with 10 mM arabinose in 1.0 ml of 0.1 M sodium phosphate buffer (pH 7.4). Second, pooled plasma (900 µl) was incubated under air at 37°C.
The tested compounds included 6 AIIR antagonists (Olmesartan [25], candesartan, irbesartan, losartan, (telmisartan, valsartan) and four ACE inhibitors temocaprilat, enalaprilat, captopril, perindprilat) provided by Pharmacology and Molecular Biology Research Laboratories, Sankyo Pharmaceutical (Tokyo, Japan), nifedipine (Sigma), aminoguanidine (Tokyo Chemical Industry, Tokyo, Japan), pyridoxamine (Sigma), and OPB-9195 (Fujii Memorial Research Institute, Otsuka Pharmaceutical, Ohtsu, Japan). They were dissolved in 100 µl of DMSO to obtain a stock solution of 50 mM and further diluted to required concentrations. DMSO at the final concentration of 10% does not influence the oxidation process.
One milliliter of the medium was incubated under air at 37°C for 7 d in the presence of the tested compounds (final concentrations: 0.8, 2.0, and 5.0 mM). In an additional set of experiments, lower drug concentrations were used (0.01, 0.05, 0.26, 1.28, 6.4, 32, 160, and 800 µM). At the end of the incubation, pentosidine and CML content were measured as described below.
Pentosidine Measurement by HPLC
For quantitation of pentosidine, each sample of the incubation mixtures (50 µl) was mixed with equal volume of 10% TCA and centrifuged at 5000 x g for 5 min. The supernatant was discarded, and the pellet was washed with 300 µl of 5% TCA. The pellet was then dried under vacuum, lyophilized, and hydrolyzed by 100 µl of 6 N HCl for 16 h at 110°C under nitrogen. The acid hydrolysates were subsequently neutralized with 100 µl of 5 N NaOH and 200 µl of 0.5 M phosphate buffer (pH 7.4), filtered through a 0.5-µm-pore filter, and diluted with phosphate-buffered saline (PBS).
The pentosidine content was analyzed on a reverse-phase HPLC as described previously (26). In brief, a 50-µl aliquot of the acid hydrolysate diluted by PBS was injected into an HPLC system and separated on a C18 reverse-phase column (Waters, Tokyo, Japan). The effluent was monitored with a fluorescence detector (RF-10A Shimadzu, Kyoto, Japan) at an excitation-emission wavelength of 335/385 nm. Synthetic pentosidine was used as a standard. The detection limit was 0.1 picomole of pentosidine per milligram of proteins.
CML Measurement by GC/MS
For quantitation of CML, samples (100 µl) were diluted with 100 µl of 0.2 M sodium borate (pH 9.1) before the addition of 20 µl of 1 M NaBH4 in 0.1 N NaOH. Reduction was performed for 4 h at room temperature. Protein was then precipitated by addition of an equal volume of 20% TCA and pelleted by centrifugation at 2000 x g for 5 min. The supernatant was discarded, and the pellet was washed with 500 µl of 10% TCA. After the addition of heavy-labeled internal standards (d4-CML), the sample was hydrolyzed in 0.3 ml of 6 N HCl at 110°C for 16 h. The hydrolysate was dried under a stream of nitrogen. CML content was measured as its N,O-trifluoroacetyl methyl esters by selected-ion monitoring gas chromatography/mass spectrometry (GC/MS) (27). The CML and d4-CML standards were gifts from Dr. John W. Baynes (University of South Carolina, Columbia, SC). Limit of detection was 1.0 picomole of CML per milligram of protein.
Inhibition of Dicarbonyl Formation by Olmesartan
Arabinose (10 mM) was incubated with various concentrations of olmesartan in 0.1 M phosphate buffer (pH 7.4) at 37°C for 1 wk. At the end of the incubation period, two major arabinose degradation products, glyoxal and methylglyoxal, for which pure standards are available, were identified and quantitated by HPLC (28). The standards were used for calibration purposes. One hundred microliters of sample was mixed with 100 µl of 20 µM 2,3-butanedione (internal standard), 80 µl of 2 M perchloric acid, and 40 µl of 1% o-phenylenediamine. After the mixture was incubated at 25°C for 3 h, quinoxaline derivatives were analyzed by reverse-phase HPLC, using a Waters Purecil C18 column (5 µm; 4.6 x 250 mm) and absorbance detection at 315 nm. The buffer gradient used for elution was 15% to 30% buffer B (85% to 70% buffer A) in 25 min: buffer A, 0.10% trifluoroacetic acid; buffer B, 80% acetonitrile containing 0.08% trifluoroacetic acid.
