doi: 10.1161/hy0202.103482
(Hypertension. 2002;39:685.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Lacidipine Inhibits Adhesion Molecule and Oxidase Expression Independent of Blood Pressure Reduction in Angiotensin-Induced Vascular Injury
Department of Nephrology, Medical School Hannover (J-K.P., A.F., F.A-R., H.H.), Germany; Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin (D.N.M., R.D., F.C.L.), Germany; Institute of Biomedicine, University of Helsinki (E.M.A.M.), Finland.
Correspondence to Hermann Haller, MD, Medizinische Hochschule Hannover, Abt. Nephrologie, Carl-Neuberg-Straße 1, 30625 Hannover, Germany. E-mail haller.hermann{at}mh-hannover.de
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Abstract |
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Dihydropyridines can inhibit gene expression in-vitro and may have a protective vascular effect independent of blood pressure reduction. We tested the hypothesis that lacidipine prevents induction of inducible NO synthase (iNOS), influences leukocyte adhesion and infiltration, inhibits nuclear factor (NF)-
B transcription factor activity, and ameliorates end-organ damage in a transgenic rat model of angiotensin (Ang) II–dependent organ sclerosis. We treated rats transgenic for human renin and angiotensinogen (dTGR) from week 4 to 7 with lacidipine (0.3 or 3 mg/kg by gavage). Blood pressure was measured by tail cuff. Organ damage was assessed by histology and immunohistochemistry. Adhesion molecules and cytokines were analyzed by immunohistochemistry. Transcription factors were analyzed by mobility shift assays. Untreated dTGR developed moderate hypertension, cardiac hypertrophy, and severe renal damage with albuminuria. Lacidipine decreased blood pressure slightly at the low dose and substantially at the higher dose. However, both treatments reduced albuminuria and plasma creatinine to the same degree (P<0.05). Intercellular adhesion molecule-1 (ICAM-1) was markedly reduced by lacidipine as well as renal neutrophil and monocyte infiltration. Lacidipine reduced mitogen-activated protein (MAP) kinase phosphorylation and iNOS expression in both cortex and medulla. NF-B and AP-1 were activated in dTGR but reduced by lacidipine. Lacidipine ameliorates Ang II-induced end-organ damage independent of blood pressure lowering, perhaps by inhibiting the MAP kinase pathway and NF-B activation.
Key Words: Angiotensin II • nitric oxide synthase • calcium antagonists • transcription • cell adhesion molecules
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Introduction |
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Dihydropyridines calcium antagonists ameliorate end-organ damage.1,2 In a nephrectomy model3 and in diabetic animals4 the drugs retarded the progression of glomerular disease and inhibited the development of glomerulosclerosis in experimental hypertension.5 The beneficial effects are a function of blood pressure reduction. However, dihydropyridines may influence the cellular mechanisms directly.6–9 In vitro studies provide supportive evidence. For instance, dihydropyridines suppress mesangial cell growth and chemokine expression.10,11 They also decreased vascular cell infiltrates and expression of adhesion molecules in endothelial cells.12–14 Dihydropyridines inhibit the activation of the protein kinases in vitro.15 Calcium signaling may be involved; however, we presented evidence indicating that other signal transduction systems such as protein kinase C are the drug targets.11,15,16 Thus, dihydropyridines could influence cellular mechanisms of renal damage via the intracellular signaling pathways and reduce the activity of down-stream signaling.2,17–19 To test this hypothesis, we used an angiotensin (Ang) II-dependent transgenic rat model with both human renin and angiotensinogen genes. The rats develop moderate hypertension and severe renal and cardiac damage resulting in 50% mortality at age 7 weeks.20,21,22
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Methods |
