Isoproterenol activates a chloride current, not the transient outward current, in rabbit ventricular myocytes

The effects of beta-adrenergic stimulation on the Ca2(+)-insensitive transient outward current (Ito) in rabbit ventricular myocytes were examined. Exposure to isoproterenol (ISO; 1 microM) activated a time-dependent current at positive membrane potentials. To determine whether this ISO-induced current was associated with Ito, sensitivity to the K+ channel antagonist, 3,4-diaminopyridine (DAP; 200 microM) was compared before and after exposure to ISO. The DAP-sensitive current was not enhanced by ISO, suggesting that the ISO-induced current was not a component of Ito. Ito and the ISO-induced current could also be dissociated by changing the membrane holding potential. Positive holding potentials, which produced significant inactivation of Ito, had little effect on the ISO-induced membrane current. Furthermore, the ISO-induced current could be observed when K+ was replaced by Cs+. The reversal potential of the ISO-induced current agreed with the predicted Cl- equilibrium potential, and exposure to Cl(-)-free extracellular solutions eliminated the response to ISO. Therefore, we conclude that ISO does not directly activate Ito in rabbit ventricular myocytes, but instead, activates a time-independent chloride current (ICl) similar to that recently described in guinea pig ventricular myocytes and shown to be regulated by adenylate cyclase (R. D. Harvey and J. R. Hume. Science Wash. DC 244: 983-985, 1989).