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Lercanidipine Reduces Matrix Metalloproteinase-9 Marcio L.L. Martinez, Pharm D,* Lı´via F. Lopes,* Eduardo B. Coelho, MD, PhD,† Fernando Nobre, MD, PhD,† Joa˜o B. T. Rocha, PhD,‡ Raquel F. Gerlach, DDS, PhD,§ Key Words: calcium channel blockers, hypertension, lercanidipine, Abstract: Increased levels of metalloproteinase (MMP)-9 have been matrix metalloproteinases, oxidative stress shown in hypertensive patients. Lercanidipine is a calcium channelblocker with antioxidant actions. We examined whether lercanidipine (J Cardiovasc Pharmacol TM 2006;47:117–122) produces antioxidant effects and reduces MMP-9 activity in hy-pertensive patients in a placebo-controlled, crossover, single-blindeddesign study including 18 healthy volunteers (control group), and 14hypertensive patients without (N = 7) or with (N = 7) diabetes Hypertension is a major risk factor for the development of atherosclerosis and coronary artery disease. When mellitus. Hypertensive patients were randomized to treatment with hypertension and diabetes mellitus are combined, the cardio- placebo (15 days) or lercanidipine 20 mg/d (15 days). Arterial blood vascular risk increases to very high levels1 and complex pressure was evaluated with ambulatory blood pressure monitoring.
changes entailing accelerated vascular remodeling take place.2 Plasma thiobarbituric acid reactive species (TBA-RS) levels were Lately, a group of zinc-dependent endopeptidases called matrix measured to assess oxidative stress, and plasma MMP-2 and MMP-9 metalloproteinases (MMPs) has been implicated in the were assayed by gel zymography before and after treatment with vascular remodeling underlying the pathogenesis of athero- placebo or lercanidipine. Plasma concentrations of tissue inhibitor of sclerosis.3 MMPs have been classically recognized as a group metalloproteinases (TIMP)-1 were measured by ELISA. Lercanidi- of enzymes involved in both physiological and pathologic pine reduced mean arterial pressure by 7% in hypertensive patients degradation of extracellular matrix components, and increased without diabetes (P , 0.05), but not in hypertensive patients with MMP expression and activity may result in inappropriate diabetes. It significantly decreased plasma TBA-RS levels in hy- cardiovascular remodeling and premature coronary athero- pertensive patients without and with diabetes (95% confidence sclerosis.3 Importantly, increased circulating levels of MMP-9 interval [CI], 226 to 246%, P = 0.048, and 222 to 233%, P = have been described in patients with hypertension4,5 and in 0.036, respectively). In addition, lercanidipine decreased activated type 2 diabetic patients.6 In addition, a recent study showed MMP-9 in hypertensive patients without and with diabetes (95% that circulating levels of MMP-9 can predict mortality in CI, 219 to 247%, P = 0.047, and 280 to 296%, P = 0.010, patients with coronary artery disease.7 Taken together, these respectively). No effects were seen on MMP-2. No significant findings are consistent with the notion that MMP-9 may play differences or changes in plasma TIMP-1 concentrations were found.
a role in the pathophysiology of the cardiovascular changes Therefore, we demonstrate for the first time that lercanidipine associated with hypertension and diabetes mellitus, and that consistently decreased MMP-9 activity and reduced oxidative stress circulating levels of MMP-9 may have prognostic value.4,7 in hypertensive patients, thus suggesting a mechanism probably Lercanidipine is a vasoselective dihydropyridine cal- involved in the pleotropic actions of lercanidipine.
cium channel blocker (CCB) used for the management ofhypertension.8 Besides reducing blood pressure, lercanidipinehas pleotropic actions that may significantly contribute to thebenefits that it produces in the therapy for hypertension. For Received for publication May 26, 2005; accepted November 1, 2005.
example, lercanidipine produced significant antioxidant effects From the *Department of Pharmacology, Faculty of Medicine of Ribeirao in patients with hypertension9,10 and in patients with combined Preto, University of Sao Paulo, Ribeirao Preto, Brazil; †Department of hypertension and diabetes mellitus type 2.11 Moreover, in- Medicine, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo,Ribeirao Preto, Brazil; ‡Chemistry Department, Federal University of cubation of endothelial cells with lercanidipine significantly Santa Maria, Santa Maria, Brazil; and §Department of Morphology, reduced oxidized-LDL-induced intracellular reactive oxygen Estomatology and Physiology, Dental School of Ribeirao Preto, species formation.12 In addition, while the effects of CCB on University of Sao Paulo, Ribeirao Preto, Brazil.