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All procedures, as outlined elsewhere, were done according to guidelines from the American Physiological Society and were approved by local authorities. The lacidipine dTGR groups (n=10 each) received the drug for 3 weeks by gavage once daily at two doses (0.3 or 3 mg/kg by gavage). Control dTGR (n=10) and SD rats (n=10) received vehicle (1% sodium carboxymethylcellulose). Systolic blood pressure was measured weekly by tail-cuff method under light ether anesthesia 20 hours after the last drug dose. Urine samples were collected over a 24-hour period. Rats were killed at age 7 weeks. The kidneys and hearts were washed with ice cold saline, blotted dry, and weighed. For immunohistochemistry, western blot, and analysis of nuclear factor (NF)-
B and AP-1, the tissues were snap-frozen in liquid nitrogen, for immunohistochemistry in isopentane (-35°C), and stored at -80°C. Our histology, immunohistochemistry, Western blotting analyses, and electrophoretic mobility shift assay techniques have been described in detail elsewhere.23,24 Data are presented as means±SEM. Statistically significant differences in mean values were tested by ANOVA and the Tukey multiple range test. A value of P<0.05 was considered statistically significant. The data were analyzed using SYSTAT® statistical software (SYSTAT Inc). |
Results |
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Lacidipine was given at two dosages 0.3 mg/kg body (low lacidipine group) or 3 mg/kg body weight (high lacidipine group). Systolic blood pressure in the untreated transgenic animals at week 7 was 203±11 mm Hg, compared with 108±3 mm Hg in the wild-type SD control animals. Lacidipine in the high treatment group lowered blood pressure by 54% to 149±7 mm Hg (P<0.001) compared with the untreated group) as shown in Figure 1 (top). In contrast, treatment in the low lacidipine group lowered blood pressure by only 9% to 185±10 mm Hg (P<0.05) compared with the untreated group). The difference in blood pressure between the two groups was 36±14 mm Hg (P<0.05). Despite the significant difference in blood pressure between the two treatment groups, the lower dose of lacidipine showed the same effect on albumin excretion as the higher lacidipine (bottom). Albuminuria in the untreated transgenic animals was 11±0.2 mg/d compared with 0.3±0.01 mg/d in the SD controls (P<0.01). Lacidipine decreased albumin excretion to 3.1±0.2 mg/d in the low treatment group and to 3.6±0.03 mg/d in the high lacidipine group.
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Vehicle-treated dTGR had severe renal damage with focal necrosis, and a 50% mortality at 7 weeks. Small vessels showed increased intimal and medial thickness as well as hyaline deposits. The renal tubules were frequently swollen and filled with proteinaceous material. Treatment with lacidipine prevented vascular injury in small renal vessels and extracellular matrix formation (data not shown). The beneficial effects of lacidipine were observed with both concentrations of lacidipine.
We quantitated the effects of lacidipine on neutrophils and monocytes as shown in Figure 2. Monocytes were present in the perivascular space and between the tubules. In contrast, granulocytes were mostly seen within the glomeuli and, to a lesser extent, in perivascular areas. Treatment with lacidipine prevented cell infiltration almost completely and only a few neutrophils were observed within glomeruli. Lacidipine had also an inhibitory effect on monocyte infiltration. Semiquantitative cell count analysis confirmed the significant reduction of both neutrophil and mononuclear cell infiltration after lacidipine treatment in kidney (P<0.01).
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We next investigated the effect of lacidipine on the expression of adhesion molecules, as shown in Figure 3 (top panels). Intercellular adhesion molecule-1 (ICAM-1) expression in the kidney was increased in the intima, adventitia, and in the perivascular space of the small vessels in untreated dTGR. Glomeruli and tubules showed increased ICAM-1 expression. The ICAM-1 was significantly reduced by treatment with lacidipine at both doses. In contrast to ICAM-1 expression, vascular cell adhesion molecule-1 (VCAM-1) was mostly observed in the intima of arterioles and, to a lesser extent in the glomerular vascular poles, as well as in the peritubular capillaries (data not shown). As in the case of ICAM-1, treatment with lacidipine prevented the upregulation of VCAM-1 at both doses.
