Circulation, Vol 82, 1826-1838, Copyright © 1990 by American Heart Association
D Piwnica-Worms, JF Kronauge and ML Chiu
The fundamental myocellular uptake and retention mechanisms of hexakis
(2-methoxyisobutyl isonitrile) technetium(I) (Tc-MIBI), a technetium-
99m-based myocardial perfusion imaging agent, are unresolved. Because of
the lipophilic cationic nature of Tc-MIBI, it may be distributed across
biological membranes in response to transmembrane potential. To test this
hypothesis, net uptake and retention of Tc-MIBI in cultured chick embryo
ventricular myocytes were determined under conditions known to alter
mitochondrial and plasma membrane potentials. Isovolumic depolarization of
plasma membrane potentials in 130 mM extracellular K (Ko) 20 mM
extracellular Cl buffer reduced net accumulation of Tc-MIBI from 171 +/- 16
(control) to 29 +/- 3.3 fmol intracellular Tc-MIBI/mg protein.nM
extracellular Tc-MIBI. Unidirectional influx of Tc-MIBI in cells
depolarized in 30 mM Ko buffer was also reduced; a resting plasma membrane
potential of -87 +/- 6 mV was calculated from the Goldman flux equation
using normal Ko/high Ko Tc-MIBI influx ratios. Addition of the potassium
ionophore valinomycin to cells incubated in 130 mM Ko buffer to
additionally depolarize mitochondrial membrane potentials further reduced
net uptake of Tc-MIBI to levels comparable to that found in nonviable
freeze-thawed preparations ([Tc-MIBI]i/[Tc-MIBI]o = 1). By depolarizing
mitochondrial (and in part plasma membrane) potentials with the
protonophores 2,4-dinitrophenol and carbonyl cyanide m-
chlorophenylhydrazone (CCCP) Tc-MIBI was rapidly depleted from 181 +/- 16
(control) to 16 +/- 2.6 and 31 +/- 4.2 fmol/mg protein.nMo, respectively,
with kinetics that did not correlate with loss of cellular ATP content.
CCCP alone inhibited 90 +/- 3% of net accumulation or 66 +/- 3% of
unidirectional influx of Tc-MIBI in a concentration-dependent manner. By
hyperpolarizing mitochondrial membrane potentials with the K+/H+ ionophore
nigericin or the ATP synthase inhibitor oligomycin, net uptake and
retention of Tc-MIBI were increased by 60 +/- 9% and 375 +/- 20%,
respectively. Caffeine, as well as the respiratory chain electron transport
inhibitor rotenone, did not significantly alter net cell uptake (p greater
than 0.2). These data indicate that the fundamental myocellular uptake
mechanism of Tc-MIBI involves passive distribution across plasma and
mitochondrial membranes and that at equilibrium Tc-MIBI is sequestered
within mitochondria by the large negative transmembrane potentials.
ARTICLES
Uptake and retention of hexakis (2-methoxyisobutyl isonitrile) technetium(I) in cultured chick myocardial cells. Mitochondrial and plasma membrane potential dependence
Department of Radiology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115.
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