MMP activity/expression are not clear,13 it is possible that xa˜o de Aparo a Pesquisa do Estado de Sa˜o Paulo (FAPESP-Brazil), Conselho Nacional de Desenvolvimento Cientı´- lercanidipine and other CCB with antioxidant effects reduce fico e Tecnolo´gico (CNPq-Brazil) and Coordenadoria de Aperfeic MMP activity/expression in patients with both hypertension de Pessoal de Nı´vel Superior (CAPES-Brazil).
and diabetes mellitus. This suggestion is supported by ex- Reprints: Jose Eduardo Tanus-Santos, Department of Pharmacology, Faculty perimental evidence indicating that enhanced oxidative stress of Medicine of Ribeirao Preto University of Sao Paulo, Av. Bandeirantes, is a major factor modulating MMP-2 and MMP-9 expres- 3900 14049-900 Ribeirao Preto, SP, Brazil (e-mail: [email protected]).
Copyright Ó 2006 by Lippincott Williams & Wilkins sion/activity14,15 and that reactive oxygen species (ROS) are J Cardiovasc Pharmacol ä  Volume 47, Number 1, January 2006 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
J Cardiovasc Pharmacol ä  Volume 47, Number 1, January 2006 involved in vascular remodeling of hypertension via MMP Measurement of Thiobarbituric Acid Reactive In this study, we hypothesized that hypertension is To assess oxidative stress, TBA-RS were determined in associated with increased oxidative stress and plasma MMP-9 triplicate plasma samples as previously described.17 activity, and that treatment of hypertensive patients withlercanidipine would produce antioxidant effects and reduce plasma MMP-9 activity. Finally, we have also determined the plasma concentrations of tissue inhibitor of metalloproteinases (TIMP)-1 because TIMP-1 is a major regulator of MMP-9 To assess plasma MMP-2 and MMP-9 activities, 10 mL and 30 mL of each plasma sample were diluted in 190 mL andin 170 mL of sample buffer (2% SDS, 125 mM Tris-HCl; pH6.8, 10% glycerol, and 0.001% bromophenol blue), re- spectively. Thereafter, 10 mL of each plasma solution were loaded in each gel lane and gelatin zymography of MMP-2 andMMP-9 was performed as previously described.18–20 Gelati- This study was approved by our institutional review nolytic activities were assayed by densitometry using a Kodak committee and each subject provided written informed consent.
Electrophoresis Documentation and Analysis System (EDAS) We studied 18 normal healthy volunteers (control group), and 290 (Kodak, Rochester, NY). The pro and active forms of 14 patients with mild to moderate arterial hypertension with- MMP-2 and MMP-9 were identified as bands at 72 and 67 out (N = 7; Hyp group) or with (N = 7; Hyp + DM group) type KDa, and at 92 and 87 KDa, respectively. Finally, the 2 diabetes mellitus. Healthy volunteers were recruited from individuals who performed the assays were blinded to the general public whereas hypertensive patients were recruited from our hospital hypertension clinic. All the subjects pro-vided a complete health history and underwent a physical examination, and laboratory analysis to exclude individuals with evidence of severe or secondary hypertension, other The plasma concentrations of TIMP-1 were measured concomitant cardiovascular diseases, respiratory, hepatic, using a commercially available (Amersham Biosciences UK renal, or hematological dysfunction.
