The dependence of accumulation of 13NH3 by myocardium on metabolic factors and its implications for quantitative assessment of perfusion.

Bergmann, Steven R.; Hack, Stanley N.; Tewson, Timothy J.; Welch, Michael J.; Sobel, Burton E.

doi:10.1161/01.cir.61.1.34

Cited by 114 publications

(24 citation statements)

References 23 publications

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“…In our study, the residual function or fraction of N-13 ammonia that became metabolically trapped during a single capillary transit was inversely related to myocardial blood flow, as described by equation 2. Thus, for a resting myocardial blood flow of 80 ml/min/100 g, E for N-13 ammonia averages 0.87 ± 0.06 but only 0.58 at flows of 350 ml/min/ 100 g as they occur in man during exercise.38, 39 The inverse relationship between E and F may also account for the observations in the isolated perfused rabbit heart recently reported by Bergmann et al 35 In these VOL 63, No 6, JUNE 1981 hearts, E for N-13 ammonia averaged 0.18 when perfused with Krebs-Heneleit buffer (KH), but was 0.55 when red blood cells were added to the perfusion medium (KH-RBC). The authors concluded that this difference in E was related to changes in metabolism of the isolated heart.…”

Section: Metabolic Fixation Of N-13 Ammonia In Myocardiummentioning

confidence: 76%

N-13 ammonia as an indicator of myocardial blood flow.

Schelbert¹,

Phelps²,

Huang³

et al. 1981

Circulation

406

116

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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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Section: Metabolic Fixation Of N-13 Ammonia In Myocardiummentioning

confidence: 76%

N-13 ammonia as an indicator of myocardial blood flow.

Schelbert¹,

Phelps²,

Huang³

et al. 1981

Circulation

406

116

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“…Because extraction and retention of both tracers are influenced by the metabolic states of myocardium, as well as by perfusion, 1,3,5,6,[8][9][10] these tracers can be used to evaluate myocardial meta-bolic activity, as well as flow,6 if enough tracer can be delivered to the myocardial segment in question.…”

Section: Discussionmentioning

confidence: 99%

Delineation of impaired regional myocardial perfusion by positron emission tomography with H2(15)O.

et al. 1988

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Positron emission tomography with`50-labeled water (H2150) can be used to delineate abnormal regional myocardial blood flow in experimental animals. To determine the feasibility of this method in humans, we studied 33 subjects (9 normal volunteers and 24 patients with angiographically documented coronary artery disease) at rest and after myocardial hyperemia induced with intravenous infusion of dipyridamole. At rest, the myocardial region demonstrating the lowest relative H2`50 activity exhibited 71 + 8% of activity in the region with peak activity in control subjects and 62 + 17% in patients (p = NS). After the dipyridamole infusion, differences between the two groups were accentuated. In control subjects, activity in the region with lowest relative radioactivity averaged 77 5% of that in the region with peak activity. In patients, it averaged 55 ±+22% of activity in the region with peak activity (p<0.01). Results in patients with ischemia with or without a history of remote myocardial infarction were not significantly different. In 22 of the 24 patients, the region with lowest relative perfusion corresponded anatomically to the region of myocardium distal to a stenosis. Thus, delineation of regional myocardial perfusion in patients with coronary artery disease is possible with positron emission tomography and H215O. Further studies will be necessary to prospectively determine sensitivity and specificity. (Circulation 1988;78:612- Received July 27, 1987; revision accepted May 5, 1988.`3 N-labeled ammonia2-4 and 52Rb5-7 have been successfully used to estimate regional myocardial blood flow in experimental animals and in patients. 82Rb is particularly attractive in the clinical setting because it is generator produced, which obviates the need for an on-site cyclotron. However, the use of these tracers for quantification of flow entails some limitations. Single-pass extraction and myocardial retention of`3N-labeled ammonia are influenced by flow23,8 as well as by cell membrane integrity9 and the metabolic state of the myocardium.8 9 Extraction of 82Rb also varies with flow and metabolism. 5,6,10 An ideal perfusion tracer should be either freely diffusible or completely extractable and retainable by myocardium on a single pass through the coronary circulation without having its kinetics altered throughout the range of flow studied or by the metabolic status of the myocardium. 150-labeled water (H2`50) is essentially a freely diffusible tracer in the heart with uptake that does not vary despite wide variations in flow rate11 or changes in the metabolic state of myocardium associated with prolonged ischemia or reperfusion. 11-14 150 is a useful

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“…13N-Ammonia has been used as a flow marker in myocardial scintigraphy, [1][2][3][4][5][6][7][8] but the ability of this tracer to quantify regional myocardial blood flow has been questioned because 13N uptake and retention depend on metabolic trapping as well as on myocardial perfusion.6, 7 The results of this study indicate that cellular uptake of '3N also depends on the integrity of the plasmalemmal membrane and possibly on an anion exchange system that can be inhibited by stilbene disulfonic acids.…”

