Inhibitory effect mediated by alpha 1-adrenoceptors on transient outward current in isolated rat ventricular cells

In order to clarify the underlying ionic mechanism(s) by which alpha 1-adrenoceptor stimulation prolongs the action potential duration (APD), single rat ventricular cells were voltage-clamped under a Na(+)-free condition using patch pipettes. Depolarizing pulses from a holding potential of -77 mV induced a 4-aminopyridine-sensitive transient outward current (Ito). Phenylephrine, in the presence of the beta-blocker propranolol (1 microM), inhibited Ito in a concentration-dependent fashion and the maximum inhibition of Ito (42.5 +/- 10.0%, n = 5) was produced by 30 microM phenylephrine. The inhibitory effect of phenylephrine on Ito was almost abolished by 1 microM prazosin, a selective alpha 1-blocker, indicating that the Ito inhibition is mediated by alpha 1-adrenoceptors. On the other hand, phenylephrine had little influence on the Ca2+ current in the presence of 4-aminopyridine. In isolated rat papillary muscles, both the alpha 1-adrenoceptor-mediated APD prolongation and positive inotropic response were markedly attenuated by pretreatment with 1.5 mM 4-aminopyridine. These results suggest that the inhibition of Ito is a primary cause of the prolongation of APD produced by alpha 1-adrenoceptor stimulation and that the Ito inhibition may be causally related to the positive inotropic effect mediated by alpha 1-adrenoceptors.