Limited, Buckinghamshire, UK) enzyme-linked immunosor-bent assay (ELISA), which is based on a 2-site ÔsandwichÕ format. The TIMP-1 assay recognizes both free TIMP-1 and The study had a placebo-controlled, crossover, single- TIMP-1 complexed with MMPs, and does not cross react with blinded design. All hypertensive subjects had their antihyper- tensive treatment changed to 25 mg of hydrochlorothiazide POplus 5 mg of ramipril PO for a period of 15 days. Subjects with both hypertension and diabetes mellitus were on oral hy- The results are expressed as means 6 SEM. One-way poglycemic therapy in addition to hydrochlorothiazide and analysis of variance followed by the Student-Newman-Keuls ramipril. Hypertensive subjects with or without diabetes were test was used to analyze differences among groups. The randomized to add placebo or lercanidipine (Asta Medica, changes in 24h-SBP, 24h-DBP, TBA-RS, TIMP-1 and MMPs Brazil) 20 mg/d, for 15 days. Thereafter they were crossed over activities were analyzed using Student t test for paired data and for a second period of 15 days of treatment with the same dose Bonferroni correction. A probability value , 0.05 was con- of lercanidipine or placebo. Normotensive healthy volunteers sidered the minimum level of statistical significance.
Venous blood samples (10–15 mL) were collected into tubes containing EDTA at baseline and after both treatments for 15 days with lercanidipine or placebo. Healthy volunteers were sampled at the same time intervals as hypertensive Table 1 summarizes the basic characteristics of the study patients. Plasma samples were stored at –70°C until assayed as subjects. There were no significant differences in the age, body mass index, serum creatinine and hemoglobin concentrationsamong groups. Whereas hypertensive patients presented higher levels of total cholesterol, LDL, and triglycerides, blood pres- An ambulatory blood pressure monitoring (ABPM, sure, and HR compared with normotensive control subjects SpaceLabs, Model 90207, USA) was used to measure 24 (all P , 0.05), no significant differences were observed when hours systolic, diastolic and mean arterial pressure (24-hour patients with hypertension were compared with patients with SBP and 24-hDBP, respectively) and heart rate (HR) before hypertension and diabetes mellitus, except for higher hemo- and after treatment with placebo or lercanidipine. The ABPM globin A1c levels in this last group of patients (P = 0.021).
was pre-set to record blood pressure every 15 minutes duringdaytime, and every 30 minutes during night-time. We used average 24h-SBP and 24h-DBP values for the assessment of Figure 1 shows that whereas lercanidipine 20 mg sig- lercanidipine antihypertensive efficacy.
nificantly reduced 24 hours ambulatory average 24h-SBP and Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
J Cardiovasc Pharmacol ä  Volume 47, Number 1, January 2006 TABLE 1. Baseline Clinical and Laboratory Data from32 Volunteers: 18 Normotensives (Controls), 7 WithHypertension (Hyp), and 7 With Hypertension and DiabetesMellitus Type 2 (Hyp + DM) BMI, Body mass index; HbA1c, hemoglobin A1c; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate.
Values are shown as mean 6 SEM.
*P , 0.05 vs. Controls.
†P , 0.05 vs. the other groups.
24h-DBP in patients with hypertension (N = 7, P = 0.041), noeffects were observed in patients with hypertension and di-abetes mellitus (N = 7; P . 0.05; Fig. 1). In addition, nosignificant changes were seen in heart rate (data not shown).
Changes in Thiobarbituric Acid ReactiveSpecies (TBA-RS) in Plasma FIGURE 1. Average 24h-systolic and 24h-diastolic bloodpressure (24h-SBP and 24h-DBP, respectively) in normotensive Figure 2 shows higher TBA-RS levels in hypertensive (NT) volunteers, and after treatment with daily lercanidipine patients compared with normotensive controls (P , 0.05). In 0 mg (placebo) or 20 mg in hypertensive (Hyp) or hypertensive addition, treatment with lercanidipine significantly decreased diabetic (Hyp + DM) patients. Values are the mean 6 SEM *P = plasma TBA-RS levels in both patients with hypertension (P = 0.041 versus 0 mg, for Hyp group, by paired t test. #P = 0.020 0.048) and in patients with hypertension and diabetes mellitus and P = 0.017, versus (NT) control group by ANOVA, for Hyp higher pro-MMP-9 values than normotensive controls (P = Whereas the bands corresponding to pro-MMP-9, 0.047), lercanidipine did not affect the circulating levels of activated MMP-9, and pro-MMP-2 were identified in gelatin zymography, no band corresponding to active-MMP-2 was Finally, whereas no significant differences were found in detected (Fig. 3). Intra-assay and interassay coefficients of pro-MMP-2 values of hypertensive patients (both sub-groups) variation were less than 3.5%, and less than 9.0%, respectively.
