D.F. Sacker

Spatial and temporal distribution of cocaine and effects of pharmacological interventions: Wholebody autoradiographic microimaging studies

Whole body timed distribution of pharmacological doses of 14C-cocaine was studied in rats using quantitative autoradiographic microimaging. Rapid, intense uptake was seen in the brain, spinal cord, adrenals and nuchal brown fat pad. Clearance of cocaine was fastest from the cerebellum. Cortex activity reached soft tissue activity within 20 min. Uptake in the heart and adrenals was very intense following the same time course as in the brain. Kidney activity increased gradually at the same time as in the liver, probably representing specific binding as well as an excretory pathway of cocaine. Desipramine decreased uptake in the heart and adrenals and a piperazine derivative (GBR 12909) caused decreased uptake in the brain, heart and adrenals. Scopolamine, pentobarbital and cold cocaine caused decreased uptake in all organs and increased uptake (excretion) in the liver. Thus, cocaine appears to bind in the brain to the dopamine transporter and to a lesser extent to transporters for norepinephrine and serotonin. In the heart cocaine binds to norepinephrine, serotonin and dopamine. The targeting of cocaine to specific organs and the time sequence correspond to the pharmacological effects of cocaine.

Studies of a new fatty acid analog (DMIVN) in hypertensive rats and the effect of verapamil using ARG microimaging

Studies of myocardial utilization of fatty acids and analogs has focused on coronary heart disease. This study addresses the topic of radioiodinated fatty acid utilization in hypertensive-cardiomyopathy. The new fatty acid analog 19-iodo-3,3-dimethyl-18 nonadecenoic acid (DMIVN) was studied by autoradiographic microimaging (ARG) in salt-sensitive (S) hypertensive (salt-fed) and in salt-sensitive (S) normotensive (low-salt diet), Dahl-strain rats. A salt fed, S-strain group was treated with verapamil and the results were compared to those in a hypertensive, non-treated group. The distribution of DMIVN in the hearts of normotensive rats was uniform. In the myocardium of hypertensive rats nonuniform DMIVN concentration was seen in the subendocardial and mid-layers of the left ventricle (LV). Verapamil given to salt-fed rats prevented hypertension and uniform DMIVN uptake similar to normotensive controls was seen. The data suggest that DMIVN may be suitable for the detection of hypertension induced myocardial changes and for assessing therapy. The distribution and clearance characteristics of DMIVN indicate that DMIVN may be a useful agent for SPECT imaging in man.

Abscess scintigraphy with 99mTc-human immunoglobulin (IgG) using a one-step labeling method

It was shown earlier that non-specific human gamma globulin (IgG) labeled with 111In can be used as an agent for abscess localization. We describe experimental results with 99mTc-IgG in animals bearing abscesses and tumors using a one-step labeling method with 99mTc. We studied this compound in several animal models: mice bearing turpentine abscesses and subcutaneously transplanted sarcomas, in rats with turpentine or E. coli abscesses and intracerebrally implanted gliomas and in rabbits with E. coli or turpentine abscesses. Blood clearance was studied in dogs. It was found that the absolute concentration of 111In-IgG in abscess and tumor was higher than that of 99mTc-IgG. However, the abscess-to-tumor ratio was higher for 99mTc-IgG. The 99mTc-IgG images were of high quality and abscesses could be detected as early as 30 min post-injection (p.i.). It appears that 99mTc-IgG has many potential advantages over 111In-IgG because of better physical properties of 99mTc, simpler preparation, lower cost and greater availability and the possibility of using higher 99mTc doses.

Quantitative autoradiographic measurement of cocaine-induced regional myocardial metabolic changes in hypertensive rats.

A rat model of hypertensive cardiomyopathy was studied to evaluate the acute effects of cocaine on the myocardium. Using autoradiographic microimaging techniques, myocardial perfusion (201Tl) and energy substrate utilization (glucose: [14C]2-fluoro-2-deoxy-D-glucose-[14C]2DG and fatty acid (15-[p-iodophenyl])-3-R,S-methyl pentadecanoic acid-[131I]BMIPP) were studied in Dahl strain salt-sensitive normotensive and hypertensive rats with and without intravenous cocaine. The right ventricle, septum, endocardium and epicardium of the left ventricle were analyzed. Increased perfusion (18%) was seen in the myocardium of the hypertensive rats as compared to the normotensive rats. There was higher [14C]2DG (254%) and lower fatty acid (13.2%) uptake in the hypertensive rats, indicative of a shift from aerobic to anaerobic substrate utilization. In cocaine-treated normotensive rats, a generalized decrease in myocardial perfusion (30%) and increased glucose metabolism (89%) was seen. In cocaine-treated hypertensive rats, the increased myocardial perfusion (16%) was heterogeneous and was more pronounced in septum and epicardium. The endocardium and epicardium in the hypertensive rats showed an overall increase (23%) in glucose utilization after cocaine which was not as dramatic as was seen in the normotensive heart and a slight increase in fatty acid utilization. These results are consistent with prior observations that under pressure overload the myocardium responds non-uniformly. It may well be that the hypertensive cardiomyopathic heart is unable to respond to the challenge of cocaine by further increasing glucose utilization. These data obtained in an animal model of hypertension seem to indicate that hypertension may increase the risk of cardiac complications related to cocaine.

The effect of diphenylhydantoin (Dilantin) on thallium-201 chloride uptake

The effect of diphenylhydantoin (Dilantin) on the myocardial uptake of 201Tl-chloride was studied in rats. Prior administration of Dilantin caused a significant (38.8) decrease in 201Tl uptake compared with the control group. No significant change in heart to blood or heart to muscle ratios was observed. Administration of Dilantin after 201Tl-chloride did not affect the myocardial concentration of the radionuclide.