Several metabolic abnormalities may be triggered secondary to
hyperglycemia in diabetes. Some of these abnormalities may alter expression of vasoactive factors in the target organs of
diabetic complications. We investigated alterations of
endothelin-1 (ET-1) and its receptors, ET(A) and ET(B), and associated structural changes in the myocardium of
streptozotocin-induced diabetic rats after 6 months of
hyperglycemia. We further assessed the preventive effects of an ET-receptor antagonist
bosentan on these changes. Compared to the non-diabetic, age- and sex-matched control animals, diabetic rats showed
hyperglycemia, glucosuria, reduced
body weight gain and elevated glycated Hb levels. Measurement of ET-1, ET(A) and ET(B) mRNAs by semiquantitative RT-PCR showed significantly increased
mRNA levels in the hearts of diabetic rats. Treatment with
bosentan failed to reduce ET-1 or ET(B)
mRNA expression in diabetes, however ET(A)
mRNA expression was reduced. Immunocytochemically, ET-1 was detected in the cardiomyocytes, endothelium and smooth muscle cells of the larger blood vessels and was increased in diabetes. Autoradiographic localization of ET-1 receptors, using (125)I-ET-1, showed increased binding in the endothelium and myocardium of diabetic animals. Histologically, focal fibrous
scarring with apoptotic cardiomyocytes, consistent with changes secondary to microvascular occlusion, was only present in the diabetic rats. In keeping with focal
fibrosis, myocardium from diabetic rats further showed significantly increased
mRNA expression of two
extracellular matrix protein transcripts,
fibronectin and
collagen alpha 1(IV) which were completely prevented by treatment with
bosentan. These data suggest that
hyperglycemia-induced upregulation of the ET-system in the heart may be important in the pathogenesis of cardiac involvement in diabetes.