Dicarbonyl Entrapment
The tested compounds (0.8, 2, 5 mM) were incubated at 37°C in the presence of glyoxal (50 µM) in 0.1 M phosphate buffer (pH 7.4) for 20 h. At the end of the incubation period, the glyoxal content was determined after derivatization with o-phenylenediamine by the HPLC methods described above.
Free Radical Scavenging Activity
The scavenging activities of olmesartan, temocaprilat, aminoguanidine, and pyridoxamine for sugar-derived free radical and hydroxyl radical were evaluated according to a previously described method with some modifications (29). Sugar-derived free radical was generated by the autoxidation of ribose. In some experiments, the phosphate buffer (0.2 M, pH 7.4) was treated with Chelex-100 (Sigma) resin (wet weight, 7 g/L) to remove contaminating trace amount of metal ions (30). Ten millimolar ribose (Wako Pure Chemical, Osaka, Japan), 1 mM of N-t-butyl-
-phenylnitrone (PBN; Wako Pure Chemical), and various drug concentrations in phosphate buffer were incubated for 75 min at 100°C in tightly sealed tubes (total, 500 µl). The resulting solution was cooled to room temperature and sucked into a flat quartz cell. The sugar-derived radical adduct of PBN was measured on an electron-spin resonance (ESR) spectrometer (JES-FE2XG; JEOL, Tokyo, Japan) under the following conditions: microwave frequency, 9.42 GHz; magnetic field, 334.5 ± 5 mT; time constant, 0.3 s; microwave power, 8 mW; field modulation width, 0.2 mT; amplitude, 1.6 x 1000; sweep time, 2 min/10 mT. The amount of nitroxide radical was determined as the relative signal height to the third signal of external instrumental standard (Mn2+ in MgO).
Hydroxyl radical was generated according to the Fenton reaction. Hydroxyl radical was trapped by 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) to produce DMPO-OH spin adduct, which should decrease if any hydroxyl radical scavenger was present in the solution. Various concentrations of the tested drugs, 1 mM DMPO, 100 µM diethylenetriaminepentaacetic acid (DTPA), and 1 mM H2O2, were mixed in this order in 0.2 M phosphate buffer. The Fenton reaction was initiated by the addition of ferrous ammonium sulfate solution in distilled water (finally, 50 µM) at 25°C. The resulting DMPO-OH was measured with the ESR spectrometer. Every ESR measurement was started 45 s after the initiation of reaction.
Inhibitory Effect on Leukocyte-Derived Superoxide Production
The inhibitory effect of olmesartan on the superoxide production by polymorphonuclear leukocytes (PMN) was examined. PMN were isolated from heparinized venous blood of healthy volunteers by gradient centrifugation (400 x g for 30 min) using Mono-Poly resolving medium (Dainippon Pharmaceutical, Osaka, Japan) at room temperature. The final cell suspension contained more than 95% PMN and was >95% viable as examined by trypan blue exclusion test. The mixture of PML (1 x 105 cells/ml) with 2-methyl-6-phenyl-3,7-dihydroimidazo [1,2-a] pyrazine-3-one (1 µM) as a chemiluminescent probe for superoxide in Hanks’ balanced salt solution buffered with 40 mM HEPES (pH 7.4) was incubated at 37°C in the presence or absence of olmesartan (5 mM). Chemiluminescence of the solution was monitored by a C1230 photon counter with an R550 photomultiplier (Hamamatsu Photonics, Shizuoka, Japan). Superoxide production of PMN was stimulated with phorbol-12-myristate-13 acetate (1 µM). After the photon count peaked, recombinant human superoxide dismutase (300 U/ml; Nippon Kayaku, Tokyo, Japan) was added to extract net superoxide-based chemiluminescence.
