In vivo PET imaging of cardiac presynaptic sympathoneuronal mechanisms in the rat.
The sympathetic nervous system of the heart plays a key role in the pathophysiology of various cardiac diseases. Small-animal models are valuable for obtaining further insight into mechanisms of cardiac disease and therapy. To determine the translational potential of cardiac neuronal imaging from rodents to humans, we characterized the rat sympathetic nervous system using 3 radiotracers that reflect different subcellular mechanisms: (11)C-meta-hydroxyephedrine (HED), a tracer of neuronal transport showing stable uptake and no washout in healthy humans; (11)C-phenylephrine (PHEN), a tracer of vesicular leakage and intraneuronal metabolic degradation with initial uptake and subsequent washout in humans; and (11)C-epinephrine (EPI), a tracer of vesicular storage with stable uptake and no washout in humans.


METHODS
We used a small-animal PET system to study healthy male Wistar rats at baseline, after desipramine (DMI) pretreatment (DMI block), and with DMI injection 15 min after tracer delivery (DMI chase). The rats were kept under general isoflurane anesthesia while dynamic emission scans of the heart were recorded for 60 min after radiotracer injection. A myocardial retention index was determined by normalizing uptake at 40 min to the integral under the arterial input curve. Washout rates were determined by monoexponential fitting of myocardial time-activity curves.


RESULTS
At baseline, HED showed high myocardial uptake and sustained retention, EPI showed moderate uptake and significant biphasic washout, and PHEN showed moderate uptake and monoexponential washout. The average (+/- SD) left ventricular retention index for HED, PHEN, and EPI was 7.38% +/- 0.82%/min, 3.43% +/- 0.45%/min, and 4.24% +/- 0.59%/min, respectively; the washout rate for HED, PHEN, and EPI was 0.13% +/- 0.23%/min, 1.13% +/- 0.35%/min, and 0.50% +/- 0.24%/min, respectively. The DMI chase resulted in increased washout only for HED. DMI block decreased myocardial uptake of all tracers by less than 90%.


CONCLUSIONS
Kinetic profiles of HED in the rat myocardium were similar to those of HED in humans, suggesting comparable neuronal transport density. Unlike in humans, however, significant washout of EPI and faster washout of PHEN were encountered, consistent with high intraneuronal metabolic activity, high catecholamine turnover, and reduced vesicular storage. This evidence of increased neuronal activity in rodents has implications for translational studies of cardiac neuronal biology in humans.
Tipre
Dnyanesh N
DN
Division of Nuclear Medicine, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland 21287-0842, USA. dnyanesht@yahoo.com
Fox
James J
JJ
Holt
Daniel P
DP
Green
Gilbert
G
Yu
Jianhua
J
Pomper
Martin
M
Dannals
Robert F
RF
Bengel
Frank M
FM
D000818:Animals; D002250:Carbon Radioisotopes; D003891:Desipramine / Q000494:pharmacology; D004809:Ephedrine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004837:Epinephrine / Q000493:pharmacokinetics*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010656:Phenylephrine / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000378:metabolism*
D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D010656:Phenylephrine; C065363:3-hydroxyephedrine; D004809:Ephedrine; D003891:Desipramine; D004837:Epinephrine