compared with normotensive controls, lercanidipine produced Figure 4 shows that patients with hypertension (with or no significant decreases in pro-MMP-2 activities in hyper- without diabetes mellitus) have higher mean values of ac- tensive patients with or without diabetes mellitus (P . 0.05; tivated MMP-9 than normotensive healthy volunteers (P = Whereas no significant change in MMP-9 activity was seen in normotensive healthy volunteers sampled at the sametime intervals as hypertensive patients (data not shown), treat- ment with lercanidipine significantly reduced the values of Figure 5 shows that whereas normotensive controls active MMP-9 in both sub-groups of patients with hyperten- tended to have higher plasma concentrations of TIMP-1 com- sion (P = 0.047 and P = 0.010 for Hyp group and Hyp+DM pared with hypertensive patients (P = 0.101), treatment with group, respectively). It should be noted that this lercanidipine- lercanidipine produced no effects in both patients with induced effect was observed in every single patient. In hypertension and in patients with hypertension and diabetes addition, whereas patients with hypertension and diabetes have Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
J Cardiovasc Pharmacol ä  Volume 47, Number 1, January 2006 FIGURE 2. Thiobarbituric acid reactive species (TBA-RS)concentrations in plasma measured as malondialdehyde(MDA) in normotensive (NT) volunteers, and after treatmentwith daily lercanidipine 0 mg (placebo) or 20 mg inhypertensive (Hyp) or hypertensive diabetic (Hyp + DM)patients. Values are the mean 6 SEM *P = 0.048 and P = 0.036,versus 0 mg, for Hyp group and Hyp+DM group, respectively,by paired t test. #P = 0.003 and P = 0.007, versus (NT) controlgroup by ANOVA, for Hyp and Hyp+DM groups, respectively.
In this study, we demonstrate for the first time that a short-term treatment with lercanidipine consistently de-creased MMP-9 activity without affecting TIMP-1 concen-trations in both patients with hypertension and in patients withhypertension and diabetes mellitus. The decrease in MMP-9activity without significant changes in TIMP-1 (a major in-hibitor of MMP-9) suggests that treatment with lercanidipinereduced net MMP-9 activity in both groups of patients. Thislercanidipine-induced effect was associated with a significantreduction in oxidative stress in both groups of patients andmay shed some light on the possible mechanisms involved inthe pleotropic actions of this third-generation L-type CCB.21 FIGURE 4. Mean values of activated MMP-9, pro-MMP-9,and pro-MMP-2 activities in plasma of normotensive (NT)healthy volunteers (control group) and after treatmentwith daily lercanidipine 0 mg (placebo) or 20 mg inhypertensive (Hyp) or hypertensive diabetic (Hyp + DM)patients. Values are the mean 6 SEM *P = 0.047 andP = 0.010, versus 0 mg, for Hyp group and Hyp+DM group,respectively, by paired t test. #P = 0.022 and P = 0.047, FIGURE 3. Representative zymogram of plasma samples versus (NT) control group by ANOVA, for active MMP-9 and showing pro-MMP-9, activated MMP-9, and pro-MMP-2 bands in normotensive healthy volunteers (NT) and aftertreatment with daily lercanidipine 0 mg (placebo) or 20 mg inhypertensive (Hyp) or hypertensive diabetic (Hyp + DM)patients.
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
J Cardiovasc Pharmacol ä  Volume 47, Number 1, January 2006 levels should be determined as soon as possible aftersampling,28 and blood samples should be drawn from allgroups of subjects at the same time.
