Increasing synaptic noradrenaline, serotonin and histamine enhances in vivo binding of phosphodiesterase-4 inhibitor (R)-[11C]rolipram in rat brain, lung and heart

Lourenço, Célia; Kenk, Miran; DaSilva, Jean N.

doi:10.1016/j.lfs.2006.01.010

Cited by 27 publications

(22 citation statements)

References 45 publications

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“…To our knowledge, there are no reports on the effect of desipramine on (R)-11 C-rolipram metabolism. Despite this potential effect, the rolipram blocking and desipramine results are in good agreement with the percentage changes reported in our previous ex vivo biodistribution studies (10,11).…”

Section: Discussionsupporting

confidence: 91%

“…This follows the increase reported using ex vivo biodistribution, for which a 21% increase in (R)-11 C-rolipram specific binding in the heart was attributed to desipramine treatment (10). Interestingly, a 23% reduction in MBF was observed in these studies using 13 N-ammonia imaging.…”

Section: Discussionsupporting

confidence: 85%

“…High liver activity is typical of radiotracers that undergo hepatic metabolism, and it has been demonstrated that liver activity associated with (R)-11 C-rolipram does not represent specific binding (11). Conversely, the tracer accumulation in cardiac and brain tissues confirms previous in vivo biodistribution studies (10,11) and imaging experiments (4-7), reflecting the high PDE4 levels in these tissues (18).…”

Section: Discussionsupporting

confidence: 69%

“…Our previous in vitro work demonstrated specific and selective PDE4 binding in the rat heart (10)(11)(12). Thus, the aim of the present study was to characterize the in vivo binding specificity, responsiveness to acute norepinephrine treatment, and reproducibility of (R)-11 C-rolipram imaging in the rat myocardium with small-animal PET.…”

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confidence: 91%

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PET of (R)-¹¹C-Rolipram Binding to Phosphodiesterase-4 Is Reproducible and Sensitive to Increased Norepinephrine in the Rat Heart

Thomas¹,

DaSilva²,

Lortie³

et al. 2011

J Nucl Med

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Phosphodiesterase-4 (PDE4) plays a critical role in the regulation of b-adrenergic receptor-stimulated cyclic adenosine monophosphate cell signaling in the heart. (R)-rolipram, a PDE4-selective inhibitor, has been studied previously as a radiotracer for the quantification of PDE4 levels. The aim of this study was to characterize (R)-11 C-rolipram binding in the rat myocardium in vivo, using small-animal PET. Methods: Male Sprague-Dawley rats (n 5 30) were administered (R)-11 C-rolipram and imaged for 60 min to evaluate tracer binding and reproducibility, quantified using Logan slope analysis of the distribution volume. Dynamic 13 N-ammonia imaging was performed to quantify myocardial blood flow and assist in cardiac regional analysis. Saturation studies evaluated the sensitivity of (R)-11 C-rolipram to PDE4 blocking by unlabeled cold (R)-rolipram (0.0001-1.0 mg/kg), for estimation of the median effective dose (ED 50 ) in the heart. (R)-11 C-rolipram response to enhanced norepinephrine stimulation of the b-adrenergic receptor with desipramine (20 mg/kg, intravenous) was also studied. Intrarat variability studies (n 5 5) were conducted with test-retest imaging at 16 6 7 d. Results: A reduction of Logan slope was observed with increasing cold mass coadministered with the tracer, with an ED 50 of 0.0019 mg/kg (95% confidence interval, 0.0014-0.0052) estimated from the saturation studies. This ED 50 predicted less than 10% enzyme occupancy at 0.0002 mg of cold (R)-rolipram per kilogram (mass/body weight). Low-occupancy imaging at 0.00018 6 0.00002 mg/kg produced a mean Logan slope of 5.5 6 0.85 mL/cm 3 . Enzyme saturation of more than 90%, compared with low-occupancy conditions, occurred at more than 0.02 mg/kg, with a complete blocking dose (.1 mg of (R)-rolipram per kilogram) resulting in a Logan slope of 3.3 6 0.1 mL/cm 3 , representing a 40% reduction. Compared with baseline, a Logan slope of 6.8 6 0.7 mL/cm 3 in desipramine-challenged animals was observed, representing a 30% increase due to acute norepinephrine stimulation, despite a reduction in myocardial blood flow. Intrarat and intraoperator variability was less than 5% between repeated measures. Conclusion: (R)-11 C-rolipram shows the ability to monitor increases and decreases in PDE4 availability in the rat myocardium, with good reproducibility.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 69%

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confidence: 91%

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PET of (R)-¹¹C-Rolipram Binding to Phosphodiesterase-4 Is Reproducible and Sensitive to Increased Norepinephrine in the Rat Heart

Thomas¹,

DaSilva²,

Lortie³

et al. 2011

J Nucl Med

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“…Imaging of brown adipose tissue, lung, and pancreas present unique and formidable challenges because of problems in localization and signal identification for brown adipose tissue (3), low in vivo tissue density hindering acquisition of high-contrast images for lung (21), and nonpancreatic abdominal uptake causing poor signalto-noise ratios for pancreas (39). Recent use of 18 F-FDG in full-body scanning has revealed anomalous tracer uptake in areas of supraclavicular fat (40), suggesting that isolation of brown adipose tissue in large mammals may be possible.…”

