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(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

Joon-Keun Park; Anette Fiebeler; Dominik N. Muller; Eero M.A. Mervaala; Ralf Dechend; Faikah Abou-Rebyeh; Friedrich C. Luft; Hermann Haller

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

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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