Sarcolemmal and mitochondrial membrane potentials measured ex vivo and in vivo in the heart by pharmacokinetic modelling of [99mTc]sestamibi

Abstract

We present a compartmental modelling approach to analyse radioactive time activity curves for first pass kinetics of [^99mTc]sestamibi in the heart. Reparametrizing the kinetic equations using the Nernst membrane-potential equation provides a novel means of non-invasively estimating the sarcolemmal (E_m) and mitochondrial (ΔΨ_m) membrane potentials in the heart. A Markov Chain Monte Carlo (MCMC) fitting approach was applied to data derived from established interventions in Langendorff perfused rat hearts where the sarcolemmal membrane was depolarised using hyperkalaemic Krebs Henseleit buffers; the mitochondrial membrane was depolarised using carbonylcyanide-3-chlorophenylhydrazone (CCCP); or both membranes were depolarised using their combination. Translating this approach to single photon emission planar scintigraphy kinetics from healthy rats allowed an estimate of these membrane potentials (voltages) in vivo for the first time; the values were E_m =-62 ± 5 mV and ΔΨ_m = -151 ± 5 mV (n = 4, mean ± SD).