Published Online
on February 20, 2006

A more recent version of this article appeared on February 28, 2006

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Submitted on September 2, 2005
Revised on December 22, 2005
Accepted on December 23, 2005

Uptake of Cardiovascular Drugs Into the Human Heart. Expression, Regulation, and Function of the Carnitine Transporter OCTN2 (SLC22A5)

Markus Grube PhD, Henriette E.U. Meyer zu Schwabedissen MD, Damaris Präger; , Jeanette Haney BSc, Klaus-Uwe Möritz PhD, Konrad Meissner MD, Dieter Rosskopf MD, Lothar Eckel MD, Michael Böhm MD, Gabriele Jedlitschky PhD, and Heyo K. Kroemer PhD^*

From the Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Department of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany (M.G., H.E.U.M.z.S., D.P., J.H., K.-U.M., K.M., D.R., G.J., H.K.K.); the Klinikum Karlsburg, Karlsburg, Germany (L.E.); and the Department of Cardiology, Saarland University, Homburg/Saar, Germany (M.B.).

^* To whom correspondence should be addressed. E-mail: kroemer{at}uni-greifswald.de.

Background--To date, the uptake of drugs into the human heart by transport proteins is poorly understood. A candidate protein is the organic cation transporter novel type 2 (OCTN2) (SLC22A5), physiologically acting as a sodium-dependent transport protein for carnitine. We investigated expression and localization of OCTN2 in the human heart, uptake of drugs by OCTN2, and functional coupling of OCTN2 with the eliminating ATP-binding cassette (ABC) transporter ABCB1 (P-glycoprotein).

Methods and Results--Messenger RNA levels of OCTN2 and ABCB1 were analyzed in heart samples by quantitative polymerase chain reaction. OCTN2 was expressed in all auricular samples that showed a pronounced interindividual variability (35 to 1352 copies per 20 ng of RNA). Although a single-nucleotide polymorphism in OCTN2 (G/C at position -207 of the promoter) had no influence on expression, administration of -blockers resulted in significantly increased expression. Localization of OCTN2 by in situ hybridization, laser microdissection, and immunofluorescence microscopy revealed expression of OCTN2 mainly in endothelial cells. For functional studies, OCTN2 was expressed in Madin-Darby canine kidney (MDCKII) cells. Using this system, verapamil, spironolactone, and mildronate were characterized both as inhibitors (EC₅₀=25, 26, and 21 µmol/L, respectively) and as substrates. Like OCTN2, ABCB1 was expressed preferentially in endothelial cells. A significant correlation of OCTN2 and ABCB1 expression in the human heart was observed, which suggests functional coupling. Therefore, the interaction of OCTN2 with ABCB1 was tested with double transfectants. This approach resulted in a significantly higher transcellular transport of verapamil, a substrate for both OCTN2 and ABCB1.

Conclusions--OCTN2 is expressed in the human heart and can be modulated by drug administration. Moreover, OCTN2 can contribute to the cardiac uptake of cardiovascular drugs.

Key words: pharmacology • drug transport • organic cation transport proteins • carnitine

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