ENDOTHELIN ANTAGONISM IN END-ORGAN DAMAGE OF SPONTANEOUSLY HYPERTENSIVE RATS - COMPARISON WITH ANGIOTENSIN-CONVERTING ENZYME-INHIBITION ANDCALCIUM ANTAGONISM

High blood pressure results in cardiac hypertrophy and fibrosis, incre ased thickness and stiffness of large artery walls, and decreased rena l function. The objective of our study was to assess the role of endot helin, angiotensin II, and high blood pressure in the end-organ damage observed in spontaneously hypertensive rats (SHR). For this purpose, SHR were treated for 10 weeks with either a mixed endothelin-A and end othelin-B receptor antagonist, bosentan (100 mg/kg per day), an angiot ensin-converting enzyme inhibitor, enalapril (10 mg/kg per day), or a long-acting calcium antagonist, mibefradil (20 mg/kg per day). A group of SHR was left untreated, and a group of normotensive Wistar rats wa s used as control. At the end of treatment, maximal coronary blood flo w was measured in isolated perfused hearts. Cardiac hypertrophy and fi brosis, aortic medial thickness, and extracellular matrix content were evaluated by quantitative morphometry. Proteinuria and urea and creat inine clearances were measured, and renal histopathology was assessed. SHR exhibited cardiac hypertrophy, perivascular fibrosis, and decreas ed maximal coronary blood Bow. Aortic medial thickness was increased, whereas elastin density was decreased. Finally, SHR showed decreased u rinary excretion and decreased urea and creatinine clearances. No rena l histological lesions were observed. Although bosentan did not affect blood pressure, it normalized renal function and slightly decreased l eft ventricular hypertrophy and fibrosis. Enalapril and mibefradil wer e both effective in significantly decreasing blood pressure, left vent ricular hypertrophy, and aortic medial thickness and improving coronar y blood flow, but in contrast to busentan, they did not improve creati nine clearance. The conclude that in SHR, high blood pressure sure pla ys a major role in end-organ damage and that endothelin may partly med iate renal dysfunction and cardiac remodeling independently of a direc t hemodynamic effect.