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We next investigated the effects of lacidipine on iNOS expression as shown in Figure 3 (lower panels). We observed a strongly increased expression in the glomeruli and in the vessel wall of renal arterioles from dTGR. Treatment with lacidipine greatly reduced the iNOS immunoreactivity both in the blood vessels and the glomeruli at both doses.
Since matrix expression is involved in scarring, we analyzed the effects of lacidipine on the expression of collagen IV and fibronectin. In untreated dTGR, collagen IV was observed in the peritubular space, as shown in Figure 4. Treatment with lacidipine at both doses prevented the increased expression of collagen IV almost completely, and no significant difference between the lacidipine-treated animals and the SD control animals was observed at week 7. We also observed an increased expression of fibronectin in the renal interstitium. Lacidipine reduced the increased expression of fibronectin significantly at both doses.
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We studied MAP kinase activation by using specific antibodies that only detect the phosphorylated, active form of the enzyme (p-ERK). In untreated dTGR, phosphorylated MAP kinase was increased in the glomeruli and in the peritubular space (data not shown). A similar increase was also present in the medulla. Treatment with lacidipine at either dose abolished this staining pattern both in the cortex and in the medulla.
We next analyzed the activation of the transcription factors NF-B and AP-1 since both regulate ICAM-1 and iNOS gene expression, as shown in Figure 5. Both, NF-B and AP-1 showed greatly increased activity in the kidneys of dTGR compared with SD rats. Lacidipine-treatment reduced the increased levels of NF-B and AP-1 activity. This effect was evident at either dose.
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Discussion |
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We tested the hypothesis that the lipophilic calcium antagonist lacidipine ameliorates renal failure and inhibits inflammatory changes independent of its blood pressure-lowering activities. We used a transgenic animal model of angiotensin II-mediated organ damage and analyzed the effects of lacidipine on adhesion molecule expression, cell infiltration, iNOS expression, and matrix molecule expression. In addition, we investigated whether specific intracellular signaling pathways are influenced by lacidipine. We showed that lacidipine reduces NF-
B activation, prevents inflammatory responses, and altogether ameliorates renal damage. Our animal model features hypertension, albuminuria, severe inflammatory changes with renal damage and focal necrosis, and a 50% mortality at 7 weeks.20 We have previously demonstrated that Ang II is responsible for these effects.21 Our findings strongly suggest that lacidipine influences the angiotensin-induced cellular mechanisms directly in a blood pressure-independent manner. Chronic treatment with a high dosage of lacidipine led to a decrease in blood pressure compared with animals treated with a lower concentration of the dihydropyridine. The decrease in blood pressure with lacidipine may have contributed to the reno-protective effect of the dihydropyridine. However, we do not believe that the blood pressure lowering effect of lacidipine had a major effect because effective antihypertensive treatment by hydralazine, reserpine, and hydrochlorothiazide in our model only partially prevented tissue damage and did not reduce inflammation.22
Treatment with the calcium antagonist lacidipine inhibited the inflammatory process in our animal model considerably. Lacidipine almost abolished neutrophil infiltration. We have previously shown that the specific inhibition of ICAM-1 prevents leukocyte infiltration in the kidney thus ameliorating tissue injury.23,24 Neutrophils are important mediators of injury in many inflammatory diseases.25,26 The prevention of neutrophil infiltration by lacidipine may partially explain the anti-inflammatory effects of dihydropyridines in our model. Furthermore, lacidipine inhibited the expression of the endothelial cell adhesion molecule ICAM-1. Because ICAM-1 is responsible for the neutrophil adhesion to the endothelium and subsequent infiltration,25 it is most likely that lacidipine inhibited neutrophil infiltration via inhibition of ICAM-1. This assumption is supported by earlier findings from Cominacini and coworkers that lacidipine inhibits the ICAM-1 expression in endothelial cells in vitro.13,16 Others have also demonstrated that dihydropyridines affect directly cell infiltration and macrophage activation in vivo.27–29 We have recently shown that dihydropyridines also lead to down-regulation of ICAM-1 and VCAM and influence endothelial cell permeability.30,31
We also demonstrated that monocyte infiltration was reduced by lacidipine. Several reports have demonstrated the participation of monocyte/macrophages in the onset and progression of various renal diseases.32 Since monocytes play a role in long-term pathological changes and chronic renal failure and have been associated with matrix accumulation and fibrosis,33 our findings may implicate that lacidipine has a direct influence on these processes. It has recently been shown that dihydropyridines improve long-term outcome in renal transplantation,34 and the positive effect of lacidipine on chronic vascular changes in the kidney may partially be due to its direct effects on monocyte/neutrophil infiltration.
