Organic cation transporter 3: expression in failing and nonfailing human heart and functional characterization.

The organic cation transporter 3 (OCT3, SLC22A3) contributes to the control of cardiac catecholamine concentrations and is important for the disposition and action of cationic drugs, such as metformin, in the myocardium. We sought to characterize the regulation of OCT3 in failing human hearts and to study commonly prescribed drugs for their potential to interact with OCT3-dependent uptake of metformin. SLC22A3 was expressed high in the human heart with strongest OCT3 immunoreactivity in vascular endothelial cells. SLC22A3/OCT3 expression was not changed in failing human left ventricular myocardium compared with nonfailing control tissues and thus is not involved in altered catecholamine homeostasis generally observed in failing hearts. Michaelis-Menten kinetics of OCT3-mediated uptake of prototypical OCT substrates 1-methyl-4-phenylpyridinium and metformin were studied in human embryonic kidney 293 cells stably overexpressing OCT3. The affinity of 1-methyl-4-phenylpyridinium for OCT3 was much higher (Km 157 ± 16 μM) than the affinity of metformin (Km 2.46 ± 0.36 mM; P < 0.01), whereas maximum transport rate of 1-methyl-4-phenylpyridinium was significantly lower than that of metformin. Verapamil, carvedilol, imipramine, and cimetidine were competitive inhibitors of OCT3-mediated metformin uptake (Ki 3.6-15.8 μM). Altogether, OCT3 might be important for the cardiac disposition of cationic drugs, and OCT3-dependent interaction with concomitantly administered compounds may limit their disposition and effect.