Modulation of delayed rectifier potassium current, ιK, by isoprenaline in rabbit isolated pacemaker cells

Permeabilized patch whole-cell voltage clamp methods were used to investigate the effects of isoprenaline (ISO) on total delayed rectifier potassium current, i(K), in rabbit sino-atrial (SA) node pacemaker cells; total i, is composed of the rapidly activating i(Kr) and the slowly activating i(Ks) but predominantly i(Kr) in this species. ISO (20 nM) increased the amplitude of total i(K) and caused a negative shift of approximately LO mV in the activation curve for i(K), both in the absence and in the presence of 300 nM nisoldipine to block the L-type Ca2+ current, i(Ca,L). The same concentration (20 nM) of ISO increased the spontaneous pacemaker rate of SA node pacemaker cells by 16%. In addition to increasing the amplitude of i(K) ISO (20-50 nM) also increased the rate of deactivation of this current. The stimulation of i(K) by ISO was reversed by 10 mu M H-89, a selective protein kinase a inhibitor, but not by 200 nM bisindolymaleimide I, a selective protein kinase C inhibitor. It therefore appears that the mechanisms by which beta-adrenoceptor agonists increase pacemaking rate in sinoatrial node pacemaker cells include an increase in the rate of deactivation of i(K) in addition to the well-documented augmentation of i(Ca,L) and the positive shift of the activation curve for the hyperpolarization-activated inward current, i(f). The observations are also consistent with a role for protein kinase A in the stimulation of i(K) by ISO in SA node cells.