Hypertensive patients with diabetes mellitus presented increased MMP-9 activity and lower TIMP-1 concentrationswhen compared with healthy controls in the present study.
These findings are similar to those previously shown in patientswith diabetes type 2 and treated hypertension, who had higherMMP-9 levels than healthy controls.6 Indeed, elevated plasmaconcentrations of MMP-9 were reported in diabetic patients,and there is increasing evidence supporting the idea that in-creased MMP-9 expression is associated with the cardiovas-cular complications of diabetes.29 Increased concentrations of ROS have been consistently FIGURE 5. Mean values of TIMP-1 in plasma of normotensive shown in both animal models of hypertension and diabetes, (NT) healthy volunteers (control group) and after treatment and in clinical hypertension and diabetes.30 In addition, it is with daily lercanidipine 0 mg (placebo) or 20 mg in now clear that enhanced oxidative stress is a major factor that hypertensive (Hyp) or hypertensive diabetic (Hyp + DM) modulates MMP-2 and MMP-9 expression/activity14,15 and patients. Values are the mean 6 SEM.
that ROS are involved in vascular remodeling via MMPactivation.16 Therefore, antihypertensive drugs that could Although the precise role of MMPs in the pathophys- abrogate these mechanisms of disease progression as iology of hypertension is not known at present, several ex- a consequence of their pleotropic effects may prove to be perimental studies have shown that hypertension is associated superior than other antihypertensive drugs that can simply with abnormal MMP activity and disturbances of extracellular lower blood pressure. Our results strongly suggest that matrix accumulation in the cardiovascular system.3,22,23 For lercanidipine can produce such beneficial pleotropic effects.
example, increased transmural arterial pressure induced We found that lercanidipine treatment decreased oxidative MMP-2 and MMP-9.24 Moreover, vascular smooth muscle stress in both groups of hypertensive patients. These results cells exposed to mechanical stretch were shown to induce ROS support previous data showing antioxidant effects of lercani- formation thereby increasing the expression and the release of dipine in patients with hypertension9,10 and in patients with MMP-2.16 Whereas many laboratory experiments suggest that combined hypertension and diabetes mellitus type 2.11 Besides increased MMP-2 and MMP-9 activities play a role in producing antioxidant effects, our results show that lercani- hypertension, previous clinical studies have shown higher dipine treatment was associated with decreased values of levels of MMP-94,5 and lower TIMP-125 concentrations in active MMP-9 in both sub-groups of patients with hyperten- hypertensive patients compared with controls. Our present sion. Taken together, these results suggest that the antioxidant results are in line with these recent studies4,5 showing effects of lercanidipine can attenuate the increased MMP-9 increased plasma MMP-9 activity in patients with hyperten- expression/activity in hypertensive patients with or without sion. Importantly, the net level of MMP-9 activity depends on diabetes mellitus. In addition, our results show that lercani- the relative concentrations of the active enzyme and its specific dipine treatment produced no significant reduction in MMP-2 tissue inhibitor (TIMP-1). In the present study, we found that activity in hypertensive patients with or without diabetes hypertensive patients presented higher MMP-9 activity and mellitus. Although other CCBs such as felodipine, lacidipine unchanged plasma concentrations of TIMP-1 when compared and amlodipine have also shown antioxidant effects,13 and with normotensive controls, thus suggesting increased net amlodipine decreased MMP-2 expression in rat cardiac MMP-9 activity in hypertensive that in normotensive subjects.
fibroblast,31 CCBs may produce differential pleotropic effects, While these present findings are supported by previous clinical and it remains to be determined whether these CCBs can affect studies,4,5 lower MMP-9 levels were reported in hypertensive MMP activity in hypertension and diabetes. Indeed, whereas patients compared with normotensive controls.26 One possible the responses to CCBs are largely attributed to their primary explanation for this discrepancy is that MMP-9 levels were mechanism of action, it is probable that their pleotropic actions assessed by ELISA in that study.26 Moreover, TIMP-1 contribute to their clinical effects.13 Presently, it is not possible concentrations were not measured in that study, thus to choose which CCB produce the best pleotropic effects.
