The Importance of the Sarcoplasmic Reticulum for the Influence of I(F) Carried by Hyperpolarization-Activated Cyclic Nucleotide-Gated Ion Channels on Pacemaker Activity in the Sino-Atrial Node

Abstract

The mechanisms underlying pacemaker activity in the sino-atrial (SA) node remain controversial, with some giving greatest prominence to I(f), others emphasising a ‘calcium clock', and some favouring membrane currents other than I(f). The aim of the present experiments was to explore the possible dependence of I(f) on cytosolic Ca2+, including that released from the sarcoplasmic reticulum (SR).ZD7288 applied to block I(f) reduced spontaneous rate from 505 ± 24 to 228 ± 24 bpm (reduction 55 ± 4 % expressed as % resting rate). Ryanodine (to interfere with SR Ca2+ release) reduced beating rate, and with ryanodine present the effects of ZD7288 were smaller: 197 ± 40 bpm (ryanodine alone) to 148 ± 40 bpm (ryanodine and ZD7288), a reduction of 27 ± 12%. Cyclopiazonic acid (CPA) to inhibit Ca2+ re-uptake by the SR reduced spontaneous rate, and ZD7288 effects were also smaller in the presence of CPA: 213 ± 13 bpm (CPA alone) to 147 ± 9 bpm (CPA and ZD7288), a reduction of 19 ± 4%. In addition, ZD7288, ryanodine and CPA in various combinations reduced the slope and maximum response of the log(concentration)-response curve for effects of isoprenaline on spontaneous rate.These observations are consistent with a role for Ca2+ released from the SR in regulating I(f) and therefore the rate of spontaneous beating of the SA node, although there appears to be an additional contribution of SR-derived Ca2+ to the effects of β-adrenoceptor stimulation on spontaneous rate that is independent of I(f).