Lacidipine greatly reduced iNOS expression in the dTGR. Nitric oxide (NO) regulates numerous physiological processes, including smooth muscle contractility, platelet reactivity, and the cytotoxic activity of leukocytes. Because of the ubiquitous nature of NO, inappropriate release of this mediator has been linked to the pathogenesis of a number of disease states.35 While NO serves beneficial roles as a messenger and host defense molecule, excessive NO production can be cytotoxic. The result of NO’s reaction with reactive oxygen and nitrogen species, leads to peroxynitrite anion formation, protein tyrosine nitration, and hydroxyl radical production. NO may contribute to the evolution of several commonly encountered renal diseases, including immune-mediated glomerulonephritis, postischemic renal failure, radiocontrast nephropathy, obstructive nephropathy, and acute and chronic renal allograft rejection.36 NO synthase inhibitors are potentially beneficial in the treatment of conditions associated with an overproduction of NO, including inflammation.37,38 It is therefore likely that the inhibition of the increased NO expression by lacidipine plays an important role in the anti-inflammatory effect of this compounds.
Lacidipine reduced the increased activity of the transcription factors NF-B and AP-1 considerably. NF-B is the main factor in the transcription of NOS, ICAM-1 and VCAM-1 and lacidipine could influence expression of these molecules through inhibition of NF-B.39 Cominachini and coworkers have previously shown that lacidipine inhibits lipopolysaccharide-induced NF-B activation in human mesangial cells in vitro.16 Activation of NF-B could occur through several mechanims. Ruiz-Ortega et al showed that ANG II stimulated NF-B in mesangial cells and that activation of NF-B in the renal cortex was reduced by ACE inhibition.40 Another possibility is the activation of NF-B through oxygen free radicals. Reactive oxygen species represent an important signal transduction pathway inside the cell and also participate in the expression of adhesion molecules on the endothelial cells.41,42 Our results indicate that dihydropyridines interfere with the MAP kinase activation proximal of NF-B activation.
Mostly, the effects of dihydropyridines have been explained via their inhibitory effects on the L-type calcium channel. Recently, several other hypotheses have been postulated. We have observed an inhibitory effect of calcium antagonists on protein kinase C activity without any change in intracellular free calcium concentration.19 The calcium antagonist-mediated effects on gene expression were observed at pharmacological concentrations that are one to two orders of magnitude lower than those required for inhibition of depolarization-induced opening of voltage sensitive L-type calcium channels. Similar observations have been made by other groups.11,19 Recently, Orth et al investigated the effects of calcium antagonists in mesangial cells and could not associate the observed inhibitory effects on cell proliferation with changes in intracellular calcium.12
In summary, we have shown that the dihydropyridine lacidipine ameliorates angiotensin II–induced renal disease independent of its blood pressure lowering effect. In a model of severe organ damage with endothelial cell activation, leukocyte infiltration and sclerosis, we observed an inhibitory effect of lacidipine on adhesion molecule expression, leukocyte infiltration, iNOS activation and matrix molecule expression. We could also demonstrate that intracellular pathways such as MAP kinase and activation of transcription factors were influenced by lacidipine. It remains open whether the observed effects are mediated by calcium channel inhibition or whether other cellular effector mechanisms play a role in the beneficial therapeutic effect of lacidipine.