precluding the analysis of net MMP-9 activity.26 In the Some limitations of our study should be taken into present study, we have used gel zymography, which is consideration. Firstly, the relatively small number of hyper- a powerful tool because it allows both the active and the latent tensive patients (N = 14) may have limited our conclusions.
forms of both MMP-2 and MMP-9 to be detected in For example, lercanidipine treatment significantly reduced concentrations as low as 1 nM.27 In addition to significant 24h-SBP and 24h-DBP in patients with hypertension.
methodological differences between studies, another explana- Conversely, no such effects were observed in hypertensive tion may be related to the instability of the MMP-9 patients with diabetes mellitus. However, the present study was measurement over time.28 It has been shown that a sharp not designed to address the antihypertensive effect of decrease in the plasma levels of MMP-9 occurs during the first lercanidipine, which has been previously demonstrated in 3 months of storage at –80°C.28 Therefore, plasma MMP-9 hypertensive patients with diabetes.32 Importantly, the main Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
J Cardiovasc Pharmacol ä  Volume 47, Number 1, January 2006 goal of the present study was to assess the effects of 11. Rachmani R, Levi Z, Zadok BS, et al. Losartan and lercanidipine attenuate lercanidipine treatment on MMP-2 and MMP-9 activities in low-density lipoprotein oxidation in patients with hypertension and type2 diabetes mellitus: a randomized, prospective crossover study. Clin hypertensive patients, and lercanidipine treatment reduced the values of active MMP-9 activity in every single patient en- 12. Cominacini L, Fratta Pasini A, Garbin U, et al. Antioxidant activity of different rolled in the present study. Secondly, although our findings dihydropyridines. Biochem Biophys Res Commun. 2003;302:679–684.
provide some evidence for the mechanisms involved in the 13. Mason RP, Marche P, Hintze TH. Novel vascular biology of third- pleotropic actions of lercanidipine, our results do not prove generation L-type calcium channel antagonists: ancillary actions ofamlodipine. Arterioscler Thromb Vasc Biol. 2003;23:2155–2163.
that lercanidipine treatment can protect against the vascular 14. Van den Steen PE, Dubois B, Nelissen I, et al. Biochemistry and molecular remodeling3 and cardiac fibrosis22 encountered in hypertensive biology of gelatinase B or matrix metalloproteinase-9 (MMP-9). Crit Rev patients. Moreover, we have not examined the effects of a chronic Biochem Mol Biol. 2002;37:375–536.
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showed that 6 months of treatment with felodipine raised 16. Grote K, Flach I, Luchtefeld M, et al. Mechanical stretch enhances mRNA MMP-2 levels, whereas diltiazem produced no effects.33 expression and proenzyme release of matrix metalloproteinase-2 (MMP-2) via Thirdly, although detection of TBA-RS is sensitive for the NAD(P)H oxidase-derived reactive oxygen species. Circ Res. 2003;92: measurement of oxidative stress, it is not specific.34 It remains, however, one of the most widely used indicators of reactive 17. Souza-Costa DC, Zerbini T, Metzger IF, et al. l-Arginine attenuates acute pulmonary embolism-induced oxidative stress and pulmonary hyperten- oxygen species formation in vitro and in vivo.34 Finally, we have examined the effects of lercanidipine treatment in hy- 18. Gerlach RF, Uzuelli JA, Souza-Tarla CD, et al. Effect of anticoagulants on pertensive patients that were taking thiazide and ramipril. In plasma matrix metalloproteinase (MMP)-2 and MMP-9 activities. Anal addition, oral hypoglycemics have complex metabolic effects.
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B O Ð S K A P U R Æ Ð S T A F O R S Æ T I S R Á Ð S I N S , J A N Ú A R 2 0 1 2 Thomas S. Monson Í upphafi nýs árs hvet ég Síðari daga heilaga hvar- seglin. Gætum þess að velja jákvæða afstöðu, til að vetna til að hefja af kostgæfni mikilvæga og per-hámarka hamingju okkar, frið og gleði. sónulega leit að því sem ég vil nefna gnægtarlíf — lífi sem

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