Published online before print September 2, 2003, doi: 10.1161/01.HYP.0000091372.14174.89
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(Hypertension. 2003;42:e10.)
© 2003 American Heart Association, Inc.
Letters to the Editor |
Antioxidant Effect of Lercanidipine
Department of Medicine and Therapeutics, The Chinese University of Hong Kong
Ageing and Health Section, School of Nursing, The Hong Kong Polytechnic University
To the Editor:
We were surprised by the effects of lercanidipine reported by Taddei et al1 on the plasma antioxidant capacity, with the ferric reducing (antioxidant) power (FRAP) value increasing from 305.0±31.3 to 435.7±142.9 µmol/L. Typical FRAP values for human plasma usually range from 800 to 1200 µmol/L.2 The apparently low baseline values may be related to the use of ascorbic acid or TroloxTM (rather than a solution of ferrous ions) as calibrator without correcting for their stoichiometric factor, which is 2.0 in the FRAP assay. However, it is more difficult to explain the almost 50% increase in plasma FRAP values after lercanidipine treatment. We have found that lercanidipine itself has no in vitro antioxidant effect in the FRAP assay, but it does undergo extensive first-pass metabolism, and some metabolites could have a direct antioxidant effect. The peak plasma concentration (Cmax) of S-lercanidipine is, at most, around 15 nmol/L,3,4 and although the Cmax for total metabolites was >40 times higher than that of the parent drug,5 this still amounts to <1 µmol/L of total metabolites. Even if each molecule of metabolite could scavenge several radicals, it is highly unlikely that this would have any appreciable direct effect on the plasma FRAP value. Similarly, captopril has virtually no contribution to plasma FRAP in vivo, despite having in vitro antioxidant activity.6
In contrast, plasma ascorbic acid at normal plasma concentrations (40 to 60 µmol/L) contributes about 15% of the total FRAP value. Bilirubin and 
-tocopherol each contribute about 5%, plasma proteins 10%, and uric acid around 60% to the FRAP value.2 Lercanidipine is unlikely to cause a substantial change in any of these parameters. Renal function was not affected according to the serum creatinine data (for which units are presumably µmol/L rather than mg/dL as presented).1
Antioxidant effects have been shown with some lipophilic calcium antagonists such as lercanidipine, but this is probably related to their accumulation within membranes or by virtue of their pharmacological effects on calcium channels, rather than a major effect on the total plasma antioxidant power.7,8 Amlodipine showed antioxidant activity in hepatic microsomal membranes which appeared to be a nonreceptor-mediated effect due to the biophysical interactions with the membrane lipid bilayer.9
We might speculate that the apparent change in FRAP could be an artifact, as several antioxidants are unstable ex vivo, especially in EDTA plasma.,10 Pre-analytical loss could have resulted in low results being obtained in basal samples, rather than high levels in post-treatment samples. Blood samples might also have been taken some time after the infusions of vitamin C when plasma ascorbic acid concentrations were still elevated. The large SD values of 10% to 30% for the mean plasma FRAP also suggest perhaps some pre-analytical change or analytical problem.
These comments do not detract from the main finding in the study and the elegant demonstration of how treatment with lercanidipine can reverse the endothelial dysfunction associated with hypertension. However, they do serve to illustrate how it can be difficult to interpret apparent changes in some parameters in the absence of a control group.
References
1. Taddei S, Virdis A, Ghiadoni L, Versari D, Salvetti G, Magagna A, Salvetti A. Calcium antagonist treatment by lercanidipine prevents hyperpolarization in essential hypertension. Hypertension. 2003; 41: 950–955.
2. Benzie IFF, Strain JJ. The ferric reducing ability of plasma as a measure of "antioxidant power": the FRAP assay. Anal Biochem. 1996; 239: 70–76.[CrossRef][Medline] [Order article via Infotrieve]
3. Meredith P. Lercanidipine: a novel lipophilic dihydropyridine calcium antagonist with long duration of action and high vascular selectivity. Expert Opin Investig Drugs. 1999; 8: 1043–1062.[Medline] [Order article via Infotrieve]
4. McClellan KJ, Jarvis B. Lercanidipine: a review of its use in hypertension. Drugs. 2000; 60: 1123–1140.[Medline] [Order article via Infotrieve]
5. Barchielli M, Dolfini E, Farina P, Leoni B, Targa G, Vinaccia V, Tajana A. Clinical pharmacokinetics of lercanidipine. J Cardiovasc Pharmacol. 1997; 29 (suppl 2): S1–S15.
