SUMMARY We have characterized N-13 ammonia as a myocardial blood flow imaging agent suitable for positron-emission computed tomography. However, the mechanisms of uptake and retention of this agent in myocardium are not known, and effects of altered metabolism were not considered. Therefore, we studied the uptake and retention of N-13 ammonia in myocardium under various hemodynamic and metabolic conditions in open-chest dogs. N-13 ammonia was extracted nearly 100% during its initial capillary transit, followed by metabolic trapping that competed with flow-dependent back diffusion. At control flows, the first capillary transit extraction fraction (E) of N-13 ammonia averaged 0.82 ± 0.06. It fell with higher flows by E = 1 -0.607 exp -125/F. Myocardial N-13 tissue clearance half-times were similarly inversely related to blood flow, and ranged from 110-642 minutes. Cardiac work and changes in the myocardial inotropic state induced by isoproterenol and propranolol did not affect E or the tissue clearance half-times. Low plasma pH reduced E by an average of 20%, while elevated plasma pH had no effect. Decreases in flow below control also were associated with a fall in E. Inhibition of glutamine synthetase with L-methionine sulfoximine impaired metabolic trapping of N-13 ammonia and implicates the glutamic acid-glutamine reaction as the primary mechanism for ammonia fixation. The product of E times flow predicts the myocardial N-13 tissue concentrations, which increased by 70% when flow was doubled. Thus, blood flow and metabolic trapping are the primary determinants of myocardial uptake and retention of N-13 ammonia. The relative constancy of metabolic trapping over a wide range of hemodynamic and metabolic conditions demonstrates the value of N-13 ammonia as a myocardial blood flow imaging agent. N-13 AMMONIA* has been characterized as an indicator for the noninvasive visualization of regional myocardial perfusion by positron computed tomography (PCT).' Use of N-13 ammonia has also permitted noninvasive detection of mild, 47% diameter coronary stenosis in the intact dog.2Because fixation of N-13 ammonia in myocardium occurs through metabolic pathways, alterations in both the hemodynamic and metabolic state of the heart could modify the uptake of N-13 ammonia, and hence, limit its value as a flow indicator. In blood, N-13 (NH3) ammonia exists primarily in its ionic species, NH4+, the ammonium ion, which apparently can substitute for K+ on the sodium-potassium transmembraneous exchange system in red blood cells.3 It thus may be actively transported into myocardium. On the other hand, NH3 can diffuse across cell membranes because of its lipid solubility and is rapidly replenished by conversion of NH4+ to NH3 as it leaves the vascular space.4" 5Transmembrane exchange therefore may occur through an active transport mechanism or *The term ammonia is used to refer to the chemical equilibrium of NH3 NH4+ in which the prominent form is NH4+.

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Summary: A technique is described that provides infor mation about relative cerebral responses to differing neu robehavioral tasks in normal subjects studied with posi tron computed tomography and oxygen-IS-labeled water. Simulation studies demonstrate that this technique is sensitive to changes in true local CBF within a physi ological range and tends to underestimate relative flow changes at high flow values (> 30 ml min -1 100 g -1) and to overestimate these changes for flow values of <25 ml min -I 100 g-I. Image acquisition times of 60 s following the arrival of oxygen-I5-labeled water in the brain were the most accurate for identifying such relative changes between radioisotope administrations and were not limPositron computed tomography (PCT) is able to measure local physiologic cerebral responses to sensory, motor, and cognitive processes in vivo (Greenberg et aI., 1981; Phelps et aI., 1981a Phelps et aI., ,b, 1982 Mazziotta et aI., 1982a Mazziotta et aI., ,b, 1983Mazziotta and Phelps, 1984 70ited by statistical noise from total image counts. Studies in normal volunteers indicate that the technique is highly reproducible, demonstrating a coefficient of variation for small «2 cm2) regions of 2.98 between studies in the same state. Visual stimulation studies in normal volun teers demonstrated relative radioisotope concentration changes between control and stimulated states that are in good agreement with similar results obtained using the same stimulation paradigm but with the use of fluoro deoxyglucose to determine cerebral glucose metabolism.

Grip strength, ring size, duration of morning stiffness, and the number of tender joints improved significantly in 9 patients with severe rheumatoid arthritis during prolonged continuous removal of thoracic duct lymphocytes through a surgical fistula. There was no improvement in 4 subjects in whom surgery failed to establish satisfactory lymph drainage. Reinfusion of unlabeled or 51Cr-labeled autologous lymphocytes resulted in transient exacerbation of disease activity in 3 subjects. Following reinfusion, some 51Cr-labeled lymphocytes could be found in the inflamed synovium and synovial fluid by autoradiography, and radioactivity was detected over the joints by surface counting of gamma radiation. Active rheumatoid arthritis recurred in all subjects at variable intervals after cessation of lymph drainage. These findings are compatible with the hypothesis that some of the lymphocytes in the thoracic duct lymph are essential for the continued activity of the inflammation associated with rheumatoid arthritis.

A noninvasive method that employs 15O-water and positron-computed tomography (PCT) was used to measure quantitative local cerebral blood flow (lCBF) in man. 15O-Water (about 30-50 mCi) was introduced through a single-breath inhalation of 15O-carbon dioxide or through an intravenous bolus injection of 15O-water. A sequence of five 2-min PCT scans was initiated at the time of tracer administration. A series of 15-20 blood samples (1 ml each) was withdrawn from the radial artery of the subject over a period of 10 min. Oxygen-15 radioactivities in the blood samples were immediately counted in a well counter to give an input function, which together with the projection data collected by PCT were processed to provide images of 1CBF and local water distribution volume. The method was found to be convenient to use and gave good-quality images of 1CBF. Quantitative values of 1CBF in images were 59 +/- 11 and 20 +/- 4 ml/min/100 g for gray and white matter, respectively, with a gray-to-white matter ratio of 2.93 and a global flow value of 42 +/- 8 ml/min/100 g. Distribution volume of water was 0.85 +/- 0.03, 0.76 +/- 0.03, and 0.81 +/- 0.02 ml/g respectively, for gray matter, white matter, and whole brain.