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

Kiyono, Yasushi; Iida, Yasuhiko; Kawashima, Hidekazu; Ogawa, Mikako; Tamaki, Nagara; Nishimura, Hiroshi; Saji, Hideo

doi:10.1007/s00259-002-0798-1

Cited by 25 publications

(19 citation statements)

References 37 publications

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“…One study, however, found similar cardiac MIBG uptake between the anterior and inferior regions of the rat heart in a model of non-insulin dependent DM. 42 We cannot plausibly explain these disparate results, including those of the present study. However, differences in the MATSUKI A et al…”

Section: Cardiac Mibg Accumulationcontrasting

confidence: 67%

“…Impaired cardiac norepinephrine uptake in diabetic hearts determined using MIBG or 11 C-hydroxyephedrine is accompanied by decreases in cardiac norepinephrine transporter density 42 and nerve growth factor protein. 43 The etiology of cardiac sympathetic nerve dysfunction in DM remains unclear, but the following mechanisms have been proposed: (1) degeneration of proteins critical to neural function by non-enzymatic glycosylation; 44 (2) reduction of neurotrophic factors; 45 (3) altered neural polyol metabolism; 10 and (4) microvascular disease with impaired blood flow.…”

Section: Cardiac Mibg Accumulationmentioning

confidence: 99%

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Fluvastatin Attenuates Diabetes-Induced Cardiac Sympathetic Neuropathy in Association With a Decrease in Oxidative Stress

Matsuki

Nozawa

Igarashi

et al. 2010

Circ J

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Background: Increased oxidative stress might contribute to diabetic (DM) neuropathy, so the effects of longterm treatment with fluvastatin (FL) on myocardial oxidative stress and cardiac sympathetic neural function were investigated in diabetic rats.Methods and Results: FL (10 mg · kg -1 · day -1 , DM-FL) or vehicle (DM-VE) was orally administered for 2 weeks to streptozotocin-induced DM rats. Cardiac oxidative stress was determined by myocardial 8-iso-prostaglandin F2α (PGF2α) and NADPH oxidase subunit p22 phox mRNA expression. Sympathetic neural function was quantified by autoradiography using 131 I- and 125 I-metaiodobenzylguanidine (MIBG). FL did not affect plasma glucose levels but remarkably decreased PGF2α levels compared with DM-VE rats (13.8±9.2 vs 175.0±93.9 ng/g tissue), although PGF2α levels were below the detection limit in non-DM rats. FL significantly reduced myocardial p22 phox mRNA expression. Cardiac 131 I-MIBG uptake was lower in DM-VE rats than in non-DM rats, but the decrease was attenuated in DM-FL rats (1.31±0.08, 1.88±0.22, and 1.58±0.18 %kg dose/g, respectively, P<0.01). Cardiac MIBG clearance was not affected by the induction of DM or by FL, indicating that the reduced MIBG uptake in DM rats might result from impaired neural function. Diabetes-Induced Cardiac NeuropathyExperimental Animals DM was induced in male Wistar rats weighing 250-300 g by an intraperitoneal injection of 65 mg/kg of streptozotocin (STZ, n=40). Non-DM control rats (n=14) were not injected with STZ. The rats with glucose levels >250 mg/dl at 1 week after STZ injection were considered diabetic (n=28) and used in the experiments. Two weeks later, fluvastatin (10 mg · kg -1 · day -1 , n=14) or vehicle (DM controls: 0.1% carboxymethyl cellulose, n=14) was orally administered by gavage for 2 weeks. Standard rat chow and tap water were provided ad libitum throughout the study.Systolic blood pressure and heart rate were measured using an indirect tail-cuff method (BP-98A, Softron) and lipid peroxides (LPO) in plasma were determined using a hemoglobin-methylene blue method that selectively detects the absolute quantity of LOOH. Cardiac oxidative stress was then assessed as the levels of 8-isoprostaglandin F2α (PGF2α) and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase subunit p22 phox mRNA expression, and cardiac sympathetic neural function was assessed using 131 I-and 125 Ilabeled MIBG.Radioactive MIBG Tracers FUJIFILM RI Pharma Co Ltd (Tokyo, Japan) prepared and supplied 131 I-and 125 I-labeled MIBG at a radiochemical purity >98%, and specific activity of 30-70 GBq/mmol. Cardiac MIBG AccumulationDual-tracer autoradiography proceeded as described. 22,23 Briefly, 0.37 MBq of 125 I-MIBG was injected via the external jugular vein under pentobarbital sodium anesthesia (30 mg/kg, ip). Two hours later, 1.85 MBq of 131 I-MIBG was intravenously injected and 30 min thereafter, the heart was removed and washed in cold saline. Specimens were frozen in isopentane, cooled in dry ice, embedded in methyl cellulose and cut in...

