alexa Uptake and retention of hexakis (2-methoxyisobutyl isonitrile) technetium(I) in cultured chick myocardial cells. Mitochondrial and plasma membrane potential dependence.
Oncology

Oncology

Journal of Nuclear Medicine & Radiation Therapy

Author(s): PiwnicaWorms D, Kronauge JF, Chiu ML

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Abstract 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.
This article was published in Circulation and referenced in Journal of Nuclear Medicine & Radiation Therapy

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