Contributions of I(F) and Sarcoplasmic Reticulum Ca2+ in the Control of Spontaneous Cardiac Beating Rate in Mouse and Guinea-Pig

Abstract

Spontaneous beating rate was studied in mouse isolated atrial preparations and in guinea-pig single myocytes isolated from the sinus node (SAN) region of the heart. In atrial preparations, the I(f) blockers ZD7288 (1 μM) and ivabradine (3 μM) both reduced spontaneous beating rate by more than 200 bpm, and the change in beating rate caused by the combination of ivabradine and ZD7288 was not significantly different from the changes caused by either drug alone. Application of cyclopiazonic acid (CPA, to inhibit SERCA) also reduced beating rate by about 150 bpm. ZD7288 alone, ivabradine and the combination of ZD7288 and ivabradine all depressed the log(concentration)-effect curves for the effect of isoproterenol on rate by similar amounts. CPA alone caused a greater depression of isoproterenol log(concentration)-effect curves than was the case with the I(f) blockers. The combination of I(f) blockers and CPA caused a profound further depression of the effects of isoproterenol on spontaneous rate so that the log(concentration)-effect curve was almost flat. The effects I(f) blockers and CPA were also investigated in guinea-pig isolated SAN myocytes loaded with the Ca2+ probe, fluo-5F, and were broadly comparable to those observed in intact spontaneously beating atria. The observations are consistent with roles for both I(f) and SR Ca2+ in the control of spontaneous beating rate. The balance between the contributions of different mechanisms to the control of spontaneous rate varies with conditions, particularly in their influence on the increase in rate caused by isoproterenol. The presence and function of Ca2+-stimulated adenylyl cyclases is likely to be an important factor with the potential to link the contributions of these interacting processes.