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Discrepant Recovery Course of Sympathetic Neuronal Function and ß-Adrenoceptors in Rat Hearts After Reperfusion Following Transient Ischemia

¹ The Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan
² First Institute of New Drug Research, Otsuka Pharmaceutical Company, Ltd., Tokushima, Japan
³ Research Laboratories, Daiichi Radioisotope Laboratories, Ltd., Chiba, Japan

Cardiac sympathetic neuronal function is closely coupled with ß-adrenoceptors and adrenergic signaling. However, the recovery process of sympathetic neuronal function and ß-adrenoceptors after reperfusion following transient ischemia is not fully understood. Accordingly, this study was performed to investigate serial changes in sympathetic neuronal function and ß-adrenoceptors after transient myocardial ischemia. Methods: The left coronary artery of male Wister rats was ligated for 15 min followed by reperfusion. A dual-tracer method of ¹³¹I-metaiodobenzylguanidine (¹³¹I-MIBG) and ¹²⁵I-iodocyanopindolol (¹²⁵I-ICYP) was used to assess cardiac sympathetic neuronal function and ß-adrenoceptor density on days 1, 3, 7, 14, and 28 after reperfusion. Myocardial norepinephrine (NE) content in ischemic regions (IR) and in remote regions (RR) and hemodynamic indices were determined. Using a membrane preparation of the rat heart after reperfusion, the maximum specific binding (B_max) of ß-adrenoceptors was compared with ¹²⁵I-ICYP accumulation. Results: The maximum value of the rate of change in left ventricular (LV) pressure (dP/dt_max) tended to decrease on day 1 after reperfusion but recovered thereafter. Myocardial NE content was significantly reduced in IR compared with RR on day 1 (272 ± 49 vs. 487 ± 93 ng/g, P < 0.01), and the decrease became more severe on day 14 (36 ± 19 vs. 489 ± 132 ng/g, P < 0.01) and day 28 (37 ± 14 vs. 455 ± 216 ng/g, P < 0.01). Decrease in the IR-to-RR uptake ratio of ¹³¹I-MIBG was modest on day 1 (0.64 ± 0.12) and became more severe on days 7 and 14 (0.38 ± 0.12 and 0.35 ± 0.13, respectively). This reduction was partially restored on day 28 (0.50 ± 0.18). In contrast, the IR-to-RR uptake ratio of ¹²⁵I-ICYP was severely decreased until day 3 (0.60 ± 0.13 on day 1 and 0.54 ± 0.19 on day 3) and recovered thereafter. On day 3, B_max was significantly lower in IR than in RR (83 ± 17 vs. 100 ± 12 fmol/mg, P < 0.05), but the dissociation constant did not differ between the 2 regions. Conclusion: The recovery course of cardiac ¹³¹I-MIBG uptake after reperfusion following transient ischemia is quite different from that of ¹²⁵I-ICYP. Simultaneous scintigraphic portrayal of ß-adrenoceptors together with ¹³¹I-MIBG would provide useful information regarding adrenergic system signaling in patients with coronary artery disease.

Key Words: myocardial ischemia • reperfusion • sympathetic nervous system • ß-adrenergic receptor • radioisotopes

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				N. Igarashi, T. Nozawa, N. Fujii, B.-i. Kato, M. Nonomura, A. Matsuki, T. Nakadate, A. Igawa, H. Asanoi, M. Inoue, et al. Evaluation of Fatty Acid Metabolism in Hearts After Ischemia-Reperfusion Injury Using a Dual-Isotope Autoradiographic Approach and Tissue Assay for Metabolites of Tracer J. Nucl. Med., January 1, 2005; 46(1): 160 - 164. [Abstract] [Full Text] [PDF]