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Acknowledgments |
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This study was supported by a grant-in-aid from Boehringer-Ingelheim., Germany. We thank Professor Gaviraghi from Glaxo-Wellcome for the compound and critical advice during the study. E.M. was supported by the Alexander von Humboldt Foundation, the Klinisch-pharmakologischer Verbund Berlin-Brandenburg, the Finnish Foundation for Cardiovascular Research, and the Academy of Finland. Ms Christel Lipka and Ms Mathilde Schmidt gave expert technical assistance.
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Footnotes |
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J.-K.P. and A.F. contributed equally to this work.
Received September 24, 2001; first decision November 7, 2001; accepted November 26, 2001.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Epstein M. Calcium antagonists and renal disease. Kidney Int. 1998; 54: 1771–1784.[CrossRef][Medline] [Order article via Infotrieve]
2. Haller H. Calcium antagonists and cellular mechanisms of glomerulosclerosis and atherosclerosis. Am J Kidney Dis. 1993; 21: 26–31.[Medline] [Order article via Infotrieve]
3. Hamaguchi A, Kim S, Wanibuchi H, Iwao H. Angiotensin II and calcium blockers prevent glomerular phenotypic changes in remnant kidney model. J Am Soc Nephrol. 1996; 7: 687–693.[Abstract]
4. Miric G, Dallemagne C, Endre Z, Margolin S, Taylor SM, Brown L. Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol. 2001; 133: 687–694.[CrossRef][Medline] [Order article via Infotrieve]
5. Sabbatini M, Vitaioli L, Baldoni E, Amenta F. Nephroprotective effect of treatment with calcium channel blockers in spontaneously hypertensive rats. J Pharmacol Exp Ther. 2000; 294: 948–954.
6. Blaheta RA, Hailer NP, Brude N, Wittig B, Oppermann E, Leckel K, Harder S, Scholz M, Weber S, Encke A, Markus BH. Novel mode of action of the calcium antagonist mibefradil (Ro 40–5967): potent immunosuppression by inhibition of T-cell infiltration through allogeneic endothelium. Immunology. 1998; 94: 213–220.[CrossRef][Medline] [Order article via Infotrieve]
7. Schiffrin EL. Small artery remodeling in hypertension: can it be corrected? Am J Med. Sci. 2001; 322: 7–11.[CrossRef][Medline] [Order article via Infotrieve]
8. Nayler WG. Calcium channels and their involvement in cardiovascular disease. Biochem Pharmacol. 1992; 43: 39–46.[CrossRef][Medline] [Order article via Infotrieve]
9. Moreyra AE, Gelpi RJ, Mosca SM, Cingolani HE. Chronic administration of nicardipine attenuates myocardial stunning in isolated rabbit hearts. J Mol Cell Cardiol. 1994; 26: 979–984.[Medline] [Order article via Infotrieve]
10. Orth SR, Nobiling R, Bonisch S, Ritz E. Inhibitory effect of calcium channel blockers on human mesangial cell growth: evidence for actions independent of L-type Ca2+ channels. Kidney Int. 1996; 49: 868–879.[Medline] [Order article via Infotrieve]
11. Roth M, Keul R, Emmons LR, Horl WH, Block LH. Manidipine regulates the transcription of cytokine genes. Proc Natl Acad Sci U S A. 1992; 89: 4071–4075.
