Abnormalities in cardiac alpha 1-adrenoceptor and its signal transduction in streptozocin-induced diabetic rats

Abstract

To investigate a mechanism of diabetic cardiomyopathy, we examined an alteration of cardiac alpha 1-adrenoceptor (alpha 1-AR) signaling in streptozotocin-induced diabetic rats. In diabetes, the cell surface alpha 1-AR concentration on isolated cardiac myocytes decreased by 45% without any change in the dissociation constant, and, moreover, norepinephrine (NE)-stimulated ventricular inositol 1,4,5-trisphosphate (IP3) production was also decreased by 34%. In contrast, basal ventricular protein kinase C (PKC) activity was elevated in both cytosolic (by 98%) and membrane (by 41%) fractions in diabetes. All of these abnormalities seen in diabetes were reversed by chronic insulin treatment. Rapid activation of PKC by phorbol ester in the normal rat heart revealed decreases in both receptor number (by 19%) and NE-stimulated IP3 production (by 21%). These results indicate that the impairment of cardiac alpha 1-AR signaling is closely associated with the diabetic state and may be linked, at least in part, with the abnormal activation of cardiac PKC.