Section: Discussionmentioning

confidence: 99%

“…figure 5) reduced the apparent initial rate to 13% and total uptake to 23% of the control value. As demonstrated by Bergmann et al 6 and Schelbert et al ,7 who measured 13N uptake and washout in the whole heart of rabbits and dogs, respectively, 13N uptake could be depressed by 1-methionine sulfoximine, an inhibitor of intracellular glutamine synthetase. '5 22 In the presence of 100 gg/ml 1-methionine sulfoximine, apparent initial rate and total uptake were reduced to 34% and 42% of the control values, respectively (figure 6).…”

mentioning

confidence: 85%

Kinetics of 13N-ammonia uptake in myocardial single cells indicating potential limitations in its applicability as a marker of myocardial blood flow.

Rauch¹,

Helus²,

Grunze³

et al. 1985

Circulation

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To study kinetics and principles of cellular uptake of '3N-ammonia, a marker of coronary perfusion in myocardial scintigraphy, heart muscle cells of adult rats were isolated by perfusion with collagenase and hyaluronidase. Net uptake of '3N, measured by flow dialysis, reached equilibrium within 20 sec in the presence of sodium bicarbonate and carbon dioxide (pH 7.4, 370 C). Total extraction, 80 sec after the reaction start, was 786 ± 159 ,umol/ml cell volume. Cells destroyed by calcium overload were unable to extract 13N-ammonia. Omission of bicarbonate and carbon dioxide reduced total extraction to 36% of control. '3N-Ammonia uptake could also be reduced by 50 gM 4,4' diisothiocyanostilbene 2,2' disulfonic acid, by 100 ,ug/ml 1-methionine sulfoximine, and by preincubation with 5 gtM free oleic acid. These results indicate that in addition to metabolic trapping by glutamine synthetase, the extraction of 13N-ammonia by myocardial cells is influenced by cell membrane integrity, intracellular-extracellular pH gradient, and possibly an anion exchange system for bicarbonate. For this reason, the uptake of 13N-ammonia may not always provide a valid measurement of myocardial perfusion. Circulation 71, No. 2, 387-393, 1985. 13N-AMMONIA (13N),* a positron-emitting radionuclide, has been used as a marker of myocardial perfusion.' 8 Because cellular extraction of an ideal flow marker must be proportional to regional myocardial blood flow, extraction of such a marker should not be influenced by cell metabolism or cell membrane transport mechanisms. Since myocardial extraction fraction of '3N-ammonia can be significantly reduced when intracellular glutamine synthetase is inhibited,67 the usefulness of this compound as a flow marker has been questioned. This study provides additional data regarding the kinetics and possible role of the plasma membrane in myocardial '3N uptake and retention in isolated adult rat heart cells. Materials and methodsPreparation of myocardial single cells. Male Wistar rats 3 to 4 months old were heparinized and anesthetized by urethane (1.5 mg/g body weight, intraperitoneally). Hearts were extracted and perfused in a nonrecycling manner for 10 min with 35 mM NaCI, 4.75 mM KCl, 1.2 mM KH2PO4, 150 mM sucrose, 25 mM NaHCO3, 10 mM HEPES buffer, 10 mM glucose, and 5 g/liter albumin bovine fraction V (pH 7.4, 370 C, 95% 02/5% CO2).9 A recycling perfusion (25 min) was carried out with the same solution also containing 150 U/ml unpurified collagenase (E.C.3.4.4.19.) and 1000 U/ml hyaluronidase (E.C.3.2.1.36.).At the end of the perfusion the softened heart was sliced into small pieces and reincubated for 10 min in the same enzymecontaining solution; the suspension was filtered through a nylon mesh and centrifuged gently for 2 min at 50 g. The supernatant was removed and the pellet was washed three times in 130 mM NaCl, 4.0 mM KCI, 1.2 mM KH2PO4, 25 mM HEPES buffer, 10 mM glucose, and 20 g/liter albumin bovine fraction V (pH 7.4, room temperature, 100% 02). A small population of completely destr...

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The dependence of accumulation of 13NH3 by myocardium on metabolic factors and its implications for quantitative assessment of perfusion.

Cited by 114 publications

References 23 publications

N-13 ammonia as an indicator of myocardial blood flow.

N-13 ammonia as an indicator of myocardial blood flow.

Delineation of impaired regional myocardial perfusion by positron emission tomography with H2(15)O.

Kinetics of 13N-ammonia uptake in myocardial single cells indicating potential limitations in its applicability as a marker of myocardial blood flow.

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