Angiotensin II type 1 and endothelin type A receptor antagonists modulate the extracellular matrix regulatory system differently in diastolic heart failure

Objective Ventricular fibrosis plays a pivotal role in the development of diastolic heart failure and is a therapeutic target; however, the effects of pharmacological interventions on the extracellular matrix (ECM) regulatory system in diastolic heart failure remain to be clarified. Design and methods Dahl salt-sensitive rats fed on a diet containing 8% NaCl from age 7 weeks-a hypertensive diastolic heart failure model-were divided into untreated rats, rats treated with angiotensin II type 1 (AT1) receptor antagonist and those treated with endothelin type A (ETA) receptor antagonist. Results Ventricular fibrosis progressed in the untreated rats, with increases in mRNA levels of type I collagen, matrix metalloproteinase-2, -9 and -13, and tissue inhibitor of metalloproteinase-1 and -2. Both antagonists attenuated ventricular fibrosis to the same degree. AT1 receptor blockade decreased the type I collagen mRNA level more than ETA receptor blockade. ETA receptor blockade did not decrease the matrix metalloproteinase-2 mRNA level that was decreased by AT1 receptor blockade, and decreased the tissue inhibitor of metal loproteinase-2 mRNA level that was not affected by AT1 receptor blockade. These led to a higher ratio of matrix metal loproteinase-2 to tissue inhibitor of metalloproteinase-2 mRNA levels and a greater 72-kDa gelatinase activity in the rats treated with ETA receptor antagonist than in those treated with AT1 receptor antagonist, and may well cancel out the lesser decline in collagen synthesis, resulting in the equivalent attenuation of ventricular fibrosis. Conclusions AT1 receptor and ETA receptor antagonists provide their beneficial effects on the ECM through different modulation of its regulatory system. J Hypertens 21:437-444 (C) 2003 Lippincott Williams Wilkins.