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Section: Cardiac Mibg Accumulationcontrasting

confidence: 67%

Section: Cardiac Mibg Accumulationmentioning

confidence: 99%

Fluvastatin Attenuates Diabetes-Induced Cardiac Sympathetic Neuropathy in Association With a Decrease in Oxidative Stress

Matsuki

Nozawa

Igarashi

et al. 2010

Circ J

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“…A report noted that in a diabetic rat model, both cardiac and plasma norepinephrine levels were unchanged between diabetic and control rats, but decreased 123 I-MIBG-derived myocardial radioactivity was related to diminished transporter density. 17 Other animal studies have reported increased cardiac uptake-1 expression in the setting of high norepinephrine concentrations. 18,19 Moreover, downregulation of the transporter by pheochromocytoma would not explain normal 6-[…”

Section: Discussionmentioning

confidence: 97%

Cardiac Uptake-1 Inhibition by High Circulating Norepinephrine Levels in Patients with Pheochromocytoma

et al. 2004

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Abstract-Neuronal reuptake (uptake-1) constitutes the main route of inactivation of the sympathetic neurotransmitter norepinephrine in the heart and therefore contributes importantly to cardiac sympathetic neuroeffector function. In laboratory animals and in vitro preparations, half saturation of the transporter occurs at norepinephrine concentrations of 0.1 to 1 mol/L. This study addressed whether endogenous norepinephrine can attain high enough plasma concentrations in humans to inhibit cardiac uptake-1. Patients with increased plasma norepinephrine levels due to pheochromocytoma were assessed by 6-[ 18 F]fluorodopamine positron emission tomography. Above an antecubital venous plasma concentration of 3 nmol/L (Ϸ500 pg/mL), left ventricular myocardial 6-[18 F]fluorodopamine-derived radioactivity varied inversely with the logarithm of the plasma norepinephrine concentration (rϭϪ0.77, PϽ0.0001). Reduction of plasma norepinephrine levels by treatment of the pheochromocytoma increased myocardial 6-[18 F]fluorodopamine-derived radioactivity. At sufficiently high plasma concentrations, endogenous norepinephrine can compete with sympathetic imaging agents for uptake-1. The results call for caution in drawing quantitative conclusions about uptake-1 in the setting of high circulating concentrations of endogenous norepinephrine. Key Words: heart Ⅲ norepinephrine Ⅲ pheochromocytoma Ⅲ radiography N euronal reuptake of the sympathetic neurotransmitter norepinephrine through the membrane norepinephrine transporter 1-3 (also known as uptake-1) is a key determinant of inactivation of norepinephrine in the heart and, therefore, of cardiac sympathetic neuroeffector function. Cardiac sympathetic neuroimaging, using radiolabeled sympathomimetic amines such as 123 I-or 131 I-metaiodobenzylguanidine (MIBG) or catecholamines such as 6-[18 F]fluorodopamine, depends on uptake of the imaging agent into sympathetic nerves through the cell membrane norepinephrine transporter.Pheochromocytoma tumor cells also express the cell membrane norepinephrine transporter. Scintigraphy or singlephoton emission-computed tomography after injection of radioiodinated MIBG or positron emission tomography after injection of 6-[18 F]fluorodopamine aids diagnostic localization of pheochromocytoma. 4 Preclinical studies dating back to the 1960s have demonstrated saturability of uptake-1, with a K m in the range of 0.1 to 1 mol/L. 5,6 Since plasma norepinephrine levels in humans normally average about 3 nmol/L, increasing by at most 10-to 20-fold in extreme situations, one might presume that circulating norepinephrine would exert little impact on the efficiency of uptake-1. Reports that patients with high circulating norepinephrine concentrations due to pheochromocytoma can have decreased myocardial MIBG-derived radioactivity, however, have called this view into question. [7][8][9] In the present study, we show that myocardial 6-[18 F]fluorodopamine-derived radioactivity decreased when plasma norepinephrine levels were markedly elevated in patients with pheoch...

