Norepinephrine transporter density as a causative factor in alterations in MIBG myocardial uptake in NIDDM model rats

Abstract.

Cardiac scintigraphic studies with iodine-123 labeled metaiodobenzylguanidine ([¹²³I]MIBG) have demonstrated global and regionally pronounced decreases in myocardial accumulation of radioactivity in diabetes. The aim of this study was to investigate the cause of the regional differential decrease in accumulation. To this end, we investigated the global and regional myocardial distribution of [¹²⁵I]MIBG in GK/Crj (GK) rats [a model of non-insulin-dependent diabetes mellitus (NIDDM)] and assessed the responsibility of regional myocardial blood flow, myocardial and plasma norepinephrine (NE) content, and norepinephrine transporter (NET) function for the regional variations in [¹²⁵I]MIBG accumulation. To investigate the responsibility of myocardial blood flow for the alterations in MIBG accumulation, dual-isotope autoradiographic studies with [¹²⁵I]MIBG and technetium-99m hexakis-2-methoxy-2-isobutylisonitrile (MIBI), a tracer for the measurement of myocardial blood flow, were carried out in GK rats and control rats. The results in respect of the uptake of radioactivity into various myocardial regions were expressed as distribution absorption ratios [DAR = (radioactivity of tissue/g of tissue) × (body weight/total injected dose)]. In control rats, uptake of [¹²⁵I]MIBG was significantly higher in the inferior wall than in the anterior wall (anterior wall, 6.35±0.90; inferior wall, 8.12±1.27: P<0.001). On the other hand, in GK rats, uptake of [¹²⁵I]MIBG was similar between the anterior wall and the inferior wall (anterior wall, 4.91±0.71; inferior wall, 4.81±0.69). Compared with control rats, uptake of [¹²⁵I]MIBG in GK rats was decreased in both the anterior wall and the inferior wall. Uptake of ^99mTc-MIBI was not significantly different between the anterior and inferior walls in control (anterior wall, 17.9±4.42; inferior wall, 18.1±4.52) and GK rats (anterior wall, 16.6±8.03; inferior wall, 16.7±7.90), indicating that myocardial blood flow did not change regionally in either control or GK rats, and that the blood flow was not responsible for the differential decrease in MIBG accumulation in GK rats. Cardiac and plasma NE levels were measured using an HPLC-electrochemical detection system. The cardiac and plasma NE concentrations were not significantly different between control (anterior wall, 347±56 ng/g; inferior wall, 354±31 ng/g; plasma 9.38±2.10 ng/ml) and GK rats (anterior wall, 323±62 ng/g; inferior wall, 344±35 ng/g; plasma, 9.41±2.39 ng/ml). The density and affinity of NET were investigated by studying the binding of [³H]desipramine to cardiac membranes. The B _max (fmol/mg protein) in the inferior wall was significantly higher than that in the anterior wall in the control rats (anterior wall, 364±28; inferior wall, 459±36: P<0.05). On the other hand, there was no significant difference in the B _max value between the anterior and inferior walls in GK rats (anterior wall, 263±42; inferior wall, 251±27). In conclusion, myocardial MIBG uptake was differentially reduced in GK rats, and this decrease was associated with a decrease in NET density, but the regional myocardial blood flow and the NE concentration were not responsible for the alterations in MIBG uptake. Thus, NET density was identified as the factor responsible for decreases in MIBG accumulation.