Lacidipine inhibits adhesion molecule and oxidase expression independent of blood pressure reduction in angiotensin-induced vascular injury.
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)-kappaB 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-kappaB 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-kappaB activation.
Park
Joon-Keun
JK
Department of Nephrology, Medical School Hannover, Germany.
Fiebeler
Anette
A
Muller
Dominik N
DN
Mervaala
Eero M A
EM
Dechend
Ralf
R
Abou-Rebyeh
Faikah
F
Luft
Friedrich C
FC
Haller
Hermann
H
D000809:Angiotensins; D000818:Animals; D001794:Blood Pressure; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D004095:Dihydropyridines / Q000494:pharmacology*; D004195:Disease Models, Animal; D010088:Oxidoreductases / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014652:Vascular Diseases / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*
D000809:Angiotensins; D015815:Cell Adhesion Molecules; D004095:Dihydropyridines; C060285:lacidipine; D010088:Oxidoreductases