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(Hypertension. 2007;49:481.)
© 2007 American Heart Association, Inc.

Original Articles

p38 Mitogen-Activated Protein Kinase Inhibition Ameliorates Angiotensin II–Induced Target Organ Damage

Joon-Keun Park; Robert Fischer; Ralf Dechend; Erdenechimeg Shagdarsuren; Andrej Gapeljuk; Maren Wellner; Silke Meiners; Petra Gratze; Nidal Al-Saadi; Sandra Feldt; Anette Fiebeler; Jeffrey B. Madwed; Alexander Schirdewan; Hermann Haller; Friedrich C. Luft; Dominik N. Muller

From the Medical Faculty of the Charité (R.F., R.D., A.G., M.W., S.M., N.A.-S., S.F., A.F., A.S., F.C.L., D.N.M.), Franz Volhard Clinic, HELIOS Klinikum, Berlin, Germany; Max Delbrück Center for Molecular Medicine (P.G., F.C.L., D.N.M.), Berlin-Buch, Germany; Institute for Molecular Cardiovascular Research (E.S.), RWTH Aachen University, University Hospital Aachen, Aachen, Germany; the Medical School of Hannover (J.-K.P., H.H.), Hannover, Germany; and Boehringer-Ingelheim Pharmaceuticals (J.B.M.), Ridgefield, Conn.

Correspondence to Dominik N. Muller, Max-Delbruck Center, Wiltberg Strasse 50, 13125 Berlin, Germany. E-mail dominik.mueller{at}mdc-berlin.de

We investigated whether or not p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II–induced target organ damage. We used double transgenic rats harboring both human renin and angiotensinogen genes (dTGRs). dTGR, with or without p38 inhibitor (BIRB796; 30 mg/kg per day in the diet), and nontransgenic Sprague–Dawley rats were studied in 2 protocols. In protocol 1 (week 7), systolic blood pressure of untreated dTGRs was 204±4 mm Hg, but partially reduced after BIRB796 treatment (166±7 mm Hg), whereas Sprague–Dawley rats were normotensive. The cardiac hypertrophy index was unchanged in untreated and BIRB796-treated dTGRs. The ß-myosin heavy chain expression of BIRB796-treated hearts was significantly lower in BIRB796 compared with dTGRs, indicating a delayed switch to the fetal isoform. BIRB796 treatment significantly reduced cardiac fibrosis, connective tissue growth factor, tumor necrosis factor-, interleukin-6, and macrophage infiltration. Albuminuria was not reduced in BIRB796-treated dTGRs. Tubular and glomerular damage with tumor necrosis factor- expression was unaltered, although serum creatinine and cystatin C were normalized. Renal macrophage infiltration, fibrosis, and vessel damage were reduced. In protocol 2 (week 8), we focused on mortality and arrhythmogenic electrical remodeling. Mortality of untreated dTGRs was 100% but was reduced to 10% in the BIRB796 group. Cardiac magnetic field mapping showed prolongation of depolarization and repolarization in untreated dTGRs compared with Sprague–Dawley rats with a partial reduction by BIRB796. Programmed electrical stimulation elicited ventricular tachycardias in 81% of untreated dTGRs but only in 48% of BIRB796-treated dTGRs. In conclusion, BIRB796 improved survival, target organ damage, and arrhythmogenic potential in angiotensin II–induced target organ damage.

Key Words: angiotensin II • p38 • electrical remodeling • cardiac and renal damage