6. Benzie IFF, Tomlinson B. Antioxidant power of angiotensin-converting enzyme inhibitors in vitro. Br J Clin Pharmacol. 1998; 45: 168–169.[CrossRef][Medline] [Order article via Infotrieve]
7. Cominacini L, Fratta Pasini A, Garbin U, Pastorino AM, Davoli A, Nava C, Campagnola M, Rossato P, Lo Cascio V. Antioxidant activity of different dihydropyridines. Biochem Biophys Res Commun. 2003; 302: 679–684.[Medline] [Order article via Infotrieve]
8. Rachmani R, Levi Z, Zadok BS, Ravid M. Losartan and lercanidipine attenuate low-density lipoprotein oxidation in patients with hypertension and type 2 diabetes mellitus: a randomized, prospective crossover study. Clin Pharmacol Ther. 2002; 72: 302–307.[CrossRef][Medline] [Order article via Infotrieve]
9. Mason RP, Mak IT, Trumbore MW, Mason PE. Antioxidant properties of calcium antagonists related to membrane biophysical interactions. Am J Cardiol. 1999; 84: 16L–22L.[Medline] [Order article via Infotrieve]
10. Chung WY, Chung J, Szeto YT, Tomlinson B, Benzie IFF. Plasma ascorbic acid: measurement, stability and clinical utility revisited. Clin Biochem. 2001; 34: 623–627.[CrossRef][Medline] [Order article via Infotrieve]
Response
Department of Internal Medicine, University of Pisa, Pisa, Italy
The issues raised by Tomlinson and Benzie with regard to our paper1 fall into 2 areas: (1) criticism of low plasma ferric reducing antioxidant power (FRAP) in our hypertensive population and (2) lack of explanation for lercanidipine-induced increase in plasma FRAP.
Concerning the first issue, we have consistently found low plasma levels of FRAP in patients with essential hypertension.2,3 This is probably related to the presence of increased oxidative stress in patients with essential hypertension, since in healthy subjects (n=40) we found greater plasma FRAP values (685±343 µmol/L) as compared with hypertensive patients.3 We are aware that these values are still lower than those quoted by Tomlinson and Benzie (normal plasma values of FRAP ranging from 200 to 1200 µmol/L).4 However, apart from the methodological points raised by Tomlinson and Benzie, it must be underlined that their values were detected in Chinese individuals, a population not comparable to Caucasians.
On the second issue, it is quite unexpected that lercanidipine has no in vitro effects on FRAP. The FRAP assay is based on the ferric/ferrous reaction and an antioxidant such as vitamin C can increase FRAP by releasing an electron and undergoing oxidation.4 It is worth noting that the dihydropyridine ring can also release an electron and undergo oxidation, a mechanism similar to that exerted by vitamin C.5 Therefore a direct effect of lercanidipine on FRAP would be expected.
However, a conceivable negative effect of acute exposure to lercanidipine in in vitro conditions does not necessarily exclude a positive effect of chronic administration of lercanidipine in humans (ie, in totally incomparable clinical conditions). Dihydropyridine compounds, including lercanidipine, have a well-established direct antioxidant activity by accumulation within membranes.5–7 In line with this possibility, in our study we observed a clear decrease in specific markers of oxidation such as plasma lipoperoxides and isoprostanes.1 When markers of oxidation decrease, this usually indicates a depressed production of oxygen free radicals.8 If the production of oxygen free radicals decreases, this causes a parallel decrease in the amount of oxidated antioxidants, since antioxidants can reduce free radical concentration by undergoing oxidation.8 Thus, it is very likely that lercanidipine-induced increase in plasma FRAP values could be a logical and expected consequence of the direct effect of lercanidipine on oxygen free radical production.
References
1. Taddei S, Virdis A, Ghiadoni L, Versari D, Salvetti G, Magagna A, Salvetti A. Calcium antagonist treatment by lercanidipine prevents hyperpolarization in essential hypertension. Hypertension. 2003; 41: 950–955.
2. Taddei S, Virdis A, Ghiadoni L, Magagna A, Favilla S, Pompella A, Salvetti A. Restoration of nitric oxide availability after calcium antagonist treatment in essential hypertension. Hypertension. 2001; 37: 943–948.
3. Ghiadoni L, Magagna A, Versari D, Kardasz I, Huang Y, Taddei S, Salvetti A. Different effect of antihypertensive drugs on conduit artery endothelial function. Hypertension. 2003; 41: 1281–1286.
4. Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay. Annal Biochem. 1996; 239: 70–76.[CrossRef][Medline] [Order article via Infotrieve]
5. Cominacini L, Fratta Pasini A, Garbin U, Pastorino AM, Davoli A, Nava C, Campagnola M, Rossato P, Lo Cascio V. Antioxidant activity of different dihydropyridines. Biochem Biophys Res Commun. 2003; 302: 679–684.[Medline] [Order article via Infotrieve]
6. Pang DC, Sperelakis N. Uptake of calcium antagonistic drugs into muscles as related to their lipid solubilities. Biochem Pharmacol. 1984; 33: 821–826.[CrossRef][Medline] [Order article via Infotrieve]
7. Gaviraghi G, Pastorino AM, Ratti E, Trist DG. Calcium channel blockers with antioxidant activity. In: Bellomo G, Finardi G, Maggi E, Rice-Evans E, eds. Free Radicals, Lipoprotein Oxidation and Atherosclerosis. London: Richelieu Press; 1995: 431–456.
8. Dhalla NS, Temsah RM, Netticadan T. Role of oxidative stress in cardiovascular diseases. J Hypertens. 2000; 18: 655–673.[CrossRef][Medline] [Order article via Infotrieve]
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