12. Alexander JJ, Miguel R, Piotrowski JJ. The effect of nifedipine on lipid and monocyte infiltration of the subendothelial space. J Vasc Surg. 1993; 17: 841–847.[CrossRef][Medline] [Order article via Infotrieve]
13. Cominacini L, Pasini AF, Pastorino AM, Garbin U, Davoli A, Rigoni A, Campagnola M, Tosetti ML, Rossato P, Gaviraghi G. Comparative effects of different dihydropyridines on the expression of adhesion molecules induced by TNF-alpha on endothelial cells. J Hypertens. 1999; 17: 1837–1841.[CrossRef][Medline] [Order article via Infotrieve]
14. Bellosta S, Bernini F. Lipophilic calcium antagonists in antiatherosclerotic therapy. Curr Atheroscler Rep. 2000; 2: 76–81.[Medline] [Order article via Infotrieve]
15. Hempel A, C. Maasch U, Heintze C, Lindschau R, Dietz FC, Luft, and Haller. H. High glucose concentrations increase endothelial cell permeability via activation of protein Kinase C alpha. Circ Res. 1997; 81: 363–371.
16. Cominacini L, Garbin U, Fratta Pasini A, Paulon T, Davoli A, Campagnola M, Marchi E, Pastorino AM, Gaviraghi G, Lo Cascio V. Lacidipine inhibits the activation of the transcription factor NF-kappaB and the expression of adhesion molecules induced by pro-oxidant signals on endothelial cells. J Hypertens. 1997; 15: 1633–1640.[CrossRef][Medline] [Order article via Infotrieve]
17. Matsumori A, Nunokawa Y, Sasayama S. Nifedipine inhibits activation transcription factor NF-B. Life Sci. 2000; 67: 2655–2661.[Medline]
[Order article via Infotrieve]
18. Hayashi M, Yamaji Y, Nakazato Y, Saruta T. The effects of calcium channel blockers on nuclear factor kappa B activation in the mesangium cells. Hypertens Res. 2000; 23: 521–525.[Medline] [Order article via Infotrieve]
19. Block LH, Emmons LR, Vogt E, Sachinidis A, Vetter W, Hoppe J. Ca2+-channel blockers inhibit the action of recombinant platelet-derived growth factor in vascular smooth muscle cells. Proc Natl Acad Sci U S A. 1989; 86: 2388–2392.
20. Bohlender J, Fukamizu A, Lippoldt A, Nomura T, Dietz R, Menard J, Murakami K, Luft F, Ganten D. High human renin hypertension in transgenic rats. Hypertension. 1997; 29: 428–437.
21. Luft F, Mervaala E, Muller D, Gross V, Park J-K, Schmitz C, Lippoldt A, Breu V, Dragun D, Dechend R, Schneider W, Ganten D, Haller H. Hypertension-induced end-organ damage: a new transgenic approach to an old problem. Hypertension. 1999; 33: 212–218.
22. Mervaala E, Muller DN, Schmidt F, Park JK, Gross V, Bader M, Breu V, Ganten D, Haller H, Luft FC. Blood pressure-independent effects in rats with human renin and angiotensinogen genes. Hypertension. 2000; 35: 587–594.
23. Dragun D, Tullius SG, Park J-K, Maasch C, Lukitsch I, Lippoldt A, Gross V, Luft FC, Haller H. ICAM-1 antisense oligodesoxynucleotides prevent reperfusion injury and enhance immediate graft function in renal transplantation. Kidney Int. 1998; 54: 590–602.[CrossRef][Medline] [Order article via Infotrieve]
24. Haller H, Maasch C, Dragun D, Wellner M, von Janta-Lipinski M, Luft FC. Antisense oligodesoxynucleotide strategies in renal and cardiovascular disease. Kidney Int. 1998; 53: 50–58.[CrossRef][Medline] [Order article via Infotrieve]
25. Brady HR. Leukocyte adhesion molecules: potential targets for therapeutic intervention in kidney diseases. Curr Opin Nephrol Hypertens. 1993; 2: 171–182.[Medline] [Order article via Infotrieve]
26. Linas SL, Whittenburg D, Parsons PE. Repine JE: Ischemia increases neutrophil retention and worsens acute renal failure: role of oxygen metabolites and ICAM 1. Kidney Int. 1995; 48: 1584–1591.[Medline] [Order article via Infotrieve]
27. Donetti E, Fumagalli R, Paoletti R, Soma MR. Direct antiatherogenic activity of isradipine and lacidipine on neointimal lesions induced by perivascular manipulation in rabbits. Pharmacol Res. 1997; 35: 417–422.[Medline] [Order article via Infotrieve]
28. Corsini A, Accomazzo MR, Canavesi M, Sartani A, Testa R, Catapano AL, Fumagalli R, Paoletti R, Bernini F. The new calcium antagonist lercanidipine and its enantiomers affect major processes of atherogenesis in vitro: is calcium entry involved? Blood Press Suppl. 1998; 2: 18–22.[Medline] [Order article via Infotrieve]
29. Hailer NP, Blaheta RA, Harder S, Scholz M, Encke A, Markus BH. Modulation of adhesion molecule expression on endothelial cells by verapamil and other Ca++ channel blockers. Immunobiology. 1994; 15: 38–51.
