Effects of tertiapin-Q and ZD7288 on changes in sinoatrial pacemaker rhythm during vagal stimulation

Heart rate slowing produced by cardiac parasympathetic (vagal) stimulation is thought to be the result of modulation of the acetylcholine-activated K⁺ current (I_K,ACh) and the pacemaker current (I_f) in sinoatrial (SAN) pacemaker cells. However, the contribution of these and other ion currents to vagal slowing is controversial. Here, we examined the contributions of I_K,ACh and I_f to vagal slowing in 15 isolated, vagal-innervated preparations of guinea-pig atria, using 300nM tertiapin-Q (TQ) and 2μM ZD7288 to obtain full and substantial block of these currents, respectively. Blocking I_K,ACh alone reduced atrial rate responses to 10-s trains of regular vagal stimulation (supramaximal stimulation, 2-ms duration, 1-10Hz) by ~50% (P<0.01; N=11); blocking I_f alone had no effect (N=7). Blocking both I_K,ACh and I_f produced ~90% reduction (P<0.01; N=4). Atrial cycle length response to a single burst of vagal stimuli (3 stimuli at 50Hz), delivered at the optimum phase of the cycle was strongly suppressed by blocking I_K,ACh (reduced by 98%; P<0.01; N=9), and modestly reduced by blocking I_f alone (by ~43%; P=0.20; N=6). The response was abolished by combined block of I_K,ACh and I_f (P=0.04; N=4). Our data show that modulation of I_K,ACh and I_f is sufficient to account for all the vagal slowing observed in this preparation. The vagally-induced negative shift in activation potential for I_f will be opposed by hyperpolarisation of SAN through activation of I_K,ACh. Thus removal of I_K,ACh by TQ may have exaggerated the overall contribution of I_f to vagal slowing.