COMPARATIVE MECHANISMS OF 4-AMINOPYRIDINE-RESISTANT I-TO IN HUMAN AND RABBIT ATRIAL MYOCYTES

The cardiac transient outward current (I-to) has been shown in several species to consist of two components: 1) a 4-aminopyridine (4-AP)-sensitive component (I-to1) and 2) a LT-AP-resistant component (I-to2) In rabbits, I-to2 is a Ca2+-dependent Cl- current [I-Cl(Ca)]; similar mechanisms have been suggested to underlie I-to2 in human atrium. We used whole cell patch-clamp techniques to define the mechanism of I-to2 (defined as the component resistant to 5 mM 4-AP) in human atrial myocytes, with parallel experiments performed in rabbit atrial cells. In rabbit atrium, I-to2 activated more slowly than I-to1 and had a bell-shaped current-voltage (I-V) relation. Ryanodine suppressed a component of I-to With properties similar to I-to2 in the rabbit, and a similar component recorded with pipette K+ replaced by Cs+ was suppressed by the substitution of methanesulfonate for Cl- in the superfusate. In human cells, a 4-AP-resistant I-to2 was recorded at a depolarizing pulse frequency of 1 Hz, but not at 0.1 Hz. I-to2 activated rapidly and inactivated earlier than I-to1, whereas its I-V relation was linear like that of I-to1. Ryanodine had no effect on human atrial I-to. When K+-free pipette solutions were used, no I-to was recorded in 30 human atrial myocytes, and external Cl- replacement with methanesulfonate failed to reveal an I-to. In 13 human myocytes, isoproterenol increased I-Ca but failed to activate an I-to compatible with I-Cl(Ca). Whereas caffeine suppressed human atrial I-to, it also suppressed I-to1 [in the presence of 200 mu M Cd2+ to block I-Ca and 5 mM intracellular ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid to buffer intracellular Ca2+] in both human and rabbit atrium, indicating an action unrelated to Ca2+-triggered Ca2+ release. In conclusion, we were unable to demonstrate the presence of I-Cl(Ca) in human atrial myocytes, and the 4-AP-resistant component of I-to appeared to be due to 4-AP unblocking.