Variation in effects of Cs+, UL-FS-49, and ZD-7288 within sinoatrial node

Abstract

The effects of Cs+, UL-FS-49, and ZD-7288 on action potentials recorded from central, transitional, and peripheral sites in the rabbit sinoatrial (SA) node have been investigated. In isolated right atrial preparations, including the whole SA node, Cs+ (2 mM), UL-FS-49 (1 microM), and ZD-7288 (3 microM), decreased the spontaneous rate by 12 +/- 2% (n = 21), 16 +/- 3% (n = 10), and 13 +/- 3% (n = 10). They decreased the slope of the pacemaker potential without affecting action potential characteristics. The decrease of pacemaker slope was maximal (69-120%) in the periphery and minimal (22-25%) in the center. In experiments on small ball-like tissue specimens (approximately 0.3 mm diam), a decrease in spontaneous rate and pacemaker slope by Cs+ (2 mM) was largest (approximately 19 and approximately 47%) in tissue from the periphery and least (approximately 7 and approximately 17%) in tissue from the center. Because the hyperpolarization-activated inward current (If) is reduced by each of these agents, the results suggest that this current might play a relatively minor role in the center but a more important role in the periphery of the SA node.

β-Adrenergic Stimulation Modulates Ryanodine Receptor Ca 2+ Release During Diastolic Depolarization to Accelerate Pacemaker Activity in Rabbit Sinoatrial Nodal Cells

“…Cs ϩ alone induced a 5.2Ϯ0.3% (nϭ5) decrease in beating rate from 205Ϯ6 bpm in control to 194Ϯ5 bpm with Cs ϩ , consistent with a prior observation in primary pacemaker cells. 35 In the presence of ISO (1 mol/L), Cs ϩ induced a 7.5Ϯ2.6% (nϭ4) decrease of the SANC beating rate from 225Ϯ18 bpm to 208Ϯ17 bpm with Cs ϩ . Thus, under the present experimental conditions, the contribution of I f to ␤-AR acceleration of rabbit SANC beating rate did not exceed 10%.…”

New Insights Into Pacemaker Activity

“…When I f is blocked, spontaneous rate slows by Ϸ14% in the rabbit sinus node ( Figure 7B). 37 Procoralan, or ivabradine, a blocker of I f , is now being marketed as the first pure heart ratelowering cardiac agent. 38 The Na ϩ -Ca 2ϩ exchanger is responsible for Ca 2ϩ extrusion from cardiac myocytes ( Figure 7D).…”

Sinoatrial Node Pacemaker Activity Requires Ca 2+ /Calmodulin-Dependent Protein Kinase II Activation

“…However, inhibition of I f causes only minor changes in AP parameters. 30 Recent studies in rabbit ventricular myocytes have demonstrated that CaMKII inhibition by peptide AC3-I has no significant effect on I Kr , 26 which suggests that I Kr and I f are not critically involved in CaMKIIdependent regulation of spontaneous excitations. Further studies are required to determine possible contributions of the other pacemaker currents to CaMKII-dependent regulation of SA node pacemaker activity.…”