Regional alterations of myocardial norepinephrine transporter density in streptozotocin-induced diabetic rats: implications for heterogeneous cardiacaccumulation of MIBG in diabetes

Cardiac scintigraphic studies using iodine-123 labeled metaiodobenzylguanid ine ([I-123]MIBG) have previously demonstrated the heterogeneous myocardial accumulation of radioactivity in diabetes. In this study, we investigated the myocardial regional distribution of [I-125]MIBG and the effects of regi onal myocardial blood flow, myocardial norepinephrine (NE) content, and nor epinephrine transporter (NET) function on regional [I-125]MIBG accumulation in streptozotocin-induced diabetic (STZ-D) rats. Dual-isotope autoradiogra phic studies using [I-125]MIBG and technetium-99m labeled hexakis (2-methox y-2-isobutylisonitrile) (Tc-99m-MIBI), a tracer for the measurement of myoc ardial blood flow, were carried out to investigate the changes in regional myocardial blood flow in STZ-D rats. Uptake of [I-125]MIBG was similar betw een the anterior wall and the inferior wall in control rats. On the other h and, in STZ-D rats, uptake of [I-125]MIBG in the inferior wall was signific antly less than that in the anterior wall. Uptake of 99mTc-MIBI was not sig nificantly different between the anterior and inferior walls in control or STZ-D rats, indicating that myocardial blood flow did not change regionally in either control or STZ-D rats, and that the blood flow was not responsib le for the heterogeneity of the distribution of [I-125]MIBG in STZ-D rats. In STZ-D rats, cardiac NE concentrations determined using an HPLC-electroch emical detection (ECD) system were significantly increased in both the ante rior and the inferior wall, although there was no significant difference in NE concentration between the anterior and inferior walls in control or STZ -D rats. Furthermore, the density and affinity of NET were investigated by studying the binding of [H-3]desipramine to cardiac membranes. The B-max va lues of the NET in the anterior wall were not significantly different betwe en control and STZ-D rats, but the B-max value of the NET in the inferior w all was significantly lower in STZ-D rats than in controls. In conclusion, myocardial MIBG uptake was reduced in the inferior wall of STZ-D rats compa red with control rats; this decrease was correlated with the decrease in NE T density, but was not dependent on the regional myocardial blood flow and NE concentration. These results suggest that regional fluctuations in NET l evels in the inferior wall contribute to heterogeneous MIBG accumulation in diabetes.