Vol. 293, Issue 2, 351-359, May 2000

Long-Term Effects of the Endothelin_A Receptor Antagonist LU 135252 and the Angiotensin-Converting Enzyme Inhibitor Trandolapril on Diabetic Angiopathy and Nephropathy in a Chronic Type I Diabetes Mellitus Rat Model

Stefan Dhein, Stefan Hochreuther, Christian aus dem Spring, Klaus Bollig, Christine Hufnagel and Manfred Raschack

Institute of Pharmacology, University of Halle, Halle, Germany (S.D.); Institute of Pharmacology, University of Cologne, Cologne, Germany (S.H., C.a.d.S., K.B.); and Knoll AG, Ludwigshafen, Germany (C.H., M.R.)

Diabetic angiopathy is a serious problem in antidiabetic therapy. We wanted to investigate whether treatment with the endothelin_A receptor antagonist LU 135252 or with the angiotensin-converting enzyme inhibitor trandolapril might prevent angiopathy in long-term type I diabetes mellitus. Six groups of male Wistar rats were investigated: untreated age-matched control rats, healthy controls treated with trandolapril (0.3 mg/kg), healthy controls treated with LU 135252 (100 mg/kg), untreated diabetic rats, and diabetic rats treated with either trandolapril or LU 135252. Rats were rendered diabetic by injection of streptozotozin. Duration of the disease was 6 months. Thereafter, rats were sacrificed, and hearts, kidneys, and a mesenterial loop were removed. Hearts and kidneys were processed histologically; the mesenterial loop was perfused with saline at constant pressure for investigation of microvessels using microvideoangiometry while treated with either 30 mM KCl, 1 µM acetylcholine, or 1 µM sodium nitroprusside. All diabetic rats developed hyperglycemia without differences among these three groups. Diabetic rats exhibited marked anemia, which was significantly antagonized by both treatments. The heart capillaries/muscle fibers ratio was decreased significantly in diabetic animals, which was prevented fully by both treatments. Renal glomerular diameter was increased in diabetic rats. This was significantly antagonized by LU 135252 but not by trandolapril. Deposition of homogeneous eosinophilic material within the glomeruli was nearly completely prevented by LU 135252. The acetylcholine-induced vasodilation in mesenteric microvessels was significantly attenuated in diabetic rats, which was significantly antagonized by both treatments. We conclude that both angiotensin and endothelin seem to contribute to the development of diabetic angiopathy and that, in addition to angiotensin-converting enzyme inhibition, blockade of endothelin_A receptors may be an interesting new approach to antiangiopathic therapy.