The organic cation transporter OCT2 mediates the uptake of β-adrenoceptor antagonists across the apical membrane of renal LLC-PK1 cell monolayers

1 Previous studies have shown that beta-adrenoceptor antagonists may be substrates of organic cation transporters in kidney and lung. In this study we examined the transport of the beta-adrenoreceptor antagonists propranolol and metoprolol, in renal LLC-PK1 cell monolayers. 2 Experiments with BCECF (2',7'-bis(2carboxyethyl)-5(6)-carboxyfluorescein) loaded LLC-PK1 cell monolayers demonstrated that metoprolol and propranolol flux across the basolateral membrane was consistent with non-ionic diffusion. Flux across the apical membrane consisted of both nonionic diffusion and the uptake of the cationic form of the beta-adrenoceptor antagonists. 3 Uptake of the cationic form of metoprolol across the apical membrane was Na+-independent, electrogenic and sensitive to external pH. Furthermore, uptake was sensitive to inhibition by Decynium-22 and the organic cations TEA (tetraethylammonium) and MPP+ (1-methyl 4-phenylpyridinium). These results, allied with the apical location of the uptake mechanism suggest that beta-adrenoceptor antagonists may be substrates for the organic cation transporter, OCT2. 4 To confirm beta-adrenoceptor antagonists as substrates for OCT2, we demonstrate, in cells transiently transfected with an epitope tagged version of hOCT2 (hOCT2-V5):(1) Decynium-22 sensitive [C-14]-propranolol uptake, (2) cis-inhibition of OCT2 by a range of beta-adrenoceptor antagonists and (3) metoprolol induced intracellular acidification.