ENDOTHELIAL RELAXATION IS DISTURBED BY OXIDATIVE STRESS IN THE DIABETIC RAT-HEART - INFLUENCE OF TOCOPHEROL AS ANTIOXIDANT

Increased oxidative stress has been suggested to contribute to disturb ances in the regulation of coronary flow and the increased cardiac ris k in diabetes mellitus, Using the isolated perfused heart of streptozo tocin-diabetic rats our study shows that basal and maximal coronary fl ow (tested by infusion of sodium nitroprusside) are not altered in dia betes, but that 5-hydroxytryptamine (5-HT) stimulated endothelium-depe ndent increase in coronary flow becomes progressively impaired. This d efect of the endothelium-dependent vasodilatation was prevented by per fusion of the hearts with superoxide dismutase and pretreatment of the diabetic rats with tocopherol-acetate. Morphological studies also rev ealed that pretreatment with tocopherol-acetate was cardioprotective, and largely prevented severe alterations of myocardial structure typic ally observed after a diabetes duration of 3 months; deterioration and fragmentation of myofilament bundles were seen less, and the numbers of areas of focal necrosis and of contraction bands were clearly reduc ed. In contrast to untreated diabetic hearts the autonomic nerve fiber s detected by catecholamine fluorescence were running in parallel in h earts of tocopherol-treated diabetic rats, and the amount of catechola mines was not different from that of healthy control rats. Trichrome s taining and immunohistochemical staining of collagen I and III showed a dramatic increase in the number and the size of deposits of collagen fibers at precapillary locations in the diabetic hearts which were si gnificantly reduced by anti-oxidative treatment. These findings demons trate that oxidative stress may not only play a major role in the impa irment of endothelium-dependent regulation of coronary flow, but also in the development of perivascular fibrosis and severe changes of the autonomic nerves and contractile system in myocardium.