Due to the particulate nature of microspheres, their deposition in small-tissue regions may not be strictly flow dependent. To evaluate the importance of rheological and geometric factors and random error, their deposition densities in small regions of rabbit hearts were examined in comparison with those of a new "molecular microsphere," 2-iododesmethylimipramine (IDMI), whose high lipid solubility allows it to be delivered into tissue in proportion to flow, and whose binding in tissue prevents rapid washout. 141Ce- and 103Ru-labeled 16.5-micron spheres in one syringe and [125I]- and [131I]DMI in another syringe were injected simultaneously into the left atrium of open-chest rabbits, while obtaining reference blood samples from the femoral artery. Hearts were removed 1 min after injection, cut into approximately 100 pieces averaging 54 mg, and the regional deposition densities calculated for each tracer from the isotopic counts. Correlations between the differently labeled microspheres were r greater than 0.95 and for the two IDMIs were greater than 0.98. Scatter plots of sphere densities vs. IDMI densities showed that differences between microspheres and IDMI had substantial scatter, 0.87 less than r less than 0.96 and were not random. Microsphere depositions tended to be lower than IDMI depositions at low flows and higher at high flows. The tendency for spheres to be deposited preferentially in high-flow regions may be explained by a bias at bifurcations toward entering the branch with higher flow and secondarily toward entering those branches that are straighter. We conclude that microspheres are generally adequate for estimating regional flows but suffer systematic error when the regions of interest are supplied via arteries of diameters only a few times those of the microspheres.
The deposition of microspheres in small tissue regions is not strictly flow dependent. In comparison with the soluble flow marker 2-iododesmethylimipramine (IDMI), deposition of 16.5-,um microspheres was mildly but systematically biased into high flow regions of rabbit hearts (Bassingthwaighte JB, Malone MA, Moffett T-C, King RB, Little SE, Link JM, Krohn KA. Am J Physiol 1987;253(Heart Circ Physiol 22):H184-H193). To examine the possibility of bias in larger hearts, a similar study was undertaken in sheep. 141Ce-and '03Ru-labeled 16.5 -,um microspheres in one syringe and 1251-and '311-DMI in another syringe were injected simultaneously into the left atrium of five open-chest sheep while obtaining reference blood samples from the femoral artery. In six other sheep, one microsphere type and one IDMI were used. Hearts were removed 1 minute after injection, cut into approximately 254 pieces averaging 217 mg, and regional deposition densities calculated for each tracer from the isotopic counts. Correlations in the five animals between the two differently labeled IDMIs and between the two microspheres were both .0.98. In all 11 sheep, scatter plots of microsphere deposition densities versus IDMI densities showed that differences between microspheres and IDMI had substantially more scatter (0.84
Autoradiography using a molecular deposition marker provides quantitative information on myocardial flow heterogeneities with resolution at the size of cardiac myocytes. Because the regions resolved are smaller than the volume of regions supplied by single arterioles, the results must slightly exaggerate the true heterogeneity of regional flows.
The detection of radioactive compounds by liquid scintillation has revolutionized modern biology, yet few investigators make full use of the power of this technique. Even though multiple isotope counting is considerably more difficult than single isotope counting, many experimental designs would benefit from using more than one isotope. The development of accurate isotope counting techniques enabling the simultaneous use of three beta-emitting tracers has facilitated studies in our laboratory using the multiple tracer indicator dilution technique for assessing rates of transmembrane transport and cellular metabolism. The details of sample preparation, and of stabilizing the liquid scintillation spectra of the tracers, are critical to obtaining good accuracy. Reproducibility is enhanced by obtaining detailed efficiency/quench curves for each particular set of tracers and solvent media. The numerical methods for multiple-isotope quantitation depend on avoiding error propagation (inherent to successive subtraction techniques) by using matrix inversion. Experimental data obtained from triple-label beta counting illustrate reproducibility and good accuracy even when the relative amounts of different tracers in samples of protein/electrolyte solutions, plasma, and blood are changed.
The extraction of serotonin from the blood during transorgan passage through the heart was studied using Langendorff-perfused rabbit hearts. Outflow dilution curves of 131I- or 125I-labeled albumin, [14C]sucrose, and [3H]serotonin injected simultaneously into the inflow were fitted with an axially distributed blood-tissue exchange model to examine the extraction process. The model fits of the albumin and sucrose outflow dilution curves were used to define flow heterogeneity, intravascular dispersion, capillary permeability, and the volume of the interstitial space, which reduced the degrees of freedom in fitting the model to the serotonin curves. Serotonin extractions, measured against albumin, during single transcapillary passage, ranged from 24 to 64%. The ratio of the capillary permeability-surface area products for serotonin and sucrose, based on the maximum instantaneous extraction, was 1.37 +/- 0.2 (n = 18), very close to the predicted value of 1.39, the ratio of free diffusion coefficients calculated from the molecular weights. This result shows that the observed uptake of serotonin can be accounted for solely on the basis of diffusion between endothelial cells into the interstitial space. Thus it appears that the permeability of the luminal surface of the endothelial cell is negligible in comparison to diffusion through the clefts between endothelial cells. In 18 sets of dilution curves, with and without receptor and transport blockers or competitors (ketanserin, desipramine, imipramine, serotonin), the extractions and estimates of the capillary permeability-surface area product were not reduced, nor were the volumes of distribution. The apparent absence of transporters and receptors in rabbit myocardial capillary endothelium contrasts with their known abundance in the pulmonary vasculature.
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