The membrane potential in cells can be estimated by electrophysiological techniques and biomedical methods using lipophilic cations labelled with 14C. However, these techniques cannot be applied to the human heart. In this study a lipophilic cation, triphenylmethylphosphonium (TPMP), was labelled with carbon-11 with the purpose of investigating its suitability for the estimation of membrane potential in vivo. A biodistribution study in mice and rats showed significant uptake of the cation in the heart a few minutes after IV injection which remained constant for 60 min. In vivo study by positron-emission tomography showed that after IV injection of 11C-TPMP in the dog, activity rose almost immediately in the myocardium and then remained constant for 60 min. A rapid injection of KCl (greater than 40 mg/kg) 20 min after injection of 11C-TPMP led to an instantaneous fall in myocardial 11C-TPMP concentration. Membrane potential (delta psi), calculated from the TPMP distribution ratio between intracellular and plasma water space by the Nernst equation, was estimated at -148.1 +/- 6.0 mV for the dog heart. This value reflected both cell membrane potential and mitochondrial membrane potential and, thus, the energy state of the myocardial cells.