Section: Discussionmentioning

confidence: 99%

Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

Thackeray¹,

Beanlands²,

DaSilva³

2007

Journal of Nuclear Medicine

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11 C-meta-Hydroxyephedrine (HED) is used in cardiac PET as an index of norepinephrine (NE) reuptake transporter (NET) density and synaptic NE levels. Whereas cardiac uptake is well documented, tracer retention in other tissues with rich noradrenergic innervation is unclear. Dysfunctional sympathetic nervous system (SNS) function in extracardiac metabolic storage tissues (i.e., adipose tissue and skeletal muscle) and endocrine organs contributes to several disorders. The aim of this study was to determine the potential of HED as an index of NE function in brown adipose tissue, lung, pancreas, skeletal muscle, and kidney by identifying NET-specific retention and determining the presence of radiolabeled metabolites. Methods: Male Sprague-Dawley rats were administered HED and sacrificed at 30 min after tracer injection. Tissues were rapidly excised and counted for radioactivity, and relative tracer retention was quantified. Pretreatment with NET inhibitors established specific HED accumulation. The effect of elevated NE was tested by subcutaneous minipump NE infusion or inhibition of monoamine oxidase. Column-switch high-performance liquid chromatography (HPLC) was used to analyze the presence of radiolabeled metabolites in heart, brown adipose tissue, pancreas, and plasma. Results: NET-specific retention was observed in heart, brown adipose tissue, lung, and pancreas but not in liver, skeletal muscle, or kidney. A dosedependent response of HED accumulation to treatments elevating NE levels was established in tissues exhibiting specific uptake. At 30 min after tracer administration, HPLC analysis revealed 93%-95% of total radioactivity signal derived from unchanged HED in heart, pancreas, and brown adipose tissue compared with 61% 6 8% unchanged HED in plasma. Conclusion: In addition to the heart, lung, pancreas, and brown adipose tissue exhibit specific and NE-responsive uptake of HED, supporting the potential for novel PET studies of SNS integrity in these tissues.Key Words: sympathetic nervous system function; norepinephrine transporter uptake-1; competition with norepinephrine; HPLC column-switch system The sympathetic nervous system (SNS) is a primary extrinsic control mechanism mediating cardiac function, metabolic processes, and adaptation to stress. In normal conditions, the neurotransmitter norepinephrine (NE) is released from the presynaptic bouton into the synapse, where it binds to and stimulates adrenoceptors on pre-and postsynaptic cells. Excess NE is recycled into the presynaptic neuron by active transport via the uptake-1 NE reuptake transporter (NET) (1,2).In myocardium, the SNS modulates heart rate, cardiac output, and stroke volume (2). In metabolic storage tissues, SNS activation stimulates 2 key processes: lipolysis-the breakdown of lipids primarily in white adipocytes-and thermogenesis-the uncoupling of mitochondrial energetics promoting heat release over energy storage, primarily in brown adipocytes and skeletal muscle (3). The SNS also partially controls pancreatic secretion of insulin and gl...

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The Role of Phosphodiesterases in Dopamine Systems governing Motivated Behavior

Snyder

Hendrick

Nishi

2014

Cyclic‐Nucleotide Phosphodiesterases in the Central Nervous System

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Increasing synaptic noradrenaline, serotonin and histamine enhances in vivo binding of phosphodiesterase-4 inhibitor (R)-[11C]rolipram in rat brain, lung and heart

Cited by 27 publications

References 45 publications

PET of (R)-¹¹C-Rolipram Binding to Phosphodiesterase-4 Is Reproducible and Sensitive to Increased Norepinephrine in the Rat Heart

PET of (R)-¹¹C-Rolipram Binding to Phosphodiesterase-4 Is Reproducible and Sensitive to Increased Norepinephrine in the Rat Heart

Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

The Role of Phosphodiesterases in Dopamine Systems governing Motivated Behavior

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Increasing synaptic noradrenaline, serotonin and histamine enhances in vivo binding of phosphodiesterase-4 inhibitor (R)-[11C]rolipram in rat brain, lung and heart

Cited by 27 publications

References 45 publications

PET of (R)-11C-Rolipram Binding to Phosphodiesterase-4 Is Reproducible and Sensitive to Increased Norepinephrine in the Rat Heart

PET of (R)-11C-Rolipram Binding to Phosphodiesterase-4 Is Reproducible and Sensitive to Increased Norepinephrine in the Rat Heart

Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

The Role of Phosphodiesterases in Dopamine Systems governing Motivated Behavior

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Product

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PET of (R)-¹¹C-Rolipram Binding to Phosphodiesterase-4 Is Reproducible and Sensitive to Increased Norepinephrine in the Rat Heart

PET of (R)-¹¹C-Rolipram Binding to Phosphodiesterase-4 Is Reproducible and Sensitive to Increased Norepinephrine in the Rat Heart