A novel anionic inward rectifier in native cardiac myocytes

Although the cationic inward rectifiers (Kir and hyperpolarization-activate d If channels) have been well characterized in cardiac myocytes, the expres sion and physiological role of anionic inward rectifiers in heart ate unkno wn, In the present study, we report the functional and molecular identifica tion of a novel chloride (Cl-) inward rectifier (Cl.ir) in mammalian heart. Under conditions in which cationic inward rectifier channels were blocked, membrane hyperpolarization (-40 to -140 mV) activated an inwardly rectifyi ng whole-cell current in mouse atrial and ventricular myocytes. Under isoto nic conditions, the current activated slowly with a biexponential time cour se (time constants averaging 179.7+/-23.4 [mean+/-SEM] and 2073.6+/-287.6 m s at -120 mV). Hypotonic cell swelling accelerated the activation and incre ased the current amplitude whereas hypertonic cell shrinkage inhibited the current. The inwardly rectifying current was carried by Cl- (I-Cl.ir) and h ad an anion permeability sequence of Cl- >I- much greater than aspartate. I -Cl.ir was blocked by 9-anthracene-carboxylic acid and cadmium but not by s tilbene disulfonates and tamoxifen. A similar I-Cl.ir was also observed in guinea pig cardiac myocytes. The properties of I-Cl.ir are consistent with currents generated by expression of ClC-2 Cl- channels. Reverse transcripti on polymerase chain reaction and Northern blot analysis confirmed transcrip tional expression of ClC-2 in both atrial and ventricular tissues and isola ted myocytes of mouse and guinea pig hearts. These results indicate that a novel I-Cl.ir is present in mammalian heart and support a potentially impor tant role of ClC-2 channels in the regulation of cardiac electrical activit y and cell volume under physiological and pathological conditions. The full text of this article is available at http ://www.circresaha.org.