30. Haller H, Lindschau C, Quass P, Luft FC. Low-density lipoprotein induces vascular adhesion molecule expression on human endothelial cells. Hypertension. 1995: 511–516.
31. Haller H. Endothelial function. General considerations. Drugs. 1997; 53 (suppl 1): 1–10.[Medline] [Order article via Infotrieve]
32. Cattell V. Macrophages in acute glomerular inflammation. Kidney Int. 1994; 45: 945–952.[Medline] [Order article via Infotrieve]
33. Eddy AA. Experimental insights into the tubulointerstitial disease accompanying primary glomerular lesions. J Am Soc Nephrol. 1994; 5: 1273–1287.[Abstract]
34. Rodicio JL. Calcium antagonists and renal protection from cyclosporine nephrotoxicity: long-term trial in renal transplantation patients. J Cardiovasc Pharmacol. 2000; 35 (3 suppl 1): S7–S11.[Medline] [Order article via Infotrieve]
35. Hobbs AJ, Higgs A, Moncada S. Inhibition of nitric oxide synthase as a potential therapeutic target. Annu Rev Pharmacol Toxicol. 1999; 39: 191–220.[CrossRef][Medline] [Order article via Infotrieve]
36. Klahr S. The role of L-arginine in hypertension and nephrotoxicity. Curr Opin Nephrol Hypertens. 1998; 7: 547–550.[Medline] [Order article via Infotrieve]
37. Kone BC. Nitric oxide in renal health and disease. Am J Kidney Dis. 1997; 30: 311–333.[Medline] [Order article via Infotrieve]
38. Hecker M, Cattaruzza M, Wagner AH. Regulation of inducible nitric oxide synthase gene expression in vascular smooth muscle cells. Gen Pharmacol. 1999; 32: 9–16.[CrossRef][Medline] [Order article via Infotrieve]
39. Alexander RW. Theodore Cooper Memorial Lecture. Hypertension and the pathogenesis of atherosclerosis. Oxidative stress and the mediation of arterial inflammatory response: a new perspective. Hypertension. 1995; 25: 155–161.
40. Ruiz-Ortega M, Bustos C, Hernandez-Presa MA, Lorenzo O, Plaza JJ, Egido J. Angiotensin II participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor-kappa B activation and monocyte chemoattractant protein-1 synthesis. J Immunol. 1998; 161: 430–439.
41. Shono T, Ono M, Izumi H, Jimi SI, Matsushima K, Okamoto T, Kohno K, Kuwano M. Involvement of the transcription factor NF-kappaB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress. Mol Cell Biol. 1996; 16: 4231–4239.[Abstract]
42. Handel ML, Watts CK, Sivertsen S, Day RO, Sutherland RL. D-penicillamine causes free radical-dependent inactivation of activator protein-1 DNA binding. Mol Pharmacol. 1996; 50; 501–505.[Medline] [Order article via Infotrieve]
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