Metal Chelating Activity
The chelating activity of the tested compounds for transition metal ions was measured by the method of Price et al. (30) with some modifications. Briefly, 15 µl of 50 µM CuCl2 and 30 µl of tested compound solution were preincubated in 1.38 ml of phosphate buffer at 30°C for 5 min. The reaction was initiated by the addition of 75 µl of 10 mM ascorbic acid (final concentrations of CuCl2 and ascorbic acid were 500 nM and 500 µM, respectively). Incubation lasted from 0 to 60 min at 30°C to allow kinetic reaction studies. Ascorbic acid content was determined by reverse phase HPLC, using a C18 reverse-phase column (5 µm, 4.6 x 250 mm) with absorbance detection at 244 nm. The buffer gradient used for elution was 0 to 50% buffer B for 5 min; buffer A, 0.10% trifluoroacetic acid; buffer B, 80% acetonitrile containing 0.08% trifluoroacetic acid.
Inhibition of Post-Amadori AGE Formation
Amadori-rich proteins were prepared according to the method of Booth et al. (31) with some modifications. Glycation was carried out by first incubating BSA (10 mg/ml) with arabinose or ribose (0.5 M) at 37°C in 0.1 M phosphate buffer (pH 7.4) for 24 h. Glycation was then interrupted to remove excess and reversibly bound sugar by extensive dialysis against frequent cold buffer changes at 4°C. The glycated BSA was then incubated with the tested compounds at 37°C in 0.1 M phosphate buffer (pH 7.4) for 1 wk. The content of pentosidine was determined by HPLC.
Entrapment of Pyridoxal 5'-Phosphate
The tested compounds (0.5 mM) were incubated with pyridoxal 5'-phosphate (50 µM) in PBS at 37°C under air. To perform kinetic studies, incubations lasted between 0 and 20 h. Aliquots were removed at various times, and pyridoxal 5'-phosphate content was assayed by HPLC (24). In brief, a 10-µl solution of reaction mixture was injected into an HPLC system and separated on a Waters Purecil C18 column (5 µm, 4.6 x 250 mm). The effluent was monitored with a fluorescence detector (RF-10A; Shimadzu, Kyoto, Japan) at excitation-emission wavelength of 300/400 nm. The buffer gradient used for elution was 0 to 3% buffer B (100 to 97% buffer A) for 25 min at a flow rate of 0.6 ml/min: buffer A, 0.10% trifluoroacetic acid; buffer B, 80% acetonitrile containing 0.08% trifluoroacetic acid.
Statistical Analyses
Statistical differences were tested using the t test. P < 0.05 was considered statistically significant. Data are expressed as the mean ± SD.
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Discussion |
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The mechanism of the AGE-lowering effect of AIIR antagonists and ACE inhibitors remains to be evaluated. The fact that AGE inhibition is demonstrated in a cell-free system suggests that it does not involve cellular intermediates and that it is independent of the activity of angiotensin II. Of course, additional effects may accrue in vivo from cellularly related mechanisms. AGE production depends on the concentration and on the production of precursors, many of which are reactive carbonyl and dicarbonyl compounds (4,5,18,33–37). AGE inhibitors might thus act either as trapping agents for RCO or, alternatively, as inhibitors of RCO production. In this study, we demonstrate that neither olmesartan, an AIIR antagonist, nor temocaprilat, an ACE inhibitor, entrap and lower in vitro the concentration of two RCO, glyoxal and methylglyoxal. This finding stands in contrast with aminoguanidine and OPB-9195, both of which, at equimolar concentrations, markedly reduce the levels of both RCO, confirming previous observations (28). Pyridoxamine has an intermediary effect. The mechanism of the AGE-lowering effect of olmesartan and temocaprilat differs markedly from that of aminoguanidine and OPB-9195.
AGE inhibitors may also decrease RCO production. The oxidative metabolism is significantly involved in the generation of RCO; hence its inhibition might lower RCO and thus AGE formation. Our results support such a mechanism of action for both AIIR antagonists and ACE inhibitors. Both olmesartan and temocaprilat interfere with at least two oxidative steps, the formation of carbon-centered radicals and hydroxyl radicals, here again in contrast with aminoguanidine. Of note, the impact on oxidative processes does not extend to the cellular release of superoxide. This drug-induced alteration of oxidative metabolism is associated with a decreased formation of RCO from arabinose as demonstrated by the effect of olmesartan on glyoxal and methylglyoxal production.
The finding that AIIR antagonists and ACE inhibitors are able to chelate transition metals is of great interest. Indeed, metal-catalyzed glucose autoxidation and oxidation of glycated residues have been proposed as potent sources of free radicals, which accelerate the browning and cross-linking of proteins and lead to the formation of AGE (30,32,38,39). The transition metal-chelating activity of AIIR antagonists far exceeds that of aminoguanidine and pyridoxamine, a result that is in agreement with a recent report by Price et al. (30).
