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

Abstract

The fundamental myocellular uptake and retention mechanisms of hexakis (2-methoxyisobutyl Despite this initial success of Tc-MIBI as a flow tracer, controversy exists from in vivo and in vitro experience over whether Tc-MIBI is a pure flow tracer by virtue of its lipophilicity or whether altered metabolic states of myocardium may influence Tc-MIBI kinetics and net accumulation. For example, prolonged metabolic blockade in cultured heart cells significantly reduces myocellular unidirectional uptake of Tc-MIBI.6 In buffer-perfused rabbit heart,7 ouabain alters cellular retention of Tc-MIBI, whereas preliminary data with hypoxia at slow flow rates has also been shown to inhibit Tc-MIBI transcapillary exchange in blood-perfused rabbit heart.8 In an open-chest dog model, Tc-MIBI significantly underestimated reperfusion flow to necrotic and perinecrotic regions compared with microsphere analysis that suggested that Tc-MIBI net uptake reflected myocardial viability.9 In addition, image disparity between 20Ifl and Tc-MIBI has been reported clinically after lytic therapy.10 Conversely, Tc-MIBI overestimated reperfusion flow to ischemic zones in another open-chest dog model.1' These observations are difficult to reconcile because the fundamental mechanisms of extraction, retention, and washout of Tc-MIBI at the vascular and myocellular levels are not established.A significant clue to the cellular mechanisms of uptake and retention of Tc-MIBI may be related to its lipophilic cationic nature. This raises the possibility that Tc-MIBI may be distributed across biological membranes in response to transmembrane potential in a manner similar to other well-characterized lipophilic cations such as tetraphenylphosphonium, rhodamine-123, or the cyanine dyes.'2-'7 Such compounds are sufficiently lipophilic (hydrophobic) to partition into biological membranes but also contain a delocalized charge distributed throughout the molecule, thereby allowing passive distribution of the compound across a bilayer in proportion to an imposed transmembrane electrical potential.12 Because normal myocardial cells maintain a negative plasma membrane potential (Em) that concentrates cations within the cytosol relative to the external buffer and because they also contain a substantial number of mitochondria that generate a large negative potential (Aqi=-150 to -200 mV14) across the inner mitochondrial membrane that will further concentrate cations relative to the cytosol, both potentials would contribute a large driving force for the sequestration of Tc-MIBI within the mitochondrial inner matrix. Therefore, the ratio of Tc-MIBI Previous studies with cultured chick myocardial cells have shown a strong inhibitory effect of prolonged metabolic blockade on Tc-MIBI uptake,6 but the approach did not resolve the fundamental myocellular uptake mechanism. However, preliminary studies in nonmyocardial preparations suggested a potentialdependent uptake mechanism for the agent.18,19 Fully characterizing accumulation in a heart preparation, this report presen...

Divergent kinetics of 201Tl and 99mTc-SESTAMIBI in cultured chick ventricular myocytes during ATP depletion.

“…29 For these experiments, 25-mm circular glass coverslips served as substrate for cell growth, and confluent preparations were used for experiments only on day 3 or 4 in culture.…”

“…Initial uptake rates of 9"Tc-SESTAMIBI in cells under physiological conditions reflect primarily potential-dependent diffusion across the plasma membrane, whereas steady-state or maximal accumulation levels reflect the ability of the mean mitochondrial and plasma membrane potentials to concentrate the majority of total cell-associated tracer within the mitochondrial inner matrix. 29,33 The fundamental myocellular uptake and retention mechanisms of 20MT1 and '99Tc-SESTAMIBI might predict differential responses of these two diagnostic pharmaceuticals to ischemic injury or metabolic inhibition and may have clinical utility in defining myocardial energetics and severity of myocellular injury. Methods …”

Dilemma in diagnosing thyroid adenoma – A case report

“…Malignant cells in particular maintain a more negative mitochondria trans membrane potential, which in turn encourages increased MIBI accumulation because of their increased metabolic need (14). Benign lesions demonstrated various uptake behavior resulting in 23% of benign nodules being MIBI positive (11,12).…”

Accuracy of 99mTc-sestamibi scintimammography for breast cancer diagnosis

“…Such tumors present high expression of cellular proliferation factors, high mitotic rates, intense angiogenesis and high mitochondrial activity and density. these factors are the main determinants for the concentration of 99m tc-sestamibi in the lesion (13)(14)(15)(16)(17)54,55).…”