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(Hypertension. 2000;35:992.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Synergistic Effects of AT₁ and ET_A Receptor Blockade in a Transgenic, Angiotensin II–Dependent, Rat Model

Jürgen Bohlender; Stephan Gerbaulet; Jochen Krämer; Michael Gross; Michael Kirchengast; Rainer Dietz

From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine (J.B., S.G., J.K., M.G., R.D.), Medical Faculty of the Charité, Humboldt University of Berlin, Germany; and Knoll AG (M.K.), Ludwigshafen, Germany.

Correspondence to Dr Jürgen Bohlender, Max-Delbrück-Center, Robert-Rössle-Str 10, D-13092 Berlin, Germany.

Abstract—Angiotensin II and endothelin may participate in increasing blood pressure and inducing end-organ damage, but the evidence is conflicting. We tested the hypothesis that endothelin_A receptor blockade would ameliorate blood pressure and end-organ damage in a rat model of human renin-dependent hypertension. We studied rats that were transgenic for both the human renin and angiotensinogen genes. Experimental groups (n=12 each) of untreated transgenic rats, transgenic rats receiving subdepressor doses of losartan (10 mg/kg), transgenic rats receiving LU 135252 (30 mg/kg), transgenic rats receiving both drugs, and nontransgenic rats were studied between 6 to 10 weeks of age. Blood pressure was measured with tail-cuff sphygmomanometry. Gene expression for atrial natriuretic peptide, collagen III, and ACE was measured. The mortality rate in untreated transgenic rats was 42%, which is consistent with previous observations in this line. Single losartan or LU 135252 treatment reduced mortality incidence to 1 rat per group (8%), without significantly lowering blood pressure. In the combination group, blood pressure was normalized and all rats survived. The drug combination also decreased elevated water intake in transgenic rats to normal levels and significantly reduced cardiac hypertrophy. Furthermore, the combination of drugs decreased cardiac atrial natriuretic peptide, ACE gene, and renal collagen III gene expression. We suggest that endothelin participates in this model of angiotensin II–induced hypertension and end-organ damage. Our findings may have clinical implications and provide a rationale for combining angiotensin II type 1 receptor and endothelin_A receptor blockade to obtain a synergistic effect.

Key Words: endothelin • angiotensin • rats, transgenic • hypertrophy, cardiac • thirst • hypertension, arterial

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