The relationship between the transition metal chelation and the inhibition of oxidative steps produced by AIIR antagonists remains to be clarified. The effect of the tested drugs on oxidative steps may reflect not only an impaired production of oxygen species by metal chelation but also the scavenging of released oxygen species. The latter hypothesis is supported by our observation that prior chelation of transition metals fails to prevent the effect of the various tested drugs on carbon-centered or hydroxyl radicals. Furthermore, we have demonstrated that nifedipine and temocaprilat have a similar potential for chelation of transition metals despite the former drug’s inability to attenuate the formation of AGE. Still, the chelation of transition metals likely inhibits oxygen species production, but the extent of its influence on AGE formation remains to be ascertained.
As shown in Figure 6, oxidation influences AGE formation at different stages, i.e., before and after the formation of Amadori products (31,40). To identify the steps at which various AGE-lowering compounds interfere, we studied their effect on Schiff base-modified BSA; upon incubation, this in vitro-modified BSA generates pentosidine through post-Amadori steps. We thus demonstrated that both olmesartan and temocaprilat, but not nifedipine, decreased the post-Amadori pentosidine production. Aminoguanidine and OPB-9195 had, on an equimolar basis, a more conspicuous effect, whereas pyridoxamine had an effect similar to that of the hypotensive compounds. The overall effect of olmesartan and temocaprilat on pentosidine generation is markedly higher than that of aminoguanidine and OPB-9195; these data therefore suggest that their influence is exerted mainly on the pre-Amadori and only to a more limited extent on the post-Amadori formation of AGE.
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The discovery that AIIR antagonists and ACE inhibitors reduce AGE formation raises prospects for new therapeutic interventions. Both families of compounds have been used for many years and are well tolerated, unlike the first AGE-lowering agents, aminoguanidine and OPB-9195, which trap not only noxious RCO but also pyridoxal and induce vitamin B6 deficiency. The demonstration that pyridoxal binding is restricted to aminoguanidine and OPB-9195 but does not occur with olmesartan or temocaprilat confirms this view.
Our in vitro observations have been made at drug concentrations far above those achieved under clinical circumstances. Still, the dose effect relationship depicted in Figure 2 demonstrates an effect at far lower concentrations that those used in most of the present assays. In this context, it is of interest that in vitro concentrations of 800 and 2000 µM of either pyridoxamine or aminoguanidine are necessary to demonstrate inhibition of pentosidine and CML generation, whereas in vivo levels of 106 and 87 µM, respectively, lower AGE levels in rat skin collagen (41). Such discrepancies are not unusual in pharmacology. They may be related to a much longer drug of exposure in vivo than in in vitro assays. Still, more data are needed to ascertain whether the unexpected AGE-lowering effect of AIIR antagonists and some ACE inhibitors contribute to some of the recently demonstrated clinical and experimental benefits of these drugs (42–51). An interaction between AGE, endothelial cell function, and nitric oxide release (29,49–51) provides a useful framework for the exploration of these systemic effects, which are often unaccounted for by BP lowering.
Chelation of transition metals by some ACE inhibitors and AIIR antagonist with an attendant effect on oxidative protein products (48,52,53) and probably on lipoxidation may also contribute to their beneficial effects on atherosclerosis progression (32).
In conclusion, we demonstrate that AIIR antagonists and ACE inhibitors markedly reduce AGE formation. Unlike aminoguanidine, these compounds do not act through the trapping of RCO precursors of AGE. Rather, they reduce the production of RCO by interfering with the oxidative metabolism, mainly by lowering the formation of carbon-centered radicals and of hydroxyl-radicals, which also contrasts with aminoguanidine. This effect is paralleled by their ability to chelate transition metals. Inhibition of AGE formation occurs both at the pre- and, to a lesser extent, at the post-Amadori steps. Finally, neither AIIR antagonist olmesartan nor ACE inhibitor temocaprilat trap pyridoxal.
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References |
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) or temocaprilat (•). The yields of pentosidine in the incubation mixtures were determined by HPLC. Olmesartan: y = -0.215 log 
+1.962; r2 = 0.906. Temocaprilat: y = -0.140 log 