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“…Once carried to the nervous terminals, the tracer is taken up by cardiac sympathetic neurons and stored in adrenergic vesicles via a specific norepinephrine transporter (NET) (9)(10)(11)(12)(13)(14)(15). Using this tool, several clinical studies (4,5,16,17) documented an accelerated tracer washout from the heart that was experimentally found to be an index of impaired norepinephrine reuptake due to reduced NET expression in the diabetic myocardium (18)(19)(20). Most of these studies, however, also reported that such an accelerated cardiac loss of MIBG was associated with a relatively preserved initial uptake in most diabetic patients (4,5,16,17), especially when tracers with high specific activity were used (21).…”

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confidence: 99%

Whole-Body Evaluation of MIBG Tissue Extraction in a Mouse Model of Long-Lasting Type II Diabetes and Its Relationship with Norepinephrine Transport Protein Concentration

Kusmic

Morbelli

Marini³

et al. 2008

J Nucl Med

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Accelerated cardiac washout of 123 I-metaiodobenzylguanidine (MIBG), which is clinically used as an index of cardiac neuropathy in diabetes, is ascribed to decreased norepinephrine reuptake into synaptic vesicles. However, accelerated washout frequently contrasts with preserved early tracer uptake, whose significance remains undetermined. The aim of this study was to investigate in a mouse model of long-lasting type II diabetes whether the mismatch between MIBG early uptake and washout is the consequence of a more generalized disorder of the autonomic nervous system. Methods: Nine mice were given low doses of streptozotocin by intraperitoneal injection for 5 consecutive days. At 7 mo after streptozotocin, MIBG kinetics were evaluated by heart and liver time-activity curves and by tracer accumulation in the bladder. Data were compared with those obtained in 10 sham mice and correlated with the cardiac and hepatic tissue expression of norepinephrine transporter (NET) as assessed with a 3 H-desipramine saturation binding assay. Results: In diabetic mice, myocardial and liver MIBG retention was reduced at 2 h and was associated with both increased tracer washout and reduced NET density. The rate of myocardial washout correlated with the degree of urinary MIBG excretion. Conclusion: The paradoxic observation of preserved early uptake associated with accelerated washout of MIBG in diabetes seems to be explained by a generalized disorder in NET function leading to reduced whole-body tracer removal from the blood and increased tracer availability for early myocardial uptake.

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

Cited by 25 publications

References 37 publications

Fluvastatin Attenuates Diabetes-Induced Cardiac Sympathetic Neuropathy in Association With a Decrease in Oxidative Stress

Fluvastatin Attenuates Diabetes-Induced Cardiac Sympathetic Neuropathy in Association With a Decrease in Oxidative Stress

Cardiac Uptake-1 Inhibition by High Circulating Norepinephrine Levels in Patients with Pheochromocytoma

Whole-Body Evaluation of MIBG Tissue Extraction in a Mouse Model of Long-Lasting Type II Diabetes and Its Relationship with Norepinephrine Transport Protein Concentration

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